10-K
0001808158falseFYP456DP456DP456DP456DA800-0000000UnlimitedUnlimitedUnlimitedUnlimitedhttp://fasb.org/us-gaap/2023#UsefulLifeShorterOfTermOfLeaseOrAssetUtilityMember1/48P0Y2017 2018 2019 2020 2021 2022 20230001808158us-gaap:AccumulatedOtherComprehensiveIncomeMember2023-12-310001808158rptx:HoffmannLaRocheIncAndFHoffmannLaRocheLtdMember2023-12-310001808158rptx:ThirdAdditionalClinicalDevelopmentPlanMemberrptx:CollaborationAndLicenseAgreementMemberrptx:HoffmannLaRocheIncAndFHoffmannLaRocheLtdMember2023-12-310001808158us-gaap:FairValueInputsLevel1Memberus-gaap:FairValueMeasurementsRecurringMember2023-12-310001808158rptx:NewYorkUniversityAgreementMember2023-12-310001808158rptx:CollaborationAndLicenseAgreementMembersrt:MaximumMemberrptx:BristolMyersSquibbCompanyMember2020-05-310001808158rptx:SteveForteMember2023-10-012023-12-310001808158rptx:RepareTherapeuticsIncorporationOptionPlanMemberus-gaap:CommonStockMember2020-06-300001808158rptx:CollaborationAndLicenseAgreementMemberrptx:BristolMyersSquibbCompanyMember2023-12-310001808158us-gaap:ShareBasedCompensationAwardTrancheOneMemberrptx:TwoThousandTwentyEquityIncentivePlanMember2023-01-012023-12-310001808158rptx:MoneyMarketFundsIncludedInCashAndCashEquivalentsMemberus-gaap:FairValueMeasurementsRecurringMember2022-12-310001808158rptx:CollaborationAndLicenseAgreementMemberrptx:OnoPharmaceuticalCompanyLimitedMemberrptx:ResearchDevelopmentAndRegulatoryMilestonesMember2019-01-012019-01-010001808158rptx:TransferOfClinicalTrialMaterialsMemberrptx:HoffmannLaRocheIncAndFHoffmannLaRocheLtdMember2023-12-310001808158rptx:HoffmannLaRocheIncAndFHoffmannLaRocheLtdMemberrptx:CompletionOfContinuingTrialsMember2022-12-310001808158rptx:CollaborationAndLicenseAgreementMemberrptx:OnoPharmaceuticalCompanyLimitedMember2021-01-102021-10-310001808158rptx:CollaborationAndLicenseAgreementMemberrptx:UndruggableTargetMemberrptx:BristolMyersSquibbCompanyMember2022-01-012022-12-310001808158rptx:TwoThousandTwentyEquityIncentivePlanMember2023-01-012023-12-310001808158rptx:LloydMSegalMember2023-10-012023-12-310001808158us-gaap:AccumulatedOtherComprehensiveIncomeMember2022-12-310001808158rptx:OnoPharmaceuticalCompanyLimitedMember2023-01-012023-12-310001808158us-gaap:EquipmentMember2023-12-310001808158us-gaap:FairValueInputsLevel2Memberus-gaap:FairValueMeasurementsRecurringMember2022-12-310001808158rptx:InducementOptionAwardMember2023-05-012023-05-310001808158us-gaap:FairValueMeasurementsRecurringMemberus-gaap:CommercialPaperMember2023-12-310001808158rptx:LloydMSegalMember2023-12-310001808158rptx:CollaborationAndLicenseAgreementMemberrptx:OnoPharmaceuticalCompanyLimitedMember2019-01-012019-01-010001808158us-gaap:EquipmentMember2022-12-310001808158rptx:BristolMyersSquibbCompanyMember2022-12-310001808158us-gaap:RetainedEarningsMember2023-12-310001808158rptx:CollaborationAndLicenseAgreementMemberrptx:HoffmannLaRocheIncAndFHoffmannLaRocheLtdMemberrptx:CompletionOfContinuingTrialsMember2023-12-310001808158srt:OfficeBuildingMemberstpr:MA2021-07-310001808158us-gaap:AdditionalPaidInCapitalMember2022-01-012022-12-310001808158us-gaap:CommonStockMember2023-12-310001808158rptx:CollaborationAndLicenseAgreementMemberrptx:HoffmannLaRocheIncAndFHoffmannLaRocheLtdMemberrptx:SecondAdditionalClinicalDevelopmentPlanMember2023-02-280001808158us-gaap:AccumulatedOtherComprehensiveIncomeMember2022-01-012022-12-310001808158us-gaap:USTreasurySecuritiesMemberus-gaap:FairValueInputsLevel1Memberus-gaap:FairValueMeasurementsRecurringMember2022-12-310001808158rptx:SteveForteMember2023-12-310001808158rptx:OptionToLicenseDruggableTargetLesionsMemberrptx:BristolMyersSquibbCompanyMember2023-12-310001808158rptx:OptionsToLicenseUndruggableTargetMemberrptx:BristolMyersSquibbCompanyMember2023-12-310001808158stpr:CA-QCrptx:OfficeAndLaboratorySpaceMember2017-06-012017-06-300001808158rptx:HoffmannLaRocheIncAndFHoffmannLaRocheLtdMemberrptx:CompletionOfContinuingTrialsMember2023-01-012023-12-310001808158rptx:CollaborationAndLicenseAgreementMemberrptx:HoffmannLaRocheIncAndFHoffmannLaRocheLtdMemberrptx:SecondAdditionalClinicalDevelopmentPlanMember2023-12-310001808158country:US2022-12-310001808158rptx:CollaborationAndLicenseAgreementMemberrptx:HoffmannLaRocheIncAndFHoffmannLaRocheLtdMemberrptx:CompletionOfContinuingTrialsMember2022-12-310001808158us-gaap:EmployeeStockOptionMember2023-12-310001808158us-gaap:RestrictedStockUnitsRSUMember2023-01-012023-12-310001808158us-gaap:USTreasurySecuritiesMemberus-gaap:FairValueInputsLevel1Memberus-gaap:FairValueMeasurementsRecurringMember2023-12-310001808158us-gaap:FairValueInputsLevel2Memberus-gaap:FairValueMeasurementsRecurringMember2023-12-310001808158rptx:CollaborationAndLicenseAgreementMemberrptx:BristolMyersSquibbCompanyMember2020-06-012020-06-300001808158us-gaap:USTreasurySecuritiesMemberus-gaap:FairValueInputsLevel2Memberus-gaap:FairValueMeasurementsRecurringMember2022-12-310001808158rptx:CollaborationAndLicenseAgreementMemberrptx:HoffmannLaRocheIncAndFHoffmannLaRocheLtdMember2022-01-012022-12-310001808158stpr:CA-QCrptx:OfficeAndLaboratorySpaceMember2023-01-010001808158rptx:TwoThousandTwentyEquityIncentivePlanMember2024-01-010001808158rptx:TwoThousandTwentyEmployeeSharePurchasePlanMember2023-12-310001808158rptx:MichaelZindaMember2023-12-310001808158rptx:OnoPharmaceuticalCompanyLimitedMembercountry:JP2022-01-012022-12-310001808158stpr:CA-QCrptx:OfficeAndLaboratorySpaceMember2023-01-012023-01-310001808158rptx:TwoThousandTwentyEmployeeSharePurchasePlanMember2020-06-012020-06-300001808158rptx:OnoPharmaceuticalCompanyLimitedMemberrptx:CollaborationAndLicenseAgreementMember2023-01-012023-01-310001808158us-gaap:OfficeEquipmentMember2022-12-310001808158rptx:BristolMyersSquibbCompanyMember2023-12-310001808158us-gaap:ComputerEquipmentMember2022-12-310001808158rptx:TwoThousandTwentyEquityIncentivePlanMember2022-01-012022-12-310001808158srt:OfficeBuildingMemberstpr:MA2021-07-012021-07-310001808158rptx:OptionsToLicenseDruggableTargetsMemberrptx:BristolMyersSquibbCompanyMember2023-12-310001808158country:USrptx:BristolMyersSquibbCompanyMember2023-01-012023-12-310001808158rptx:CollaborationAndLicenseAgreementMemberrptx:HoffmannLaRocheIncAndFHoffmannLaRocheLtdMemberrptx:ResearchAndDevelopmentServicesMember2022-01-012022-12-310001808158us-gaap:AdditionalPaidInCapitalMemberrptx:TwoThousandTwentyEmployeeSharePurchasePlanMember2022-01-012022-12-310001808158rptx:OtherCurrentReceivablesMember2023-12-310001808158rptx:CollaborationAndLicenseAgreementMemberrptx:AdditionalClinicalDevelopmentPlanMemberrptx:HoffmannLaRocheIncAndFHoffmannLaRocheLtdMember2023-12-310001808158us-gaap:USTreasurySecuritiesMemberus-gaap:FairValueInputsLevel2Memberus-gaap:FairValueMeasurementsRecurringMember2023-12-310001808158country:CA2022-12-310001808158us-gaap:AdditionalPaidInCapitalMember2023-01-012023-12-310001808158rptx:OnoPharmaceuticalCompanyLimitedMember2023-07-012023-07-010001808158us-gaap:FairValueInputsLevel2Memberus-gaap:FairValueMeasurementsRecurringMemberus-gaap:CommercialPaperMember2023-12-310001808158rptx:LeaseLiabilitiesMember2023-12-310001808158rptx:ResearchActivitiesMemberrptx:BristolMyersSquibbCompanyMember2023-01-012023-12-310001808158us-gaap:CashAndCashEquivalentsMemberus-gaap:CommercialPaperMember2023-12-310001808158rptx:LeaseLiabilitiesMember2022-12-310001808158us-gaap:RetainedEarningsMember2022-12-310001808158rptx:CollaborationAndLicenseAgreementMemberrptx:UndruggableTargetMemberrptx:BristolMyersSquibbCompanyMember2023-01-012023-12-310001808158rptx:BristolMyersSquibbCompanyMember2023-01-012023-12-3100018081582022-12-310001808158rptx:EstimatedSharesIssuableUnderTheEsppMember2023-01-012023-12-310001808158rptx:OnoPharmaceuticalCompanyLimitedMemberrptx:CollaborationAndLicenseAgreementMember2023-01-012023-12-310001808158us-gaap:ResearchAndDevelopmentExpenseMember2023-01-012023-12-310001808158rptx:AccruedExpenseAndOtherCurrentLiabilitiesMember2022-12-310001808158rptx:MichaelZindaMember2023-10-012023-12-310001808158us-gaap:USTreasurySecuritiesMemberrptx:MarketableSecuritiesMember2023-12-310001808158stpr:CA-QCrptx:OfficeAndLaboratorySpaceMember2019-11-300001808158rptx:TheUniversityOfTexasMDAndersonCancerCenterMemberrptx:PreclinicalStudiesAndClinicalTrialsMember2023-12-310001808158us-gaap:AccountsPayableMember2023-12-310001808158stpr:CA-QCrptx:OfficeAndLaboratorySpaceMember2017-11-012017-11-300001808158rptx:TwoThousandTwentyEmployeeSharePurchasePlanMember2022-01-012022-12-310001808158rptx:SalesAgreementMemberus-gaap:CommonStockMember2023-01-012023-12-310001808158rptx:TheUniversityOfTexasMDAndersonCancerCenterMemberrptx:PreclinicalStudiesAndClinicalTrialsMember2020-03-012020-03-310001808158us-gaap:CommonStockMemberrptx:TwoThousandTwentyEmployeeSharePurchasePlanMember2022-01-012022-12-310001808158rptx:OnoPharmaceuticalCompanyLimitedMemberrptx:ResearchActivitiesMember2023-01-012023-12-310001808158us-gaap:AdditionalPaidInCapitalMember2022-12-310001808158rptx:OnoPharmaceuticalCompanyLimitedMemberrptx:CollaborationAndLicenseAgreementMember2022-01-012022-12-310001808158rptx:OnoPharmaceuticalCompanyLimitedMember2022-01-012022-12-310001808158us-gaap:GeneralAndAdministrativeExpenseMember2023-01-012023-12-310001808158rptx:CollaborationAndLicenseAgreementMemberrptx:BristolMyersSquibbCompanyMember2022-12-310001808158us-gaap:CommonStockMember2022-01-012022-12-310001808158us-gaap:RestrictedStockUnitsRSUMember2022-12-310001808158us-gaap:CashAndCashEquivalentsMemberus-gaap:MoneyMarketFundsMember2023-12-310001808158rptx:OptionsToPurchaseCommonSharesMember2022-01-012022-12-310001808158us-gaap:CashAndCashEquivalentsMemberus-gaap:MoneyMarketFundsMember2022-12-3100018081582023-12-310001808158us-gaap:RetainedEarningsMember2023-01-012023-12-310001808158us-gaap:RestrictedStockUnitsRSUMember2023-12-310001808158rptx:CollaborationAndLicenseAgreementMemberrptx:UpfrontNonRefundableFirstPaymentReceivedMemberrptx:HoffmannLaRocheIncAndFHoffmannLaRocheLtdMember2023-12-310001808158us-gaap:CashAndCashEquivalentsMember2023-12-310001808158rptx:CollaborationAndLicenseAgreementMemberrptx:ClinicalRegulatoryCommercialAndSalesMilestoneMemberrptx:HoffmannLaRocheIncAndFHoffmannLaRocheLtdMember2023-01-012023-12-310001808158rptx:AccruedExpenseAndOtherCurrentLiabilitiesMember2023-12-3100018081582023-01-012023-12-310001808158rptx:CollaborationAndLicenseAgreementMemberrptx:BristolMyersSquibbCompanyMember2020-05-012020-05-310001808158us-gaap:ResearchAndDevelopmentExpenseMember2022-01-012022-12-310001808158us-gaap:CommonStockMember2023-01-012023-12-310001808158us-gaap:CashMember2022-12-310001808158us-gaap:CashAndCashEquivalentsMemberus-gaap:CashMember2022-12-310001808158rptx:StateAndUsFederalMember2023-12-3100018081582023-06-300001808158rptx:OptionsToLicenseUndruggableTargetMemberrptx:BristolMyersSquibbCompanyMember2022-12-310001808158rptx:CollaborationAndLicenseAgreementMemberrptx:CombinedLicensesMemberrptx:HoffmannLaRocheIncAndFHoffmannLaRocheLtdMember2022-01-012022-12-310001808158rptx:ResearchActivitiesMemberrptx:BristolMyersSquibbCompanyMember2023-12-310001808158us-gaap:CashAndCashEquivalentsMember2022-12-310001808158us-gaap:AccumulatedOtherComprehensiveIncomeMember2023-01-012023-12-310001808158rptx:OptionToLicenseDruggableTargetLesionsMemberrptx:BristolMyersSquibbCompanyMember2023-01-012023-12-310001808158rptx:TwoThousandTwentyEmployeeSharePurchasePlanMember2024-01-010001808158rptx:CollaborationAndLicenseAgreementMemberrptx:BristolMyersSquibbCompanyMember2020-05-310001808158rptx:BroadInstituteIncMemberrptx:SpecialtyScreeningServicesMember2022-07-312022-07-310001808158srt:MaximumMemberrptx:SalesAgreementMemberus-gaap:CommonStockMember2022-08-012022-08-310001808158rptx:MariaKoehlerMember2023-10-012023-12-310001808158rptx:BristolMyersSquibbCompanyMember2022-01-012022-12-310001808158rptx:TwoThousandTwentyEmployeeSharePurchasePlanMember2020-06-300001808158us-gaap:USTreasurySecuritiesMemberrptx:MarketableSecuritiesMember2022-12-310001808158us-gaap:USTreasurySecuritiesMemberus-gaap:FairValueMeasurementsRecurringMember2023-12-310001808158rptx:CollaborationAndLicenseAgreementMemberrptx:OnoPharmaceuticalCompanyLimitedMember2022-12-310001808158rptx:OptionsToLicenseUndruggableTargetMemberrptx:BristolMyersSquibbCompanyMember2023-01-012023-12-310001808158us-gaap:RetainedEarningsMember2021-12-310001808158us-gaap:CommonStockMember2022-12-310001808158stpr:CA-QCrptx:OfficeAndLaboratorySpaceMember2017-11-300001808158rptx:CollaborationAndLicenseAgreementMemberrptx:HoffmannLaRocheIncAndFHoffmannLaRocheLtdMember2023-12-310001808158rptx:NewYorkUniversityAgreementMember2023-01-012023-12-310001808158rptx:MarketableSecuritiesMemberus-gaap:CommercialPaperMember2023-12-310001808158rptx:CollaborationAndLicenseAgreementMemberrptx:TransferOfClinicalTrialMaterialsMemberrptx:HoffmannLaRocheIncAndFHoffmannLaRocheLtdMember2023-12-310001808158us-gaap:EmployeeStockOptionMember2023-01-012023-12-310001808158rptx:NewYorkUniversityAgreementMember2018-07-012018-07-310001808158us-gaap:LeaseholdsAndLeaseholdImprovementsMember2023-12-310001808158rptx:CollaborationAndLicenseAgreementMemberrptx:DruggableTargetMemberrptx:BristolMyersSquibbCompanyMember2022-01-012022-12-310001808158rptx:CollaborationAndLicenseAgreementMemberrptx:TransferOfClinicalTrialMaterialsMemberrptx:HoffmannLaRocheIncAndFHoffmannLaRocheLtdMember2022-01-012022-12-310001808158us-gaap:OfficeEquipmentMember2023-12-310001808158rptx:OnoPharmaceuticalCompanyLimitedMemberrptx:ResearchActivitiesMember2022-12-310001808158us-gaap:AdditionalPaidInCapitalMember2021-12-310001808158us-gaap:ShareBasedCompensationAwardTrancheTwoMemberrptx:TwoThousandTwentyEquityIncentivePlanMember2023-01-012023-12-310001808158us-gaap:RestrictedStockUnitsRSUMember2023-01-012023-12-310001808158us-gaap:FairValueMeasurementsRecurringMember2023-12-310001808158rptx:MoneyMarketFundsIncludedInCashAndCashEquivalentsMemberus-gaap:FairValueMeasurementsRecurringMember2023-12-310001808158country:USrptx:BristolMyersSquibbCompanyMember2022-01-012022-12-310001808158us-gaap:CashAndCashEquivalentsMemberus-gaap:CashMember2023-12-310001808158us-gaap:EmployeeStockOptionMember2022-01-012022-12-310001808158us-gaap:FairValueInputsLevel1Memberus-gaap:FairValueMeasurementsRecurringMember2022-12-310001808158rptx:NewYorkUniversityAgreementMember2022-12-3100018081582024-02-230001808158us-gaap:GeneralAndAdministrativeExpenseMember2022-01-012022-12-310001808158us-gaap:CommonStockMemberrptx:TwoThousandTwentyEmployeeSharePurchasePlanMember2023-01-012023-12-310001808158us-gaap:USTreasurySecuritiesMemberus-gaap:FairValueMeasurementsRecurringMember2022-12-310001808158rptx:CollaborationAndLicenseAgreementMembersrt:MaximumMemberrptx:CommercialMilestonesMemberrptx:BristolMyersSquibbCompanyMember2020-05-310001808158stpr:CA-QCrptx:OfficeAndLaboratorySpaceMember2017-06-300001808158rptx:BroadInstituteIncMemberrptx:SpecialtyScreeningServicesMember2023-12-310001808158rptx:OnoPharmaceuticalCompanyLimitedMembercountry:JP2023-01-012023-12-310001808158rptx:OptionsToPurchaseCommonSharesMember2023-01-012023-12-310001808158country:US2023-12-310001808158rptx:CollaborationAndLicenseAgreementMemberrptx:DruggableTargetMemberrptx:BristolMyersSquibbCompanyMember2023-01-012023-12-310001808158us-gaap:FairValueMeasurementsRecurringMember2022-12-310001808158rptx:CombinedLicensesMemberrptx:HoffmannLaRocheIncAndFHoffmannLaRocheLtdMember2023-12-310001808158rptx:HoffmannLaRocheIncAndFHoffmannLaRocheLtdMemberus-gaap:SubsequentEventMember2024-02-290001808158rptx:TwoThousandTwentyEmployeeSharePurchasePlanMember2023-01-012023-12-310001808158rptx:ResearchActivitiesMemberrptx:BristolMyersSquibbCompanyMember2022-12-310001808158us-gaap:FairValueInputsLevel1Memberus-gaap:FairValueMeasurementsRecurringMemberus-gaap:CommercialPaperMember2023-12-310001808158rptx:CollaborationAndLicenseAgreementMemberrptx:ResearchActivitiesMemberrptx:BristolMyersSquibbCompanyMember2022-01-012022-12-310001808158country:CHrptx:HoffmannLaRocheIncAndFHoffmannLaRocheLtdMember2022-01-012022-12-310001808158rptx:HoffmannLaRocheIncAndFHoffmannLaRocheLtdMember2023-01-012023-12-310001808158us-gaap:RetainedEarningsMember2022-01-012022-12-310001808158us-gaap:FairValueInputsLevel1Memberrptx:MoneyMarketFundsIncludedInCashAndCashEquivalentsMemberus-gaap:FairValueMeasurementsRecurringMember2023-12-3100018081582022-01-012022-12-310001808158us-gaap:SubsequentEventMemberrptx:TwoThousandTwentyEmployeeSharePurchasePlanMember2024-02-290001808158rptx:CollaborationAndLicenseAgreementMembersrt:MaximumMemberrptx:BristolMyersSquibbCompanyMemberrptx:ResearchDevelopmentAndRegulatoryMilestonesMember2020-05-310001808158us-gaap:CashMember2023-12-310001808158rptx:MariaKoehlerMember2023-12-310001808158rptx:CollaborationAndLicenseAgreementMemberrptx:HoffmannLaRocheIncAndFHoffmannLaRocheLtdMember2023-01-012023-12-310001808158rptx:MarketableSecuritiesMember2023-12-310001808158rptx:EstimatedSharesIssuableUnderTheEsppMember2022-01-012022-12-310001808158rptx:SalesAgreementMemberus-gaap:CommonStockMember2022-01-012022-12-310001808158us-gaap:CommonStockMember2021-12-310001808158us-gaap:FairValueInputsLevel1Memberrptx:MoneyMarketFundsIncludedInCashAndCashEquivalentsMemberus-gaap:FairValueMeasurementsRecurringMember2022-12-310001808158stpr:CA-QCrptx:OfficeAndLaboratorySpaceMember2021-08-012021-08-310001808158rptx:CollaborationAndLicenseAgreementMemberrptx:ResearchActivitiesMemberrptx:BristolMyersSquibbCompanyMember2023-01-012023-12-310001808158us-gaap:ComputerEquipmentMember2023-12-310001808158us-gaap:LeaseholdsAndLeaseholdImprovementsMember2022-12-310001808158us-gaap:AdditionalPaidInCapitalMember2023-12-310001808158rptx:OptionToLicenseDruggableTargetLesionsMemberrptx:BristolMyersSquibbCompanyMember2022-12-310001808158rptx:OtherCurrentReceivablesMember2022-12-310001808158us-gaap:AdditionalPaidInCapitalMemberrptx:TwoThousandTwentyEmployeeSharePurchasePlanMember2023-01-012023-12-310001808158us-gaap:RestrictedStockUnitsRSUMember2022-01-012022-12-3100018081582021-12-310001808158rptx:TwoThousandTwentyEmployeeSharePurchasePlanMember2022-12-310001808158country:CHrptx:HoffmannLaRocheIncAndFHoffmannLaRocheLtdMember2023-01-012023-12-310001808158country:CA2023-12-310001808158rptx:OnoPharmaceuticalCompanyLimitedMemberrptx:CollaborationAndLicenseAgreementMember2021-10-312021-10-310001808158us-gaap:LeaseholdImprovementsMember2023-12-310001808158rptx:OnoPharmaceuticalCompanyLimitedMemberrptx:ResearchActivitiesMember2023-12-310001808158rptx:TwoThousandTwentyEmployeeSharePurchasePlanMember2023-01-012023-12-310001808158rptx:TwoThousandTwentyEmployeeSharePurchasePlanMember2022-01-012022-12-310001808158rptx:MarketableSecuritiesMember2022-12-310001808158rptx:CollaborationAndLicenseAgreementMemberrptx:HoffmannLaRocheIncAndFHoffmannLaRocheLtdMember2024-01-310001808158rptx:HoffmannLaRocheIncAndFHoffmannLaRocheLtdMemberrptx:CompletionOfContinuingTrialsMember2023-12-310001808158us-gaap:RestrictedStockUnitsRSUMember2022-01-012022-12-310001808158rptx:HoffmannLaRocheIncAndFHoffmannLaRocheLtdMember2022-01-012022-12-310001808158us-gaap:AccountsPayableMember2022-12-31xbrli:pureiso4217:JPYiso4217:USDxbrli:sharesxbrli:sharesiso4217:CADiso4217:USDrptx:Lease

 

 

UNITED STATES

SECURITIES AND EXCHANGE COMMISSION

Washington, D.C. 20549

FORM 10-K

(Mark One)

 

ANNUAL REPORT PURSUANT TO SECTION 13 OR 15(d) OF THE SECURITIES EXCHANGE ACT OF 1934

For the fiscal year ended December 31, 2023

OR

TRANSITION REPORT PURSUANT TO SECTION 13 OR 15(d) OF THE SECURITIES EXCHANGE ACT OF 1934 FOR THE TRANSITION PERIOD FROM TO

Commission File Number 001-39335

Repare Therapeutics Inc.

(Exact name of Registrant as specified in its Charter)

 

Québec

Not applicable

(State or other jurisdiction of

incorporation or organization)

(I.R.S. Employer

Identification No.)

7171 Frederick-Banting, Building 2, Suite 270

St-Laurent, Québec, Canada

H4S 1Z9

(Address of principal executive offices)

(Zip Code)

Registrant’s telephone number, including area code: (857) 412-7018

Securities registered pursuant to Section 12(b) of the Act:

 

Title of each class

 

Trading

Symbol(s)

 

Name of each exchange on which registered

Common Shares, no par value

 

RPTX

 

The Nasdaq Stock Market LLC

 

Securities registered pursuant to Section 12(g) of the Act: None

Indicate by check mark if the Registrant is a well-known seasoned issuer, as defined in Rule 405 of the Securities Act. YES ☐ No

Indicate by check mark if the Registrant is not required to file reports pursuant to Section 13 or 15(d) of the Act. YES ☐ No

Indicate by check mark whether the Registrant: (1) has filed all reports required to be filed by Section 13 or 15(d) of the Securities Exchange Act of 1934 during the preceding 12 months (or for such shorter period that the Registrant was required to file such reports), and (2) has been subject to such filing requirements for the past 90 days. Yes ☒ NO ☐

Indicate by check mark whether the Registrant has submitted electronically every Interactive Data File required to be submitted pursuant to Rule 405 of Regulation S-T (§232.405 of this chapter) during the preceding 12 months (or for such shorter period that the Registrant was required to submit such files). Yes ☒ NO ☐

Indicate by check mark whether the registrant is a large accelerated filer, an accelerated filer, a non-accelerated filer, a smaller reporting company, or an emerging growth company. See the definitions of “large accelerated filer,” “accelerated filer,” “smaller reporting company,” and “emerging growth company” in Rule 12b-2 of the Exchange Act.

Large accelerated filer

Accelerated filer

 

 

 

 

Non-accelerated filer

Smaller reporting company

 

 

 

 

 

 

 

Emerging growth company

 

 

 

 

 

If an emerging growth company, indicate by check mark if the registrant has elected not to use the extended transition period for complying with any new or revised financial accounting standards provided pursuant to Section 13(a) of the Exchange Act. ☐

Indicate by check mark whether the registrant has filed a report on and attestation to its management’s assessment of the effectiveness of its internal control over financial reporting under Section 404(b) of the Sarbanes-Oxley Act (15 U.S.C. 7262(b)) by the registered public accounting firm that prepared or issued its audit report.

If securities are registered pursuant to Section 12(b) of the Act, indicate by check mark whether the financial statements of the registrant included in the filing reflect the correction of an error to previously issued financial statements.

Indicate by check mark whether any of those error corrections are restatements that required a recovery analysis of incentive-based compensation received by any of the registrant’s executive officers during the relevant recovery period pursuant to §240.10D-1(b). ☐

Indicate by check mark whether the Registrant is a shell company (as defined in Rule 12b-2 of the Exchange Act). YES ☐ NO

The aggregate market value of the registrant’s common shares held by non-affiliates was $383,103,514 as of June 30, 2023, based on a total of 36,210,162 common shares held by non-affiliates and a closing price of $10.58 as reported on The Nasdaq Stock Market on June 30, 2023.

The number of shares of registrant’s common shares outstanding as of February 23, 2024 was 42,182,177.

DOCUMENTS INCORPORATED BY REFERENCE

 


 

Portions of the definitive proxy statement for the registrant’s 2024 annual meeting of shareholders, which is to be filed within 120 days after the end of the registrant’s fiscal year ended December 31, 2023, are incorporated by reference into Part III of this Form 10-K, to the extent described in Part III.

 

 


 

Table of Contents

 

Page

SUMMARY RISK FACTORS

1

SPECIAL NOTE REGARDING FORWARD LOOKING STATEMENTS

3

PART I

5

Item 1.

Business

5

Item 1A.

Risk Factors

61

Item 1B.

Unresolved Staff Comments

116

Item 1C.

Cybersecurity

116

Item 2.

Properties

117

Item 3.

Legal Proceedings

117

Item 4.

Mine Safety Disclosures

117

 

PART II

118

Item 5.

Market for Registrant’s Common Equity, Related Stockholder Matters and Issuer Purchases of Equity Securities

118

Item 6.

[Reserved]

118

Item 7.

Management’s Discussion and Analysis of Financial Condition and Results of Operations

119

Item 7A.

Quantitative and Qualitative Disclosures About Market Risk

138

Item 8.

Financial Statements and Supplementary Data

139

Item 9.

Changes in and Disagreements With Accountants on Accounting and Financial Disclosure

176

Item 9A.

Controls and Procedures

176

Item 9B.

Other Information

180

Item 9C.

Disclosure Regarding Foreign Jurisdictions that Prevent Inspections

180

 

PART III

181

Item 10.

Directors, Executive Officers and Corporate Governance

181

Item 11.

Executive Compensation

181

Item 12.

Security Ownership of Certain Beneficial Owners and Management and Related Stockholder Matters

181

Item 13.

Certain Relationships and Related Transactions, and Director Independence

181

Item 14.

Principal Accounting Fees and Services

181

 

PART IV

182

Item 15.

Exhibits and Financial Statement Schedules

182

Item 16

Form 10-K Summary

186

 

 

i


 

SUMMARY RISK FACTORS

 

Investing in our common shares involves numerous risks, including the risks described in “Part I—Item 1A. Risk Factors” of this Annual Report on Form 10-K. Below are some of our principal risks, any one of which could materially adversely affect our business, financial condition, results of operations, and prospects:

Our limited operating history may make it difficult for you to evaluate the success of our business to date and to assess our future viability.
We will require substantial additional funding to finance our operations. If we are unable to raise capital when needed, we could be forced to delay, reduce, or terminate certain of our product development programs or other operations.
We are very early in our development efforts. If we are unable to advance our product candidates into and through clinical development, obtain regulatory approval and ultimately commercialize our product candidates, or experience significant delays in doing so, our business will be materially harmed.
Our business substantially depends upon the successful development of product candidates generated through the application of our SNIPRx platform, and in particular, our initial product candidates, camonsertib (also known as RP-3500) and lunresertib (also known as RP-6306). If we or our collaborators, are unable to obtain regulatory approval for, and successfully commercialize, products developed through the application of our SNIPRx platform, our business may be materially harmed.
The successful development of targeted therapeutics, including our portfolio of synthetic lethality small molecule inhibitors, as well as any related diagnostics, is highly uncertain.
Our current and future collaborations will be important to our business. If we are unable to enter into new collaborations as appropriate, or if these collaborations are not successful, our business could be adversely affected.
The regulatory approval processes of the FDA and comparable foreign regulatory authorities are lengthy, time consuming and inherently unpredictable, and if we are ultimately unable to obtain regulatory approval for our product candidates, on a timely basis or at all, our business will be substantially harmed.
Synthetic lethality represents an emerging class of precision medicine targets, and negative perceptions of the efficacy, safety, or tolerability of this class of targets, including any that we develop, could adversely affect our ability to conduct our business, advance our product candidates or obtain regulatory approvals.
We may not be successful in applying our SNIPRx platform to discover synthetic lethality targets with therapeutic and commercial potential or in the discovery and development of commercially viable product candidates.
Difficulty in enrolling patients could delay or prevent clinical trials of our product candidates. We may find it difficult to enroll patients in our ongoing and planned clinical trials with the genomic alterations that these trials are designed to target.
We face substantial competition, which may result in others developing or commercializing drugs before or more successfully than us.
If we fail to develop new products and product candidates or compete successfully with respect to acquisitions, joint ventures, licenses or other collaboration opportunities, our ability to continue to expand our product pipeline and our growth and development would be impaired.
We rely on third parties to supply and manufacture our product candidates, and we expect to continue to rely on third parties to manufacture our products, if approved. The development of such product candidates and the commercialization of any products, if approved, could be stopped, delayed, or made less profitable if any such third party fails to provide us with sufficient quantities of product candidates or products or fails to do so at acceptable quality levels or prices or fails to maintain or achieve satisfactory regulatory compliance.

1


 

Our success depends in part on our ability to obtain intellectual property rights for our proprietary technologies and product candidates, as well as our ability to protect our intellectual property. It is difficult and costly to protect our proprietary rights and technology, and we may not be able to ensure their protection.
Our future success depends on our ability to retain key executives and to attract, retain and motivate qualified personnel.
The trading price of our common shares has been and is likely to continue to be volatile and fluctuate substantially.

2


 

SPECIAL NOTE REGARDING FORWARD LOOKING STATEMENTS

This Annual Report on Form 10-K, or Annual Report, contains forward-looking statements about us and our industry that involve substantial risks and uncertainties. All statements other than statements of historical facts contained in this Annual Report, including statements regarding our strategy, future financial condition, future operations, research and development costs, plans and objectives of management, are forward-looking statements. In some cases, you can identify forward-looking statements by terminology such as “aim,” “anticipate,” “assume,” “believe,” “contemplate,” “continue,” “could,” “design,” “due,” “estimate,” “expect,” “goal,” “intend,” “may,” “objective,” “plan,” “predict,” “positioned,” “potential,” “seek,” “should,” “target,” “will,” “would” and other similar expressions that are predictions of or indicate future events and future trends, or the negative of these terms or other comparable terminology. Although we believe that we have a reasonable basis for each forward-looking statement contained in this Annual Report, we caution you that these statements are based on a combination of facts and factors currently known by us and our expectations of the future, about which we cannot be certain.

The forward-looking statements in this Annual Report include, among other things, statements about:

the initiation, timing, progress and results of our current and future preclinical studies and clinical trials and related preparatory work and the period during which the results of the trials will become available, as well as our research and development programs;
our estimates regarding expenses, future revenue, capital requirements and needs for additional financing;
our ability to obtain regulatory approval of camonsertib, lunresertib and any of our other current and future product candidates that we develop;
our ability to identify and develop additional product candidates using our SNIPRx platform;
business disruptions affecting the initiation, patient enrollment, development and operation of our clinical trials, including a public health emergency or pandemic;
the evolving impact of macroeconomic events, including health pandemics, changes in inflation, the U.S. Federal Reserve raising interest rates, disruptions in access to bank deposits or lending commitments due to bank failures and the Russia-Ukraine and Middle-East conflicts, on our operations, supply chains, general economic conditions, our ability to raise additional capital, and the continuity of our business, including our preclinical studies and clinical trials;
our ability to enroll patients in clinical trials, to timely and successfully complete those trials and to receive necessary regulatory approvals;
the timing of completion of enrollment and availability of data from our current preclinical studies and clinical trials, including ongoing clinical trials of camonsertib and lunresertib;
the expected timing of filings with regulatory authorities for any product candidates that we develop;
our expectations regarding the potential market size and the rate and degree of market acceptance for any current or future product candidates that we develop;
our ability to receive any milestone or royalty payments under our collaboration and license agreements;
the anticipated impact of the termination of our collaboration with Hoffmann-La Roche Inc. and F. Hoffmann-La Roche Ltd for the development and commercialization of camonsertib, including our expectations regarding the development of camonsertib following the transition of commercial and development rights in camonsertib back to us;
our ability to realize the benefits of the collaboration compounds retained by us following the termination of our collaboration with F. Hoffmann-La Roche Ltd and Hoffman-La Roche Inc.;
the effects of competition with respect to camonsertib, lunresertib, or any of our other current or future product candidates, as well as innovations by current and future competitors in our industry;
our ability to fund our working capital requirements;

3


 

our intellectual property position, including the scope of protection we are able to establish, maintain and enforce for intellectual property rights covering our product candidates;
our financial performance and our ability to effectively manage our anticipated growth;
our ability to obtain additional funding for our operations; and
other risks and uncertainties, including those listed under the section titled “Risk Factors” in this Annual Report.

Although we believe that the expectations reflected in these forward-looking statements are reasonable, these statements relate to our strategy, future operations, future financial position, future revenue, projected costs, prospects, plans, objectives of management and expected market growth, and involve known and unknown risks, uncertainties and other factors including, without limitation, risks, uncertainties and assumptions regarding the impact of the macroeconomic events on our business, operations, strategy, goals and anticipated timelines, our ongoing and planned preclinical activities, our ability to initiate, enroll, conduct or complete ongoing and planned clinical trials, our timelines for regulatory submissions and our financial position that may cause our actual results, levels of activity, performance or achievements to be materially different from any future results, levels of activity, performance or achievements expressed or implied by these forward-looking statements. You are urged to carefully review the disclosures we make concerning these risks and other factors that may affect our business and operating results in this Annual Report. You are cautioned not to place undue reliance on these forward-looking statements, which speak only as of the date of this document. Except as required by law, we do not intend, and undertake no obligation, to update any forward-looking information to reflect events or circumstances.

4


 

PART I

Item 1. Business.

Overview

We are a leading clinical-stage precision oncology company enabled by our proprietary synthetic lethality approach to the discovery and development of novel therapeutics. Synthetic lethality (SL) represents a clinically validated approach to drug development. We use our proprietary, genome-wide, CRISPR-enabled SNIPRx platform to systematically discover and develop highly targeted cancer therapies that preferentially treat cancers due to mechanisms of genomic instability, including DNA damage repair. SL arises when a deficiency in either of two genes is tolerated in cells, but simultaneous deficiencies in both genes cause cell death. Cancer cells that contain a mutation in one gene of a SL pair are susceptible to therapeutic intervention targeting the other gene pair. Using our SNIPRx platform, we have internally developed four clinical or near-term clinical therapeutic candidates:

1.
Lunresertib (RP-6306) is a first-in-class, selective and potent oral small molecule inhibitor of PKMYT1 (Protein Kinase Membrane-associated tyrosine- and threonine- specific cdc-2 inhibitory kinase), a cancer target Repare discovered and identified as synthetic lethal with cyclin E1 (CCNE1) amplification, or deleterious alterations in FBXW7 or PPP2R1A in solid tumors such as gynecological, colorectal and upper gastrointestinal malignancies. Lunresertib is currently the sole PKMYT1 inhibitor known to be in clinical trials and is being evaluated alone and in combinations across several clinical trials in the US, UK/EU4, and Canada.

We presented positive initial Phase 1 data from our ongoing Phase 1 MYTHIC trial demonstrating proof of concept for lunresertib alone and in combination with camonsertib at the 35th AACR-NCI-EORTC International Conference in October 2023. Lunresertib was shown to be well tolerated with a compelling safety profile. We further presented anti-tumor activity for lunresertib in combination with camonsertib. Initial combination data included an overall RECIST response rate of 50% in the 10 patients with heavily pre-treated gynecological tumors treated at the preliminary recommended Phase 2 dose. We expect to provide MYTHIC data from expansion cohorts of the lunresertib and camonsertib combination in the second half of 2024. In the third quarter of 2023, we received fast track designation for lunresertib in combination with camonsertib for the treatment of adult patients with CCNE1 amplified, or FBXW7 or PPP2R1A mutated endometrial cancer.

We initiated additional Phase 1 combination clinical trials of lunresertib with gemcitabine (MAGNETIC) in December 2021 and with FOLFIRI (MINOTAUR) in August 2022, for which we expect to share data in the second half and first half of 2024, respectively. In the fourth quarter of 2022, we received fast track designation for lunresertib in combination with gemcitabine for the treatment of adult patients with CCNE1 amplified, or FBXW7, or PPP2R1A mutated platinum resistant ovarian cancer. We are collaborating with the Canadian Cancer Trials Group in an ongoing basket Phase 2 Investigator Sponsored Clinical Trial (IST) that is enrolling patients with selected, advanced cancers receiving lunresertib as combination (NCT05605509). A sub-study to that protocol that will evaluate lunresertib in combination with gemcitabine in patients with CDK4/6 inhibitor treated ER+/HER2- metastatic breast cancer (NCT05601440) was activated more recently and is also enrolling patients. We are also collaborating with University Health Network, Toronto on an investigator-sponsored Phase 1 clinical trial of luneresertib in combination with carboplatin and paclitaxel in TP53 ovarian and uterine cancer (NCT06107868) that is expected to be activated shortly.

In January 2024, we announced our sponsorship of a global trial as a new arm in the ongoing MYTHIC trial combining lunresertib with Debiopharm's Debio 0123, a highly selective clinical WEE1 inhibitor. Dosing of the first patient with the synergistic lunresertib and Debio 0123 combination is expected to occur in the first half of 2024.

5


 

2.
Camonsertib (RP-3500) is a potent and selective oral small molecule inhibitor of ATR (Ataxia-Telangiectasia and Rad3-related protein kinase) in clinical development for the treatment of solid tumors with specific DNA damage repair-related genomic alterations, including those in the ATM gene (ataxia telangiectasia mutated kinase).

In a Clinical Trials Plenary Session at the 2023 AACR Annual Meeting, we presented initial clinical data from the Phase 1/2 TRESR and ATTACC clinical trials evaluating camonsertib in combination with three poly (ADP-ribose) polymerase (PARP) inhibitors - talazoparib, niraparib, and olaparib. Camonsertib demonstrated 48% overall CBR in patients with advanced solid tumors across tumor types regardless of choice of PARP inhibitor or platinum resistance, with a favorable safety and tolerability profile. The Phase 1/2 TRESR and ATTACC clinical trials are fully-enrolled and we expect to complete these trials in 2024.

In June 2022, we entered into a worldwide license and collaboration agreement with Hoffmann-La Roche Inc. and F. Hoffmann-La Roche Ltd (collectively “Roche”) for the development and commercialization of camonsertib, which resulted in an initial $125 million upfront payment. In January 2024, we earned a $40 million milestone payment from Roche upon dosing of the first patient with camonsertib in Roche’s TAPISTRY trial, which was subsequently received in February 2024. Since inception of the Roche camonsertib collaboration, we have earned a cumulative total of $182.6 million, including the upfront payment, the milestone payment, as well as additional reimbursements from Roche. On February 7, 2024, we received written notice from Roche of their election to terminate the Roche camonsertib collaboration. The termination will become effective in May 2024, at which time we will regain global development and commercialization rights for camonsertib from Roche. We are currently actively engaged in transition activities related to the termination and expect to provide further guidance on our plans for camonsertib in the second quarter of 2024.

3.
RP-1664 is a first-in-class, highly selective, oral PLK4 inhibitor designed to harness the synthetic lethal relationship with TRIM37 amplification or overexpression in solid tumors. Tumors rely on PLK4 for centriole biogenesis in S-phase of the cell cycle when TRIM37, an E3 ligase that reduces pericentriolar material, is high. Preclinical studies demonstrate that RP-1664 selectively inhibits PLK4 and drives potent synthetic lethality in TRIM37-high tumor models, both in vitro and in vivo. Elevated TRIM37 is a feature found across a range of solid tumors and in approximately 80% of high-grade neuroblastoma. RP-1664 is the only selective PLK4 inhibitor known to be in the clinic.

We reported comprehensive preclinical data for RP-1664 in November 2023, including deep tumor growth inhibition and regressions in multiple TRIM37-high solid tumor or neuroblastoma xenograft models. The preclinical in vivo animal model evaluations were performed both internally and in collaboration with Children’s Hospital of Philadelphia (CHOP). In February 2024, we dosed the first patient in the LIONS (PLK4 Inhibitor in Advanced Solid Tumors) clinical trial, a multicenter, open-label Phase 1 clinical trial to investigate safety, pharmacokinetics, pharmacodynamics, and the preliminary efficacy of RP-1664. After evaluating safety in adult patients with recurrent solid tumors in the LIONS clinical trial, we expect to move into a Phase 1/2 clinical trial in high risk, recurrent pediatric neuroblastoma, in which children have limited treatment options and high prevalence of TRIM37-altered tumors.

4.
RP-3467 is a potential best-in-class inhibitor of adenosinetriphosphatase (ATPase) activity on the helicase domain of DNA polymerase theta (Polθ). Polθ is a synthetic lethal target associated with homologous recombination deficiency (HRD) tumors, including those with BRCA1/2 mutations or other genomic alterations. Data suggest that RP-3467 works effectively and synergistically with therapies that result in double stranded DNA breaks, such as PARP inhibition, radioligand therapy (RLT) and multiple chemotherapies and antibody-drug conjugates (ADCs). Initial data suggest that Polθ inhibition may interfere with mechanisms central to the development of PARPi resistance, which could be relevant to currently marketed PARP 1/2 inhibitors and the emerging PARP1-selective inhibitors. We also reported comprehensive preclinical data for RP-3467 in November 2023, in which RP-3467 demonstrated complete, sustained regressions in combination with PARP inhibitors and compelling anti-tumor activity

6


 

in combination with RLT and chemotherapy. We expect to initiate a Phase 1 trial of RP-3467 in the second half of 2024.

We believe our powerful SL-based approach to the development of new precision oncology therapeutics has multiple potential benefits:

Ability to address previously un-targetable tumor biology, including, for example, loss-of-function mutations;
Enhanced benefit-risk profile, by precisely targeting tumor cells with the defined mutation while sparing normal, non-cancerous cells;
Genetic stratification of patients, potentially enabling higher response rates; and
Tumor-agnostic approach, focusing on specific genetics and enabling the application to multiple tumor types.

A cornerstone of our company is our SNIPRx platform, which enables us to accurately identify SL gene pairs and the corresponding patients who are most likely to benefit from our therapies based on the genetic profile of their tumors. We are developing a portfolio of product candidates based on these differentiated patient selection insights to identify targets that may treat cancers with high unmet medical need. For example, camonsertib is designed as a selective inhibitor of the DNA repair protein ataxia telangiectasia and Rad3-related protein (ATR), a kinase that is activated by DNA replication stress. Tumors containing alterations in genes encoding other DNA repair proteins, such as ataxia-telangiectasia mutated kinase (ATM), are SL with ATR inhibition and were observed to be hypersensitive to camonsertib in our preclinical models. We believe that the preclinical selectivity and pharmacokinetic properties of camonsertib support the profile of a differentiated therapy with the potential to enhance anti-tumor activity as compared to third party ATR inhibitors currently in development. Based on our preclinical studies, we believe camonsertib has the potential to provide therapeutic benefit to identified patient populations both as a monotherapy and in combination with other therapies such as PARP inhibitors.

The core of our SNIPRx platform is the ability to identify both known and novel SL targets. Our SNIPRx platform begins with a genome-wide CRISPR-based screening approach that utilizes our proprietary isogenic cell lines, which are cell lines that are identical with the exception of a single genomic alteration, to identify SL gene pairs. Our systematic and comprehensive screening approach has been optimized to significantly reduce false negatives, providing the opportunity to identify a larger and more accurate set of SL interactions as compared to what others have reported with CRISPR-based screening technologies.

We have systematically analyzed genomic data from approximately 60,000 tumor samples and identified a set of clinically relevant tumor genomic alterations, which we refer to as tumor lesions, that are linked to genomic instability. The initial tumor lesions are present in approximately 30% of tumors. For each of these tumor lesions, we have completed a SNIPRx screen campaign to identify both previously reported and unreported targets that are SL with the tumor lesion of the campaign. The majority of our SNIPRx screen campaigns have identified multiple potential targets, which allows us to prioritize and select targets based on their potential to be amenable to small molecule inhibitors with drug-like properties. Once a SL product candidate is identified, we perform our proprietary SNIPRx Targeted Expansion of Patient Populations (STEP2) screens to identify additional genomic alterations that are SL to our product candidate. Using these screens, we are able to enrich the patient population in our clinical trials and expand the patient populations that may be addressable with our product candidates.

We are a leader in developing innovative SL therapies and have built our SNIPRx platform based on three primary pillars:

1.
Identify novel SL targets using our proprietary, genome-wide, CRISPR-enabled screening technology against clinically relevant genomic alterations in tumors with high unmet medical need;
2.
Design and synthesize potent and selective small molecule inhibitors of these targets; and
3.
Expand beyond the initial target population based on the additional genomic alterations identified by our proprietary STEP2 screens that are SL with our inhibitors.

7


 

Our Pipeline

We are leveraging our proprietary SNIPRx platform to discover, validate and build a robust pipeline of SL-based therapeutics. Our current pipeline is represented in the diagram below.

https://cdn.kscope.io/b1da4b78003f62f54ff6e3a200263933-img193244649_0.jpg 

 

Our Corporate History and Team

Our company was founded in 2016 by field-leading academics and Versant Ventures to systematically employ SL insights and platforms and develop new precision oncology medicines. Our co-founder, Daniel Durocher, Ph.D., a principal investigator at the Lunenfeld-Tanenbaum Research Institute, was an early pioneer of genome-wide, SL screening using CRISPR, which formed the framework for our SNIPRx platform. Our other co-founders, Agnel Sfeir, Ph.D. now at Memorial Sloan Kettering Cancer Center and Frank Sicheri, Ph.D. at the Lunenfeld-Tanenbaum Research Institute, also played a key role in the development of our company.

We have assembled a highly qualified management team with broad experience in drug discovery and development to execute our mission to develop novel precision oncology therapies based on SL. Our scientific co-founders and members of our management team collectively have extensive experience in oncology drug discovery and development and are pioneers in the SL field. Our management team includes industry veterans with prior experience at companies such as Pfizer, AstraZeneca, GSK, Merck, Eli Lilly and Company, Bicycle Therapeutics, Y-mAbs Therapeutics, Santhera Pharmaceuticals and Clementia Pharmaceuticals. We have an experienced research and development team focused on leveraging our deep expertise and differentiated know-how across genomic target identification, target prioritization and selection, drug discovery chemistry and clinical development to develop highly potent and selective small molecule inhibitors based on SL for the treatment of cancer.

Our Strategy

Our goal is to be the leading biopharmaceutical company developing precision oncology, small molecule therapies based on SL. The key elements of our strategy are to:

Advance lunresertib through clinical development by leveraging our innovative patient selection approach and identifying the optimal combination treatment among our active and planned clinical trials to move forward into a potential registration-directed clinical trial. To date, we have initiated clinical trials evaluating lunresertib in monotherapy and multiple combinations, including combinations with camonsertib (MYTHIC Module 2), FOLFIRI (MINOTAUR) and gemcitabine (MAGNETIC). In January 2024, we also announced our sponsorship of a global study as a new arm in the ongoing MYTHIC trial combining lunresertib with Debiopharm's Debio 0123, a highly selective clinical WEE1 inhibitor.

8


 

Dosing of the first patient with the synergistic lunresertib and Debio 0123 combination is expected to occur in the first half of 2024.

 

We have achieved the first clinical proof-of-concept for a synthetic lethal strategy with a PKMYT1 inhibitor combined with an ATR inhibitor in patients with molecularly-selected cancers when we presented positive initial Phase 1 data from our ongoing Phase 1 MYTHIC trial demonstrating proof of concept for lunresertib alone and in combination with camonsertib at the 35th AACR-NCI-EORTC International Conference in October 2023. We expect to provide MYTHIC data from expansion cohorts of the lunresertib and camonsertib combination in the second half of 2024. We also expect to provide data readouts of MAGNETIC and MINOTAUR in the second half and first half of 2024, respectively. Our goal is to identify the optimal combination treatment amongst all lunrsertib clinical trials to move forward into a potential pivotal or registration-directed clinical trial as an outcome of these data readouts.

Advance camonsertib ongoing clinical development and determine future development strategy following the return of global rights from Roche. To date, we have initiated clinical trials evaluating camonsertib in monotherapy and multiple combinations. In July 2020, we began monotherapy dosing in our open-label Phase 1/2 clinical trial (TRESR Module 1). In parallel with the monotherapy dose-escalation portion of the trial, in February 2021, we initiated patient recruitment of the combination therapy arm to evaluate the safety and efficacy of camonsertib in combination with a PARP inhibitor, talazoparib, in the same patient subgroups (TRESR Module 3). In August 2021, we initiated patient recruitment in our open-label Phase 1b/2 ATTACC trial of camonsertib in combination with niraparib and olaparib, two additional PARP inhibitors. In October 2021, we presented initial Phase 1 monotherapy clinical data from our open-label Phase 1/2 TRESR trial of camonsertib in patients with solid tumors. We then presented comprehensive Phase 1 monotherapy clinical data from this trial in April 2022. In a Clinical Trials Plenary Session at the 2023 AACR Annual Meeting, we presented initial clinical data from the Phase 1/2 TRESR and ATTACC clinical trials evaluating camonsertib in combination with three PARP inhibitors - talazoparib, niraparib, and olaparib. The Phase 1/2 TRESR and ATTACC clinical trials are fully-enrolled and we expect to complete these clinical trials in 2024. In May 2024, we will regain global development and commercialization rights for camonsertib from Roche. We are currently actively engaged in transition activities related to the termination and expect to provide further guidance on our plans for camonsertib in the second quarter of 2024.
Advance RP-1664 as the first highly selective PLK4 inhibitor in the clinic with a differentiated patient selection strategy. RP-1664 is the only selective PLK4 inhibitor known to be in the clinic. We reported comprehensive preclinical data for RP-1664 in November 2023, including deep tumor growth inhibition and regressions in multiple TRIM37-high solid tumor or neuroblastoma xenograft models. The preclinical evaluation was performed both internally and in collaboration with Children’s Hospital of Philadelphia (CHOP). We did not observe any RP-1664 activity against the Aurora kinase family, which we would consider to be an off-target effect. In February 2024, we dosed the first patient in the LIONS (PLK4 Inhibitor in Advanced Solid Tumors) clinical trial, a multicenter, open-label Phase 1 clinical trial to investigate safety, pharmacokinetics, pharmacodynamics, and the preliminary efficacy of RP-1664. The LIONS clinical trial is the first time a selective PLK4 inhibitor program has utilized a genomically-targeted patient selection approach, which has been enabled by our SNIPRx platform. After evaluating safety in adult patients with recurrent solid tumors in the LIONS clinical trial, we expect to move into a Phase 1/2 clinical trial in high risk, recurrent pediatric neuroblastoma, in which children have limited treatment options and high prevalence of TRIM37-altered tumors. In this study, we expect to create a separate oral, pediatric formulation, distinct from that used in the LIONS clinical trial, to facilitate dosing of smaller children.
Continue to advance our preclinical programs into clinical development. We expect to initiate a Phase 1 trial of RP-3467, our Polθ ATPase inhibitor, in the second half of 2024. RP-3467 is a potential best-in-class inhibitor based on preclinical data presented in November 2023, in which we demonstrated complete, sustained regressions in combination with PARP inhibitors and compelling anti-tumor activity in combination with RLT and chemotherapy. We believe RP-3467’s greatest therapeutic opportunities are in combination with dsDNA damaging agents. We observed RP-3467 synergies with both PARP1/2 and PARP1 selective inhibitors in vitro. Further, we observed highly durable regressions, following tumors treated with the combination of RP-3467 and olaparib for up to 90 days post treatment, with no additive

9


 

nor synergistic toxicity in the haematopoetic compartment. RLT is a driver of dsDNA breaks and we found the combination with RP-3467 drove a statistically significant overall survival benefit versus a full dose of the RLT in a homologous recombination proficient background. In other words, patients with unselected tumor backgrounds may benefit from RP-3467 in combination with RLT. Since chemotherapies also result in dsDNA breaks, we studied both carboplatin and topoisomerase inhibitor (SN-38/Irinotecan) combinations, in vitro and in vivo. Both combinations demonstrated in vitro synergy and clear in vivo combination benefit with no additional toxicity.
Extend our leading position in SL drug discovery. We have systematically analyzed genomic data from approximately 60,000 tumor samples and have identified a set of tumor lesions that are linked to genomic instability. This current set of tumor lesions provides us with the opportunity to be among the first to mine this substantial, largely non-overlapping genomic space for new SL gene pairs and develop a robust portfolio of novel targeted therapeutics. We intend to continue leveraging our leading position in the identification of novel oncology SL gene pairs and systematically applying our STEP2 screens to expand the addressable patient populations for each of our product candidates. We believe our approach will allow us to continue to build a sustainable and long-term pipeline of novel product candidates for the targeted treatment of cancers with high unmet medical need.
Opportunistically pursue strategic partnerships to maximize the full potential of our pipeline and SNIPRx platform. The large number of pre-existing mutations affecting genomic stability in tumors combined with the high throughput of our SNIPRx platform has the potential to provide us with an abundance of novel targets. We believe this provides the opportunity to selectively enter into strategic partnerships and leverage our partners’ complementary capabilities. We regularly evaluate the potential of partnerships and other collaborative efforts to maximize the long-term value of our portfolio.

Background

Targeted Oncology Therapeutics

The first-generation of approved targeted therapies were predominately directed at driver mutations, which target specific types of receptor tyrosine kinases, such as, bcr-abl, EGFR and HER2, and have largely represented the focus of the targeted oncology sector for the last 20 years. A rapid evolution in the understanding of tumor biology coupled with an improved ability to segment subsets of tumors based on genomic alterations have led to the development of new generations of targeted cancer therapies for a variety of additional tumor-specific genomic abnormalities.

Targeting DNA repair genes and specifically loss of function alterations is an emerging area of research with PARP inhibitors pioneering the field. The growing number of compounds in development and multiple clinical studies have begun to reveal patterns of clinical benefit alone and in combination with several other agents. We expect both monotherapy and combination trials with these agents to emerge quickly and reshape the therapeutic landscape across many disease areas. Consistent with this trend and the specific cell cycle-related mechanisms of action for our lead assets, we have initiated comprehensive development plans for camonsertib and lunresertib alone or in combination with multiple agents.

The speed at which the field has identified genetic changes associated with tumors has outpaced the discovery and development of precision medicines that can target those alterations. Oncology drug development has been primarily focused on genes with readily druggable alterations that confer new or enhanced protein activity, known as gain-of-function targets, such as EGFR. These include both gain-of-function alterations, such as CCNE1, as well as loss-of-function alterations, such as BRCA1. In June 2019, the New England Journal of Medicine referred to SL as a particularly attractive means to target the complex and gene-network oriented relationships associated with this previously undiscovered domain of oncology targets.

10


 

The more recent ability to identify a tumor’s genetic vulnerabilities and networks of genes responsible for more complex gene functions underlying many cancers has been enabled through new and disruptive technical breakthroughs in the field including:

Clinically-relevant tumor genomic data: the increasing adoption and regulatory acceptance of molecular tumor testing, enabling the accurate profiling of patient tumors;
Consolidated and annotated databases: the availability of multiple new and publicly accessible databases that consolidate, analyze, and synthesize new genetic data on tens of thousands of tumors; and
Tools to apply emerging genetic knowledge: the emergence of new tools and methodologies, including CRISPR/Cas9, enabling large-scale studies of genetic networks underlying cancer biology.

The Synthetic Lethality Opportunity and Challenge

Synthetic lethality is a powerful approach and opportunity in oncology drug development that combines two key principles in treating patients with cancer through precision oncology: (1) identifying and selecting patient subgroups with specific genomic alterations in tumors that are most likely to benefit from these therapies and (2) improving tolerability and reducing toxicity by not affecting normal, non-cancerous cells.

SL arises when deficiencies in a pair of genes occur simultaneously to result in cell death, but if that deficiency exists in only one gene, the cell will survive. As depicted below, cancer cells that contain an alteration in one gene of a SL pair are susceptible to therapeutic intervention targeting the other gene pair, resulting in cell death, whereas normal cells are not affected by the inhibition of the targeted gene and remain viable.

 

11


 

Illustration of Synthetic Lethality Approach

 

https://cdn.kscope.io/b1da4b78003f62f54ff6e3a200263933-img193244649_1.jpg 

 

The first clinically-validated SL gene pair was PARP-BRCA1/2, and based on the efficacy of PARP inhibitors, the SL approach to treating cancer has achieved substantial commercial validation. PARP enzymes regulate critical DNA repair pathways that cancer cells rely on as they grow and divide. PARP inhibition blocks these pathways, preventing DNA repair in cancer cells with a BRCA1/2 alteration and resulting in cancer cell death while sparing normal cells. Multiple PARP inhibitors, including olaparib (AstraZeneca), niraparib (GlaxoSmithKline), talazoparib (Pfizer), rucaparib (Clovis) and pamiparib (Beigene), have been approved for the treatment of tumors with BRCA and other DNA damage repair alterations, including ovarian, breast, prostate and pancreatic cancers.

While SL offers a new route to uncover important gene targets for the treatment of cancers, identifying these SL gene pairs has been a challenge due to the lack of systematic, prospective, and large-scale methods to capture and exploit these gene-gene relationships for new drug discovery and development.

Our Approach: An Overview of Our Drug Discovery and Development Platform

Our SNIPRx platform integrates our deep expertise and differentiated know-how across genomic target identification, target prioritization and selection, drug discovery chemistry and clinical development. Our approach can be divided into six steps, as depicted in the graphic below.

12


 

Our Integrated Approach to Drug Discovery and Development

 

https://cdn.kscope.io/b1da4b78003f62f54ff6e3a200263933-img193244649_2.jpg 

 

1. Select tumor lesion of interest.

Apply our deep understanding of tumor lesions with a bias for alterations associated with genomic instability and cancers with high unmet medical need.

Since 2016, we have systematically analyzed genomic data from approximately 60,000 tumor samples. We consult with leading oncology clinicians and key advisors to identify cancer types and subtypes where the current standard of care is not adequately improving patient survival. We then prioritize genetic lesions based on various criteria including mutation frequency and the feasibility of identifying lesion-positive patients. Of those, we focus on lesions that are known to directly or indirectly impact processes involved in genomic instability, such as DNA repair and cell cycle regulation.

2. Execute SNIPRx screen campaign.

Utilize our SNIPRx screening technology to identify target gene candidates that induce SL in the context of our set of tumor lesions.

For each of the tumor lesions we identified, each of which we refer to as an original tumor lesion, we have completed a screen campaign utilizing CRISPR technology and other tools to create proprietary isogenic cell lines, which are pairs of cell lines that are identical with the exception of a single genomic alteration. This allows us to identify, on a genome-wide basis, both known and novel targets that are SL with each original tumor lesion. Our SNIPRx platform has been optimized to both sensitivity and reproducibility, resulting in a significant decrease in false negatives compared to what has been reported with other CRISPR-based screening technologies.

3. Prioritize, select, and validate druggable targets.

Evaluate the multiple SL targets identified for each original tumor lesion.

Our screen campaigns result in the identification of multiple SL targets for each original tumor lesion. We prioritize and select targets to advance into drug discovery based on a systematic and proprietary set of criteria, which include thresholds for biological validation, cellular function, known and likely toxicity, druggability with small molecules, patentability, and the potential for clinical impact versus alternative therapies. Our processes include extensive in vitro, genetic, and in vivo animal validation of targets and comprehensive development of tool compounds for initial pharmacological corroboration.

13


 

4. Develop potent and selective inhibitors.

Develop small molecule product candidates that are highly potent and selective and advance them from lead discovery through the identification of a clinical candidate.

We have assembled an internal research team that has extensive experience in small molecule drug discovery with a proven track record of identifying development candidates and delivering them into and through the clinic. Our team has deep in-house capabilities in cell biology, molecular biology, biochemistry, enzymology, medicinal chemistry, computational chemistry, and molecular modeling. We also have proven capabilities in drug metabolism, pharmacokinetic/pharmacodynamics, and absorption, distribution, metabolism, and excretion evaluation, as well as pharmacology, including dedicated in vivo animal facilities to internally drive translational studies for human clinical trials. We believe these capabilities were demonstrated in the discovery and development of camonsertib and lunresertib.

5. Perform SNIPRx Targeted Expansion of Patient Populations (STEP2) screens.

Expand our potential patient populations beyond those identified by the original SL pair.

Once we have identified a clinical candidate, our STEP2 screens utilize a set of cell lines that, when treated with our clinical candidate, elucidate genes that, when knocked down, cause sensitivity to our selected inhibitor. These screens not only confirm the SL relationship with the original tumor lesion, but also identify additional genomic alterations that confer a response to our product candidates and are mutually exclusive from the original tumor lesion. We believe the identification of these new SL pairs allows us to rationally expand our targeted patient populations by enabling us to potentially treat patients with tumors across multiple genomic alterations with the same product candidate.

6. Conduct clinical trials in an enriched patient population.

Design our clinical trials for efficient clinical development.

For our clinical trials, we plan to enroll patients with tumors that contain either the original tumor lesion or any one of the genomic alterations identified by our STEP2 screens. We believe this strategy will allow us to enroll only those patients who are most likely to achieve clinical benefit from our product candidates. In addition, we are prioritizing tumor types for which there are no effective therapies currently available. We plan to evaluate multiple cohorts of patients based on specific genomic alterations, which may enable us to pursue an accelerated regulatory approval pathway for certain targeted patient populations.

Our SNIPRx Platform

The core of our SNIPRx platform is the ability to identify both known and novel SL targets. We believe that our platform and approach provide many key advantages as highlighted below.

Designed to Address Previously Untargetable Tumor Biology. Oncology drug development has been primarily focused on genes with readily druggable alterations that confer new or enhanced protein activity, known as gain-of-function targets, such as EGFR. The remaining targets have historically been considered undruggable. These include both gain-of-function alterations, such as CCNE1, as well as loss-of-function alterations, such as BRCA1. Our SNIPRx platform has demonstrated an ability to identify novel SL relationships, including those that address previously untargetable tumor biology.
Applies Our Proprietary Genome-wide Library. Genome-scale screens often identify many genes coding for the same protein complex or cellular pathway, thereby increasing confidence in those hits. These screens allow us to screen the entire genome to determine the top hits across all genes, as compared to the more limited druggable gene libraries. In addition, because the definition of what is druggable is continuously evolving, by using genome-scale screens, we are able to mine the results of our existing screens as new therapeutic modalities emerge. Our genome-wide libraries, together with our industrialized and optimized screening approach and technology, result in a significant reduction in false negative hits.

14


 

Utilizes Isogenic Cell Lines. We believe a key differentiator of our SNIPRx platform is the utilization of thoroughly characterized proprietary isogenic cell lines for our CRISPR-based genome-wide SL screen campaigns. We use normal, non-cancerous cell lines to engineer our isogenic cell models, which enable us to mine for SL interactions between two genes in models with clean genetic backgrounds that have minimal mutations and normal chromosome numbers. We have also developed a proprietary computational algorithm that is specifically designed to identify SL interactions from our isogenic screens. We believe using isogenic cell lines gives us a significant competitive advantage since most SL screening approaches used by others are based on cancer cell line panels, which we believe are less accurate due to their propensity to result in variable data.
Focuses on Niche of Genomic Instability. Based on the well-established network of SL interactions in DNA synthesis and repair across model organisms, we have found and believe we will continue to find clear and reproducible SL interactions through our SNIPRx platform. Genomic instability is an early event that underlies all cancer, and many of the genes we screen represent early hits in cancer that may have less heterogeneity in later stage tumors. The genomic instability space is enriched with genes encoding enzymatic activity, which provides us with ample opportunity to identify novel druggable genes for development into small molecule precision oncology therapies. We believe developing product candidates that target genomic instability may lead to durable responses with resulting clinical benefits for patients.

One example that illustrates the power of our SNIPRx platform is a SL screen campaign that we conducted in an isogenic pair of cell lines in which one cell line had a BRCA1 mutation and the other cell line was normal for BRCA1. The results of this screen campaign are graphically depicted below. The top-right quadrant of Graphic A highlights the SL hits resulting from our screen and shows that we were able to identify PARP1 as a SL hit with BRCA1. In addition, two additional sets of genes were identified to be SL with BRCA1: (1) the genes encoding the Fanconi Anemia pathway, which are depicted in purple, and (2) the genes coding for the BLM-RMI1-RMI2 complex, which are depicted in green. The independent identification by our SNIPRx screen campaign of multiple genes within a pathway or complex greatly increases confidence that those are true SL hits. In contrast, external cell panel screens that look for SL hits by comparing a panel of cancer cell lines that have either BRCA1-mutant or normal BRCA1 cell lines do not identify these validated BRCA1 SL genes. As shown in Graphic B below, multiple cancer cell line panel screens utilizing CRISPR or shRNA all failed to identify PARP1 as a SL hit with BRCA1.

SNIPRx Screen Campaign Identifies Both Known and Novel SL Pairs Undetected by Cancer Cell Line Panels

A. SNIPRx BRCA1 Isogenic SL Screen

 

https://cdn.kscope.io/b1da4b78003f62f54ff6e3a200263933-img193244649_3.jpg 

 

15


 

B. External BRCA1 Cell Panel SL Screens

 

https://cdn.kscope.io/b1da4b78003f62f54ff6e3a200263933-img193244649_4.jpg 

 

Our Clinical Stage Product Candidates

Lunresertib, Our Novel, First-in-Class PKMYT1 Inhibitor Program

Overview

Using our proprietary, CRISPR-based SNIPRx discovery platform, we identified PKMYT1 as a strong hit in a CCNE1-overexpression SL screen. PKMYT1 is a kinase that phosphorylates CDK1, thereby holding the cyclin B-CDK1 complex in an inactive state until the cell is ready to enter mitosis. Lunresertib is being developed as a highly potent and selective PKMYT1 inhibitor that preferentially kills tumor cells overexpressing CCNE1 and was shown to inhibit the growth of a broad range of CCNE1-amplified tumors in xenograft/patient-derived xenograft (PDX) preclinical models, both as a single agent and in combination therapy settings. Lunresertib has a favorable preclinical PK profile as well as low potential for drug-drug interactions. Application of our STEP2 genome-wide chemical screen has identified other gene alterations beyond CCNE1 amplification that are uniquely targetable by lunresertib, including tumors that have loss of FBXW7 function, a cell-cycle regulator that has been implicated as a key genetic driver in a broad range of cancers, and represent further areas of unmet medical need. We initiated patient recruitment in our open-label Phase 1 MYTHIC trial, as a monotherapy, for this program in April 2021. Our Phase 1 trial is enrolling patients suffering from recurrent tumors characterized by CCNE1 amplification and other genomic alterations which our STEP2 preclinical studies predicted to be sensitive to lunresertib. We are evaluating more than one schedule, if necessary, at which the capsules are given in this dose escalation trial. The primary objective is to establish the recommended Phase 2 dose and schedule for lunresertib for further studies as monotherapy and assess preliminary safety, tolerability, PK, and PD in patients. In December 2021, we enrolled the first patient in our open-label Phase 1 MAGNETIC trial to evaluate the safety and tolerability of lunresertib in combination with gemcitabine. In January 2022, we initiated patient recruitment in our open-label Phase 1 MINOTAUR trial to evaluate the safety and tolerability of lunresertib in combination with FOLFIRI. In May 2022, we initiated patient recruitment in a new arm of the Phase 1 MYTHIC clinical trial, which is designed to evaluate the safety and tolerability of lunresertib in combination with camonsertib in patients with advanced solid tumors. In the fourth quarter of 2022, we received fast track designation for lunresertib in combination with gemcitabine for the treatment of adult patients with CCNE1 amplified, or FBXW7 or PPP2R1A mutated platinum resistant ovarian cancer and in the third quarter of 2023, we received fast track designation for lunresertib in combination with camonsertib for the treatment of adult patients with CCNE1 amplified, or FBXW7 or PPP2R1A mutated endometrial cancer. We are collaborating with the Canadian Cancer Trials Group in an ongoing basket Phase 2 Investigator Sponsored Clinical Trial (IST) that is enrolling patients with selected, advanced cancers receiving lunresertib as combination (NCT05605509). A sub-study to that protocol that will evaluate lunresertib in combination with gemcitabine in patients with CDK4/6 inhibitor treated ER+/HER2- metastatic breast cancer (NCT05601440) was activated more recently and is also enrolling patients. We are also collaborating with University Health Network, Toronto on an investigator-sponsored Phase 1 study of luneresertib in combination with carboplatin and paclitaxel in TP53 ovarian and uterine cancer (NCT06107868) that is expected to be activated shortly.

We expect to report data readouts across all ongoing lunresertib clinical trials and add a Wee1 combination clinical trial in partnership with Debiopharm in 2024. We expect to report initial data from the Phase 1 MINOTAUR

16


 

study evaluating lunresertib in combination with FOLFIRI for the treatment of advanced solid tumors in the first half of 2024. We have closed enrollment in the Phase 1 MAGNETIC study evaluating lunresertib in combination with gemcitabine for the treatment of advanced solid tumors, and expect to report initial data from this study in the second half of 2024. We also expect to report data from the dose expansion cohorts of the Phase 1 MYTHIC trial evaluating lunresertib in combination with camonsertib in selectively advanced solid tumors in the second half of 2024.

Mechanism of Action

PKMYT1, the gene targeted by lunresertib has not previously been published as a SL gene pair with CCNE1 amplification, and we are not aware of any advanced drug discovery efforts against this target. In preclinical studies, we observed that the deletion of this gene was well tolerated in wild-type cells, but it caused lethality in isogenic cancer cells that overexpressed CCNE1.

High levels of CCNE1 protein, an activating subunit of cyclin dependent kinase 2 (CDK2), are often observed in patients across multiple tumor types. Deregulation of cell cycle control is thought to be a prerequisite for tumor development, and several studies have demonstrated accelerated entry of cells into the S phase, or DNA synthesis phase, of the cell cycle, due to constitutive, or “always-on,” expression of CCNE1. Such an accelerated entry of cells into the S phase is a common sign of unregulated, cancerous growth. CCNE1 amplification can induce chromosome instability, another sign of cancer, by contributing to inappropriate initiation of DNA replication. Several studies have demonstrated that CCNE1 amplification or constitutive expression is associated with disease progression in various malignancies as well as poor clinical prognosis in patients across multiple cancers, including ovarian, breast, bladder, and colorectal cancer. For example, clinical data from patients with ovarian cancer indicate that those with CCNE1-amplified tumors have significantly shorter overall survival than those with tumors without CCNE1 amplification, as shown below.

CCNE1 Amplification is Associated with Significantly Shorter Overall Survival

in Patients with Ovarian Cancer

 

https://cdn.kscope.io/b1da4b78003f62f54ff6e3a200263933-img193244649_5.jpg 

CCNE1 amplification is found in 4% of tumors in the pan-cancer TCGA studies. Over 40% of uterine carcinosarcoma cancers and 10% to 20% of ovarian and stomach cancers harbor CCNE1 amplification. Together, these cancers lead to over 40,000 deaths each year in the United States. Additional cancer types also harbor CCNE1 amplification at a lower frequency, including up to 3% to 8% of esophagus, bladder, lung, and pancreatic cancers, as shown below.

17


 

Top 10 Tumor Types with Highest Frequency of CCNE1 Amplification

 

https://cdn.kscope.io/b1da4b78003f62f54ff6e3a200263933-img193244649_6.jpg 

Our Solution, Lunresertib

We identified PKMYT1 as a critical SL target for patients with CCNE1 amplification through our SNIPRx screening campaign and selected PKMYT1 as a target for our lead product candidate, lunresertib, based on:

i.
the target validation for PKMYT1;
ii.
our ability to design potent and selective PKMYT1 inhibitors; and
iii.
the results of our STEP2 screens, which identified at least two additional genomic alterations beyond CCNE1 amplification to be SL with PKMYT1 inhibitor facilitating the expansion of the addressable patient populations.

We designed lunresertib as an oral small molecule PKMYT1 inhibitor with significant potency and an encouraging selectivity profile as a first in class compound. Lunresertib has demonstrated a favorable pharmacokinetic profile in multiple preclinical models, including rodent and canine, and a distribution, metabolism and excretion profile that suggests a low potential for drug-drug interactions in the clinic. The clinical trial of lunresertib in patients with recurrent cancers is ongoing.

Our STEP2 screens have generated proprietary patient selection insights that we believe provide the rationale to expand the potential patient populations addressable by lunresertib beyond patients with tumors carrying CCNE1 amplification. We have specifically identified FBXW7 and PPP2R1A genomic alterations, in addition to CCNE1 amplification, that confer sensitivity to lunresertib. This set of genes addresses approximately 90,000 patients, including approximately 65,000 among top tumors, such as approximately 29% of uterine cancer and 13% of colorectal cancer and other high unmet need tumors within select markets, as presented in the graph below.

18


 

https://cdn.kscope.io/b1da4b78003f62f54ff6e3a200263933-img193244649_7.jpg 

The proposed alterations specific to lunresertib tumors are easily identifiable in commercially available Next Generation Sequencing cancer panels or CLIA-validated panels used in large academic centers. For our Phase 1/2 clinical trial, we identified and partnered with multiple large, leading clinical centers globally where tumor sequencing is a component of standard of care. These centers’ panels are validated and sufficiently large to accommodate screening for alterations in FBXW7 and CCNE1 or our other STEP2-identified genes. By working in collaboration with our clinical partners to access their existing patient databases, we are able to efficiently identify patients who may be eligible for our clinical trial.

Based on the prevalence of lunresertib relevant genomic alterations across various solid tumors, as shown in the graph above, we believe that lunresertib has the potential to benefit a significant number of patients representing a large unmet medical need.

Preclinical data: Monotherapy

We observed that lunresertib has a favorable tolerability and PK profile preclinically which we believe supported advancement of the product candidate into clinical trials. We tested lunresertib as a single agent in two preclinical cell line derived models of cancer selected to represent our target patient populations by having amplification of CCNE1. The HCC1569 breast cancer model and the OVCAR3 ovarian cancer model with CCNE1 copy numbers of 34-fold and 14-fold above ploidy, respectively. In the HCC1569 breast cancer xenograft model, lunresertib was orally administered at doses of 2.5, 7.5 or 20 mg/kg twice daily (BID) for 28 days. Lunresertib produced a dose-dependent reduction in tumor growth reaching a statistically significant difference at all doses and a maximum effect of 77%. In the 20 mg/kg group, mice exhibited body weight loss of 3.2% at the end of study. In the OVCAR3 ovarian cancer xenograft model, lunresertib was orally administered at doses of 2.5, 7.5 or 20 mg/kg twice daily (BID) for 28 days. Lunresertib produced a dose-dependent reduction in tumor growth reaching a statistically significant difference at all doses and a maximum effect of 82%. In the 20 mg/kg group, mice exhibited body weight loss of 6.9% at the end of study.

In preclinical studies, lunresertib demonstrated in vivo anti-tumor activity in two cell line derived xenograft models with CCNE1 amplification. In both models, we observed statistically significant dose-dependent tumor growth suppression across a range of doses from 2.5 to 20 mg/kg BID (twice-daily administration for lunresertib).

19


 

Lunresertib Demonstrates Tumor Growth Suppression in CCNE1-Amplified Cell Line Derived Xenograft Models

https://cdn.kscope.io/b1da4b78003f62f54ff6e3a200263933-img193244649_8.jpg

Preclinical Data: Combination Therapies with Lunresertib

Chemotherapeutic drugs have diverse mechanisms of action, and some target DNA replication and induce DNA replication stress. During the S-phase of the cell cycle, DNA is replicated to create DNA for two daughter cells following cell division. S-phase disrupting drugs increase dependence on cell cycle checkpoints. Combining this S-phase vulnerability with lunresertib, which forces S-phase replicating cells into premature mitosis, is expected to be catastrophic to tumor cells.

Gemcitabine prolongs the S-phase by both interfering with DNA polymerase and disrupting the supply of nucleotides. Clinically, gemcitabine has been used as a single agent or in combination with carboplatin, cisplatin, or paclitaxel for the treatment of pancreatic, ovarian, breast, bladder, testicular, and non-small cell lung cancer. Recent studies have tested gemcitabine in combination with DNA damage repair inhibitors (PARP and ATR inhibitors), as well as cell cycle inhibitors (WEE1, CDK4/6, and Chk1 inhibitors) across a spectrum of relapsed or refractory advanced solid tumors. Attempts to combine gemcitabine with inhibitors of these checkpoints have struggled with toxicity, impacting proliferating tumor and normal tissue with similar effect. In a setting of CCNE1, FBXW7, PPP2R1A, and potentially other lunresertib STEP2 genetic alterations, it is expected that gemcitabine will exacerbate the replication stress environment where PKMYT1 is essential for survival and provide synthetic lethal synergy with enhanced benefit and therapeutic index.

The rationale behind combining lunresertib and FOLFIRI in CCNE1-amplified or FBXW7-mutated tumors is similar to that of gemcitabine. The two main agents found in FOLFIRI are irinotecan (metabolized in tissues to SN-38) and fluorouracil, both of which act specifically in S-phase. SN-38 acts on the topoisomerase I-DNA complex and prevents re-ligation of the DNA strand, resulting in double-strand DNA breaks and cell death. Fluorouracil acts as a thymidylate synthase inhibitor which blocks synthesis of the pyrimidine thymidine, required for DNA replication. Combining this chemotherapy-induced S-phase vulnerability with lunresertib, which forces S-phase replicating cells into premature mitosis, is expected to be catastrophic to tumor cells.

 

20


 

The combination of lunresertib and gemcitabine was evaluated in CCNE1 amplified model of ovarian cancer (OVCAR3) on a continuous BID dosing of lunresertib at 10mg/kg and gemcitabine at 20mg/kg once weekly. The combination resulted in complete tumor regression that was significantly better than either agent alone with minimal impact on body weight loss (6.8% for the combination at the end of dosing).

Lunresertib + Gemcitabine Drives Regression and No Serious Toxicity in CCNE1-Amplified Cell Line Derived Xenograft

https://cdn.kscope.io/b1da4b78003f62f54ff6e3a200263933-img193244649_9.jpg

The combination of lunresertib and irinotecan was evaluated in CCNE1-amplified model of breast cancer (HCC1569) on a continuous BID dosing of lunresertib at 5 mg/kg and irinotecan at 30 mg/kg three times a week. The combination resulted in tumor regression that was significantly better than either agent alone with minimal impact on weight loss (1.5% for the combination at the end of dosing).

Lunresertib + Irinotecan Drives Regression and is Well Tolerated in CCNE1-Amplified Cell Line Derived Xenograft

https://cdn.kscope.io/b1da4b78003f62f54ff6e3a200263933-img193244649_10.jpg

The combination of low dose lunresertib and camonsertib was evaluated in a pair of isogenic models of colorectal cancer having normal FBXW7 or FBXW7 loss-of-function. Lunresertib was administered at 5mg/kg BID and camonsertib was administered at 10mg/kg QD three times a week. Neither compound alone nor the combination substantially impacted tumor growth of FBXW7-normal tumors. In contrast, a low dose of lunresertib in combination

21


 

with camonsertib resulted in profound regression of FBXW7 loss-of-function tumors with 3 of 8 mice tumor free on day 22. The combination was well tolerated with a < 8% maximal mean body weight loss.

Lunresertib + Camonsertib Selectively Drives Regression and is Well Tolerated in a FBXW7 Loss-of-Function Cell Line Derived Xenograft


https://cdn.kscope.io/b1da4b78003f62f54ff6e3a200263933-img193244649_11.jpg 

Preclinical Validation of STEP2 Screens

To identify additional genetic lesions which might have a synthetic lethal relationship with PKMYT1, several STEP2 screens were conducted. These genome wide CRISPR screens were conducted with sub-cytotoxic concentrations of PKMYT1 inhibitor and identified FBXW7 and several additional genetic alterations. FBXW7 is known to be mutated in colorectal cancers and NSCLC, among others. FBXW7 is an E3-ubiquitin ligase that targets Cyclin E1 (as well as other oncogenes) for degradation by the proteosome and has been shown to be a tumor suppressor gene. Therefore, there exists a strong mechanistic rationale for synthetic lethality with PKMYT1, and they represent a significant opportunity to expand the clinical utility of lunresertib.

In preclinical studies, lunresertib demonstrated in vivo anti-tumor activity in two patient derived xenograft models with FBXW7 inactivating mutations. In both models, we observed statistically significant tumor growth suppression with twice daily administration for lunresertib.

Lunresertib Demonstrates Tumor Growth Suppression of FBXW7-Mutated Patient Derived Xenograft Models

https://cdn.kscope.io/b1da4b78003f62f54ff6e3a200263933-img193244649_12.jpg

 

22


 

Lunresertib Clinical Trial Program

Design of Trials

In April 2021, we initiated our open-label Phase 1 MYTHIC clinical trial of lunresertib as a monotherapy. MYTHIC is a first-in-human, global, open-label Phase 1 dose-escalation clinical trial to evaluate safety, pharmacokinetics, pharmacodynamics and preliminary anti-tumor activity of lunresertib as a monotherapy (Module 1) or in combination with camonsertib (Module 2) in patients with advanced solid tumors harboring CCNE1 amplification or FBXW7 or PPP2R1A deleterious alterations. The trial is designed to evaluate the oral administration of lunresertib in patients with advanced recurrent tumors of different histologies in tumors with detected CCNE1 amplification, deleterious alterations in FBXW7, PPP2R1A and other STEP2 genes, for which recent in vitro studies suggested a higher confidence of success. The primary objective of Module 1 was to establish dose and schedule for lunresertib for further studies as monotherapy and assess preliminary safety and tolerability in patients.

The clinical plan beyond the dose escalation and initial explorations of dose and safety is presented below. In parallel with the monotherapy dose escalation phase, two other trials were initiated in February 2022 and December 2021, which we refer to as the MINOTAUR and MAGNETIC trials, to evaluate lunresertib in combination with FOLFIRI and gemcitabine, respectively. In May 2022, we initiated patient recruitment in a new arm of the Phase 1 MYTHIC clinical trial, which is designed to evaluate the safety and tolerability of lunresertib in combination with camonsertib in patients with advanced solid tumors. In the fourth quarter of 2022, we received fast track designation for lunresertib in combination with gemcitabine for the treatment of adult patients with CCNE1 amplified, or FBXW7 or PPP2R1A mutated platinum resistant ovarian cancer and in the third quarter of 2023, we received fast track designation for lunresertib in combination with camonsertib for the treatment of adult patients with CCNE1 amplified, or FBXW7 or PPP2R1A mutated endometrial cancer. We presented positive initial Phase 1 data from our ongoing Phase 1 MYTHIC trial demonstrating proof of concept for lunresertib alone and in combination with camonsertib, including at the 35th AACR-NCI-EORTC International Conference in October 2023. In January 2024, we announced our sponsorship of a global study executed as a new arm in the ongoing MYTHIC trial combining lunresertib with Debiopharm’s Debio 0123, a highly selective clinical WEE1 inhibitor. Dosing of the first patient with the synergistic lunresertib and Debio 0123 combination is expected to occur in the first half of 2024. We expect to provide MYTHIC data from selected expansion cohorts of the lunresertib and camonsertib combination in the second half of 2024.

We are collaborating with the Canadian Cancer Trials Group in an ongoing basket Phase 2 investigator-sponsored clinical trial (IST) that is enrolling patients with selected, advanced cancers receiving lunresertib as combination (NCT05605509). A sub-study to that protocol that will evaluate lunresertib in combination with gemcitabine in patients with CDK4/6 inhibitor treated ER+/HER2- metastatic breast cancer (NCT05601440) was activated more recently and is also enrolling patients. We are also collaborating with University Health Network, Toronto on a Phase 1 IST of luneresertib in combination with carboplatin and paclitaxel in TP53 ovarian and uterine cancer (NCT06107868) that is expected to be activated shortly.

The designs of our Phase 1 clinical trials and ISTs are summarized in the diagram below.

23


 

https://cdn.kscope.io/b1da4b78003f62f54ff6e3a200263933-img193244649_13.jpg

 

Monotherapy Data from Phase 1 MYTHIC Trial Module 1 Presented at June 2023 Conference Call:

 

In June 2023, we reported clinical proof of concept for lunresertib, as well as early insights from the ongoing combination trials. Findings from the initial monotherapy data from the Phase 1 MYTHIC clinical trial demonstrated a favorable and distinctive tolerability profile for lunresertib monotherapy, which included 63 enrolled patients as of the April 28, 2023 data cutoff. Monotherapy antitumor activity was observed, including a confirmed partial response and several patients with long stable disease. We identified both intermittent and continuous schedules to enable combination studies. We observed encouraging early responses across gemcitabine, camonsertib and FOLFIRI clinical combinations.

 

The tolerability profile of lunresertib monotherapy appeared favorable and differentiated from other clinical cell cycle inhibitors, which have been characterized with myelotoxicity and diarrhea (Meric-Bernstam, AACR 2022; Fu, JCO 2023; Takebe, Clin Cancer Res 2021). No grade 4 toxicity was observed with lunresertib, where grade 3 treatment emergent adverse events of interest included rash in 7.9%, anemia in 6.3%, and nausea or vomiting in 1.6% of patients. The only dose limiting toxicity was reversible rash, alleviated with dose modifications and simple supportive measures. Two recommended dose/schedules were identified – 240mg daily continuously and 80-100mg BID intermittent weekly – to offer maximum flexibility in combination studies. Pharmacodynamic analysis confirmed lunresertib treatment results in PKMYT1 target inhibition at active doses, based on a 50% reduction of phosphorylated CDK1 on Threonine 14, and increases in DNA damage, based on a two-fold increase in the widely-accepted biomarker, γH2AX. Preliminary anti-tumor activity was observed, including moderate tumor shrinkages and a confirmed partial response per RECIST 1.1 criteria, with maximum tumor burden decreased of 41% in a 73 year old patient with metastatic recurrent uterine carcinosarcoma who had received 3 prior lines of therapy. Several patients demonstrated long stable disease and remained on treatment for greater than 11 months and ongoing.

 

Initial Combination Data from Phase 1 MYTHIC Trial Presented at 35th AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics in October 2023:

 

In a plenary session titled, “New Drugs on the Horizon” at the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics in October 2023, we reported positive initial data from Modules 1 and 2 of the ongoing Phase 1 MYTHIC clinical trial evaluating lunresertib alone and in combination with camonsertib. The study achieved clinical proof of concept. As of September 5, 2023, the cutoff date for the data presented at the AACR-NCI-EORTC conference, 67 patients were enrolled in Module 1 and 59 patients in Module 2. The lunresertib and camonsertib combination demonstrated clear signals of anti-tumor activity across multiple tumor types and all selected genotypes. The protocol-defined overall response (OR; RECIST or GCIG CA-125 responses) was 33.3% in

24


 

18 patients. The CBR at the combination preliminary RP2D, defined as overall response or stable disease of at least 16 weeks without tumor progression, was 50.0%. In all 55 evaluable patients, across all doses, OR was 23.6% and CBR was 41.8%. In 10 evaluable patients with gynecologic tumors at the combination preliminary RP2D, the RECIST response was 50%, OR 60%, and CBR 70%. Patients in this cohort had a median of 3 and up to 9 prior lines of therapy. RECIST responses in this ongoing combination trial included 8 confirmed and 3 unconfirmed partial responses (PR). Additionally, 3 patients with ovarian tumors had cancer antigen 125 (CA-125) responses. RECIST responses and clinical benefit with combination therapy was seen across all three lunresertib-sensitizing alterations: CCNE1 amplification or FBXW7 or PPP2R1A deleterious alterations. The MRR was significantly higher in combination compared to monotherapy (p=0.003), providing further evidence of enhanced anti-tumor activity – observed MRR in combination therapy was 50% (n=24), compared to 10% (n=30) with lunresertib monotherapy.

 

Encouraging and manageable safety and tolerability were observed for the combination therapy (n=59). The recommended Phase 2 dose was proposed as 80mg twice daily of lunresertib and 80mg camonsertib, both given 3 days a week. The most common treatment-related adverse event (TRAE) was anemia, with grade 3 occurring in 42% of patients. The occurrence of anemia was highly correlated with the baseline degree of anemia in these heavily pretreated patients and the level of pretreatment, with more significant anemia occurring in those with 4 or more prior therapies and with advanced age. Anemia usually improved with a one-week treatment interruption and standard supportive care, and did not lead to any therapy discontinuations at the preliminary RP2D. At the proposed RP2D, there were no Grade 4 or Grade 5 TRAEs reported. Data indicates that anemia management can be individualized and alleviated with simple schedule modification based on patient monitoring. This approach is now being tested in the MYTHIC trial.

Camonsertib, Also Known as RP-3500, an Oral ATR Inhibitor

Overview

Our initial clinical-stage product candidate, camonsertib, is a potent and selective oral small molecule inhibitor of ATR that we are developing for the treatment of tumors with mutations in ATM and a network of other genomic alterations that we discovered to be SL with ATR. ATR is a critical DNA damage response (DDR) protein that acts as both the master regulator of the response to DNA replication stress, as well as a central effector of the DNA damage checkpoint. Based on the previously published SL relationship between ATR and ATM, ATR has been the target of prior drug discovery efforts, and ATR inhibitors in development have demonstrated promising, durable clinical responses in a small number of patients in early clinical trials. Through our STEP2 screens, we believe that we have more precisely identified and expanded the patient populations that would benefit from camonsertib, which allows us to differentiate and enrich our clinical development strategy as well as address multiple types of solid tumors.

Camonsertib has demonstrated an optimized anti-tumor effect, selectivity, and pharmacokinetics profile in preclinical studies that we believe supports the potential for it to be a leading ATR inhibitor, if approved. We also conducted multiple STEP2 screens in which we confirmed the SL relationship between ATR and ATM and identified an additional 19 genes that are also SL with ATR, potentially expanding the patient populations that may benefit from our product candidate. In July 2020, we began dosing in our open-label Phase 1/2 clinical trial of camonsertib in patients with advanced tumors that have alterations in the ATM gene or a subset of 16 additional genetic alterations identified through our STEP2 screens. We believe the design of our trial allows us to enrich the patient population in our trials with those who are most likely to respond to camonsertib. In parallel with the monotherapy dose-escalation portion of the trial, in February 2021 we initiated patient recruitment of the combination therapy arm to evaluate the safety and efficacy of camonsertib in combination with a PARP inhibitor, talazoparib in the same patient subgroups. In August 2021, we initiated patient recruitment in our open-label Phase 1b/2 ATTACC trial of camonsertib in combination with niraparib and olaparib, two additional PARP inhibitors. In October 2021, we presented initial Phase 1 monotherapy clinical data from our open-label Phase 1/2 TRESR trial in patients with solid tumors at the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics. The presentation included the recommended Phase 2 dose and schedule choice and confirmed camonsertib activity in tumors with alterations hypothesized by our SNIPRx platform.

In April 2022, we presented comprehensive Phase 1 monotherapy clinical data from the TRESR Phase 1/2 trial, reflecting analysis of 120 patients, of which 99 patients were evaluable for efficacy as of the data cutoff date of

25


 

February 14, 2022 (excluding one patient evaluated as of March 22, 2022). The study included 95 patients who received therapeutically active doses or at the recommended Phase 2 dose schedule of 3 days on / 4 days off, and reflecting the data cutoff of mid-February 2022. Monotherapy with camonsertib continued to appear safe and well tolerated. Anemia was the most common treatment-related adverse event and easily manageable. Only 24.2% of all patients in the 3 days on / 4 days off schedule experienced Grade 3 anemia, and none experienced Grade 4 anemia. Camonsertib monotherapy resulted in durable clinical benefit across tumor types and genomic alterations, with enriched benefit demonstrated in specific patient subsets. These updated monotherapy results showed a 43% clinical benefit rate (CBR), which was defined as response or treatment duration of at least 16 weeks without progression, an overall response rate of 14%, and a median progression free survival (mPFS) of 15 weeks in solid tumors across genotypes, with potential best-in-class safety and tolerability. The overall CBR in patients after PARP inhibitor failure was 47%. We observed camonsertib demonstrated robust activity in patients with ovarian cancer (n=20), demonstrating 75% CBR after dosing with camonsertib, an overall response rate of 25%, and a mPFS of 35 weeks. The ovarian cancer patient population was heavily pretreated and comprised a hard to treat population: of which 90% had previous treatment with PARP inhibitors and 85% were platinum resistant. The responders included one complete response, three partial responses as determined by RECIST 1.1 criteria, and one durable and ongoing CA- 125 response in a patient with stable disease. The TRESR study comprises the largest set of tumors with detailed genomic analysis evaluated with ATR inhibitor (ATRi) monotherapy. Genomic subsets of tumors beyond ATM included tumors harboring alterations in ATR-sensitizing genes, with responses observed in tumors harboring BRCA1/2, SETD2 and RAD51C alterations. In patients with BRCA1/2 mutated tumors (n = 37), response rate was 14% and included two patients with ovarian cancer, and one each with breast cancer, head and neck squamous cell carcinoma, and melanoma. In patients with tumors carrying BRCA1 mutations, the CBR was 48%. In patients with tumors with ATM loss-of-function (LOF) (n = 34), response rate was 9% including one RECIST 1.1 confirmed/unconfirmed response, and two prostate specific antigen responses. An additional patient with pancreatic cancer and ATM LOF had a late response, just after the data cutoff after 54 weeks of treatment. The CBR in the patients with ATM LOF was 44% and mPFS was 17 weeks. Sequencing data demonstrated biallelic gene LOF, an emerging biomarker for synthetic lethal therapies, could potentially be leveraged to further enrich for patients most likely to benefit from camonsertib. CBR in patients with biallelic LOF was significantly higher (47%) compared to the CBR in patients with non-biallelic tumors (15%).

In June 2022, we announced a worldwide license and collaboration agreement with Roche for the development and commercialization of camonsertib for the treatment of tumors with specific synthetic-lethal genomic alterations. Under the terms of the collaboration, Roche assumed all subsequent development of camonsertib with the potential to expand development into additional tumor indications and multiple combination studies. Under the terms of the agreement, we received an initial $125 million upfront payment in July 2022. In January 2024, we earned a $40 million milestone upon dosing of the first patient in the camonsertib-based arm of the Roche TAPISTRY trial, which was subsequently received in February 2024. Roche has been conducting the TAPISTRY and MORPHEUS LUNG clinical trials. TAPISTRY is a Phase 2, global, multicenter, open-label, multi-cohort clinical trial designed to evaluate the safety and efficacy of targeted therapies or immunotherapy in participants with unresectable, locally advanced or metastatic solid tumors determined to harbor specific oncogenic genomic alterations. MORPHEUS LUNG is a Phase 1b/2 clinical trial of multiple immunotherapy-based treatment combinations in participants with metastatic non-small cell lung cancer. Since inception of the Roche camonsertib collaboration, we have earned a cumulative total of $182.6 million, including the upfront payment, the milestone payment, as well as additional reimbursements from Roche. On February 7, 2024, we received written notice from Roche of their election to terminate the Roche camonsertib collaboration. The termination will become effective in May 2024, at which time we will regain global development and commercialization rights for camonsertib from Roche.

In a Clinical Trials Plenary Session at the 2023 AACR Annual Meeting, we presented initial clinical data from the Phase 1/2 TRESR and ATTACC clinical trials evaluating camonsertib in combination with three PARP inhibitors - talazoparib, niraparib, and olaparib. The presentation included initial data from the ongoing Phase 1/2 TRESR clinical trial evaluating camonsertib in combination with talazoparib and initial data from the ongoing Phase 1b/2 ATTACC clinical trial evaluating camonsertib in combination with niraparib or olaparib in patients with advanced solid tumors. The clinical trials included 107 patients, of which 90 patients were evaluable for efficacy and treated at least 13 weeks prior to the data cutoff of February 27, 2023. This trial population comprised patients with a broad range of historically difficult to treat tumors, including patients with platinum-resistant tumors, patients who had either recurred or progressed during or after treatment with PARP inhibitors, and patients who had developed known BRCA-reversion mutations. The camonsertib-PARP inhibitor combinations demonstrated durable 48% CBR in patients with

26


 

unmet medical needs, across tumor types and different genomic alterations, and regardless of PARPi partner or platinum resistance, with a favorable safety and tolerability profile. Patients with platinum-resistant tumors had an overall response rate (ORR) of 12% and CBR of 49%, and benefited similarly to non-platinum-resistant tumors (ORR 13%, CBR 46%). Combination results showed the most benefit in late-line ovarian cancer in 19 patients demonstrating 32% overall response, 58% CBR and mPFS of approximately seven months, with treatment greater than 16 weeks and ongoing in nine patients. Early ctDNA molecular responses observed in 66% of evaluable patients (31/47) confirmed the antitumor activity of low dose intermittent PARP inhibitor and camonsertib therapy. Further, the ctDNA data showed a strong correlation with the degree of tumor shrinkage and duration of disease control, and provided a mechanistic explanation for the observed durable clinical benefit in heavily pretreated patients, beyond the natural history of the disease. The molecular response rate (MRR) was significantly higher in patients with clinical benefit (83%) compared to those without (48%; p=0.015), confirming treatment effect. Molecular responses were observed in patients with prior PARPi exposure (57%) and platinum resistance (64%). The camonsertib-PARP inhibitor combinations appeared to be well tolerated. Dose limiting toxicity (DLTs) in 68 patients were related to myelotoxicity only, including Grade 3 or higher anemia of 3%, thrombocytopenia of 6%, neutropenia of 7%, and febrile neutropenia of 3%. No prophylactic growth factors were required when administering the PARP inhibitors at evaluated doses.

The TRESR and ATTACC clinical trials have completed enrollment. FDA endorsed the camonsertib monotherapy recommended dose. Our proposals for drug dose optimization are in line with the principles of FDA's Project Optimus. We are finalizing the camonsertib and PARP inhibitors combination data analysis.

Mechanism of Action

ATR is a protein kinase that acts at multiple levels of the DDR network. It is activated when problems with ongoing DNA replication are identified, a phenomenon known as DNA replication stress. It uses its kinase activity to stabilize the DNA replication machinery locally and to suppress the initiation of DNA replication globally. As a consequence, ATR prevents the formation of DNA damage when DNA replication is stressed. In addition to these roles, ATR also restrains cell cycle progression when it is activated, a phenomenon known as the DNA damage checkpoint. ATR is one member of an extensive network of proteins that serve to recognize early stages of DNA damage, prevent replication from proceeding through these damaged sites and repair the damage. Cancer cells with alterations in genes encoding this network of DDR proteins are highly dependent on ATR for survival. ATR’s central role in the regulation of replication stress has led to the development of multiple ATR inhibitors that have demonstrated durable responses in early clinical trials.

The ATR Partner Genes and Proposed Synthetic Lethality Pairs

ATM is a DDR protein related to ATR that is responsible for sensing and signaling DNA double-strand breaks. Our ATR inhibitor STEP2 screen campaigns confirmed that ATM-deficient cells rely on ATR activity for survival. ATM orchestrates the response to double-strand break repair and thus, ATM-deficient tumors have an impaired response to DNA breaks. SL screens conducted in our laboratories have identified that at least 16 additional genes are SL with ATR inhibition, making cancer cells that are deficient in those genes highly sensitive to killing by ATR inhibitors. An overview of the ATM-ATR SL relationship, as one of the examples of the sensitivity genes, is illustrated below.

27


 

Mechanism of ATM-ATR Synthetic Lethality

 

https://cdn.kscope.io/b1da4b78003f62f54ff6e3a200263933-img193244649_14.jpg 

 

The gene encoding for ATM is frequently mutated in cancer. An analysis of sequence data collected as part of The Cancer Genome Atlas (TCGA) found that between 1% and 4% of solid tumors, such as breast, bladder, pancreatic and lung cancers, have deficiencies in ATM, as depicted in the graphs below. Beyond ATM, 16 of 19 additional, mutually exclusive genomic alterations identified as SL with camonsertib, with average prevalence of approximately 10% across multiple tumors, were eligible for recruitment into clinical trials.
 

28


 

 

https://cdn.kscope.io/b1da4b78003f62f54ff6e3a200263933-img193244649_15.jpg 

 

Clinical Validation of ATR Inhibitors in ATM-Deficient Tumors and in Other Genetic Backgrounds Hypothesized to Sensitize Tumors to ATRi

Early phase studies evaluating third party ATR inhibitors as a monotherapy support the rationale for prospective patient selection for tumors carrying genomic alterations hypothesized to sensitize tumors ATR inhibition. A Phase 1 of Bayer’s ATR inhibitor suggested antitumor activity in solid tumors with certain DDR defects, including ATM loss (Yap, Cancer Discovery 2020). The subsequent dose expansion cohort enrolled an additional 143 patients, prospectively selected for presence of DDR gene defects. While the overall response rate was low (4%), durable responses were observed in tumors with ATM or BRCA mutations (Yap, AACR 2022). In addition, out of a cohort of 17 patients receiving EMD’s ATR inhibitor, the single responder was a patient with metastatic colorectal cancer with loss of ATM (Yap, JCO 2020).
 

The Phase 1/2 TRESR study, which has completed enrollment in all modules, prospectively selected for patients with tumors carrying DNA damage repair loss-of-function mutations predicted to sensitize to camonsertib. Following our first clinical data release at the AACR-ASCO-NCI meeting in October 2021, we presented comprehensive Phase 1 monotherapy data from this study at the AACR annual conference in April 2022. Camonsertib monotherapy resulted in durable responses across tumor types and genomic alterations, including ATM, BRCA1, BRCA2, RAD51C, CDK12, and SETD2. Antitumor activity was validated by molecular responses in 41% of evaluable patients.
 

In June 2023, we published initial data from the Phase 1/2 TRESR clinical trial in Nature Medicine highlighting the clinical benefit of camonsertib in advanced solid tumors. We demonstrated not only single agent activity of camonsertib, but also the importance of enhanced precision medicine approaches, such as the identification of bi-allelic alterations affecting the target DNA repair genes and other biomarkers, as well as the use of longitudinal liquid biopsies to guide its delivery to the right patients. This study provided a framework for the testing of novel therapeutic approaches based on the principles of synthetic lethality and informed by genome-wide CRISPR screens. Multiple follow up publications and presentations, based on the data from TRESR study, were published or presented and further learnings are being prepared for potential publication.

In a Clinical Trials Plenary Session at the 2023 AACR Annual Meeting, we presented initial clinical data from the Phase 1/2 TRESR and ATTACC clinical trials evaluating camonsertib in combination with three PARP inhibitors - talazoparib, niraparib, and olaparib. Of the 90 evaluable patients with difficult to treat tumors, including patients with platinum-resistant tumors, patients who had either recurred or progressed during or after treatment with PARP inhibitors, and patients who had developed known BRCA-reversion mutations, we observed durable 48% CBR in patients with unmet medical needs, across tumor types and different genomic alterations, and regardless of PARPi partner or platinum resistance, with a favorable safety and tolerability profile. The combination results showed the most benefit in late-line ovarian cancer in 19 patients demonstrating 32% overall response, 58% CBR and mPFS of approximately 7 months, with treatment greater than 16 weeks and ongoing in 9 patients. Early ctDNA molecular

29


 

responses observed in 66% of evaluable patients (31/47) confirmed the antitumor activity of low dose intermittent PARP inhibitor and camonsertib therapy.

Our Solution, Camonsertib

We identified ATR as one of the SL targets through our SNIPRx screen campaign of ATM and selected ATR as a target for our initial product candidate, camonsertib, based on:

i.
existing third party clinical and preclinical support for the potential of ATR inhibition as a precision oncology therapy;
ii.
our ability to design an ATR inhibitor with enhanced chemical properties, such as potency and selectivity; and
iii.
the results of our STEP2 screens, which identified 19 additional genomic alterations beyond ATM deficiency to be SL with ATR, facilitating the expansion of the addressable patient populations.

We designed camonsertib as an oral small molecule ATR inhibitor with increased potency and a similar or improved selectivity profile compared to other known ATR inhibitors. Camonsertib has demonstrated a favorable pharmacokinetic profile in multiple preclinical models, including rodent and canine, and a distribution, metabolism and excretion profile that suggests a low potential for drug-drug interactions in the clinic. The clinical trial of camonsertib in patients with recurrent cancers is ongoing.

Our STEP2 screens have generated proprietary patient selection insights that we believe provide the rationale to expand the potential patient populations addressable by camonsertib beyond patients with tumors carrying ATM genetic defects. We have identified 19 genomic alterations, in addition to ATM deficiency, that confer sensitivity to camonsertib. This 19 gene set, which we refer to as our STEP2-identified genes, includes several novel genes that have not been previously reported as rendering sensitivity to ATR inhibitors. In addition, many of the genes we have selected do not overlap with previously identified genes in the homologous recombination defect panel, which is utilized to identify patients for treatment with PARP inhibitors and is currently used by others to test for sensitivity to ATR inhibitors. Furthermore, our STEP2 screens demonstrated that two genes previously reported by others to be sensitive to ATR inhibition were not sensitive and hence, those genes were excluded from our set of STEP2-identified genes.

The sensitivity and accuracy of our STEP2 screens enable the identification of several novel gene alterations, including certain genes that are not yet included in commercially available Next Generation Sequencing cancer panels or Clinical Laboratory Improvement Amendments, or CLIA, validated panels used in large academic centers. For our Phase 1/2 clinical trial, we identified and partnered with multiple large, leading clinical centers globally where tumor sequencing is a component of standard of care. These centers’ panels are validated and sufficiently large to accommodate screening for alterations in ATM or our STEP2-identified genes. These panels include the majority, and in the case of whole genome or whole exome sequencing, all of these genes. For genes that are not available on certain panels at a particular clinical site, we identified surrogate genes that are co-deleted with the STEP2 genes and have an approximate 30% to 80% probability of concomitant loss, which we believe has and will provide sufficient enrichment for our clinical trial. By working in collaboration with our clinical partners to access their existing patient databases, we believe that we will be able to efficiently identify existing and new patients who may be eligible for our clinical trial. Based on the prevalence of ATM deficiencies and our STEP2-identified genomic alterations across various solid tumors we believe that camonsertib has the potential to benefit a significant number of patients representing a large unmet medical need.

As part of our development strategy for camonsertib, we are evaluating the potential anti-tumor activity of camonsertib in combination with an approved PARP inhibitor based on the synergies we have observed in our preclinical studies. PARP inhibitors lead to the stabilization of PARP-DNA complexes that block the progression of replication forks. ATR activity stabilizes the DNA replication forks that are destabilized by PARP inhibition and inhibition of ATR causes stalled replication forks to collapse and form cytotoxic DNA double-strand breaks. As a consequence, ATR inhibition can potentiate the cytotoxic effects of PARP inhibitors. We note that this phenomenon is particularly prominent under conditions where some cancer-relevant DDR genes, such as those identified through our STEP2 screens, are inactivated, thereby creating a potential therapeutic window.

30


 

Preclinical Data: Monotherapy

We observed camonsertib to have a favorable tolerability and pharmacokinetics profile across multiple preclinical studies and animal models, which we believe supports advancing the product candidate into clinical trials. In a preclinical study, we evaluated continuous daily dosing of camonsertib in a colon cancer xenograft model with CW-2 cancer cells, which contain an inactivating mutation in ATM that confers sensitivity to ATR inhibition. In this study, we injected mice with tumor cells and waited for tumor growth to approximately 200 mm3 before initiating daily dosing over a period of 14 days with vehicle, camonsertib at its maximum tolerated dose, or MTD, of 10 mg/kg/day, or Bayer’s ATR inhibitor product candidate, BAY1895344, at what we determined to be its MTD of 35 mg/kg/day (n=10 mice per group). Both camonsertib and BAY1895344 demonstrated statistically significant suppression of tumor growth as compared to vehicle. Importantly, we observed statistically significant higher suppression of tumor growth with camonsertib as compared to BAY1895344 (p=0.018). Body weight loss as a measurement of tolerability was similar for both compounds in this trial.

Statistically Significant Tumor Growth Suppression in Colon Cancer Model

 

https://cdn.kscope.io/b1da4b78003f62f54ff6e3a200263933-img193244649_16.jpg 

 

In another preclinical study using an intermittent dosing schedule, we evaluated camonsertib in comparison to BAY1895344 in a Granta-519 mantle cell lymphoma xenograft model. Similar to CW-2 cancer cells, Granta-519 cancer cells also contain an inactivating mutation in ATM that confers sensitivity to ATR inhibition. In this study, we injected mice with tumor cells and waited for tumor growth to approximately 150 mm3 before initiating intermittent dosing with vehicle or either treatment (n=9 mice per group). We observed that both camonsertib and BAY1895344 exhibited tolerability at higher doses when administered on a three days per week schedule than their respective MTDs from the daily dosing CW-2 colon cancer study. The MTDs utilizing this intermittent dosing schedule were determined to be 30 mg/kg daily for camonsertib and 50 mg/kg twice-daily for BAY1895344. Both agents demonstrated similar and significant suppression of tumor growth in this model without body weight loss. However, significant anemia, or hematocrit reduction, was observed in mice treated with BAY1895344 (p=0.0002), whereas we did not observe these tolerability issues with camonsertib, which we believe supports our hypothesis of a favorable tolerability profile for camonsertib.

31


 

Camonsertib Exhibits Tumor Growth Suppression Without Significant Anemia

Measured as Hematocrit in Mantle Cell Lymphoma Model

 

https://cdn.kscope.io/b1da4b78003f62f54ff6e3a200263933-img193244649_17.jpg 

 

Preclinical Data: Combination Therapy with PARP

Of our 19 STEP2-identified genes for camonsertib as a monotherapy, we have identified a subset of genes that are particularly sensitive to the combination of camonsertib and PARP inhibitors. The graphs below illustrate two examples of this subset of genes where synergy was demonstrated between camonsertib and PARP inhibitors.

Significant Synergy Demonstrated by Combination of Camonsertib and PARP Inhibitors

 

https://cdn.kscope.io/b1da4b78003f62f54ff6e3a200263933-img193244649_18.jpg 

+/+: Wild Type

-/-: Genomically altered

We observed in vitro killing of cells carrying this subset of genomic alterations at low concentrations of both compounds, whereas only a minimal effect was seen on control wild-type cells. Based on this finding, we believe that the combination of camonsertib with lower doses of PARP inhibitors could lead to efficient anti-tumor activity while

32


 

potentially addressing the tolerability issues observed with PARP inhibitors, where a majority of patients in clinical trials of niraparib and talazoparib required a dose reduction or interruption in dosing. We are currently exploring the ATR-PARP inhibitor synergy in additional ongoing studies in xenograft models.

Preclinical Data: Combination Therapy with Gemcitabine

Gemcitabine is an antimetabolite chemotherapeutic agent that is commonly used in various solid tumors such as pancreatic, breast, ovarian, and non-small cell lung cancer. Gemcitabine is metabolized by the tumor cells and incorporated in their DNA, resulting in blockage of DNA polymerases and replication fork stalling. This gemcitabine-induced replication stress increases the tumor cells’ dependency on the ATR pathway and gemcitabine is therefore known to strongly enhance the cytotoxic effects of ATR inhibitors.

Our preclinical data demonstrate that gemcitabine shows strong synergy with camonsertib in ATM-deficient (ATM-KO) cells, whereas much higher doses are required to achieve the same degree of synergy in ATM-proficient (ATM-WT) cells (Figure A below). Consequently, camonsertib combined with gemcitabine kills ATM-KO cells at low concentrations that show little effect in WT cells (Figure B below). We therefore believe that the combination with gemcitabine may enhance the anti-tumor activity of camonsertib in ATM-deficient cancers at tolerated doses. We are currently evaluating this combination in tumor cells carrying additional STEP2 alterations as well as in animal models.

Sensitivity of ATM-deficient cells to the combination of camonsertib and gemcitabine

https://cdn.kscope.io/b1da4b78003f62f54ff6e3a200263933-img193244649_19.jpg 

Preclinical Validation of STEP2 Screens

Through our STEP2 screens of ATR inhibitors, we confirmed the SL relationship between ATR and ATM and identified an additional 19 genomic alterations that confer sensitivity to camonsertib. In follow-up studies with cancer cell line pairs, in which the only difference is the inactivation of the target genes, we are confirming the sensitivity of these genomic alterations to camonsertib, and this extensive validation effort is still being expanded. We are also creating xenograft models using both the parent cell lines and the inactivated cell line. In such a model using one of

33


 

the STEP2-identified genes, camonsertib led to statistically significant suppression of tumor growth, whereas it had no anti-tumor effect in tumors created with wild-type parent cells, as shown in the model below.

Tumor Growth Suppression in a RNASEH2B -/- 5637 Bladder Isogenic Xenograft Model

 

https://cdn.kscope.io/b1da4b78003f62f54ff6e3a200263933-img193244649_20.jpg 

Camonsertib Clinical Trial Program

Design of Trials:

In July 2020, we initiated our open-label Phase 1/2 clinical trial of camonsertib as both a monotherapy and in combination with talazoparib, an approved PARP inhibitor. The trial is designed to evaluate the oral administration of camonsertib in patients with advanced recurrent tumors of different histologies with ATM loss-of-function or a subset comprised of 16 of the 19 STEP2-identified genomic alterations, for which recent in vitro studies suggested a higher confidence of success.

In the ongoing monotherapy dose escalation phase of our trial, we evaluated the dosing regimen and safety of camonsertib to establish the recommended dose for the expansion phase of the trial. In three expansion cohorts, each of which was designed to enroll patients based on ATM loss-of-function or different STEP2-identified genomic alterations, we assessed the preliminary efficacy of camonsertib at the recommended dose and schedule. In parallel with the monotherapy dose escalation phase, the trial was designed to enroll a separate arm to evaluate camonsertib in combination with talazoparib, an approved PARP inhibitor. An efficacy evaluation was performed every six weeks for the first five months and every nine weeks thereafter. As of the date of this Annual Report, we activated thirteen clinical trial sites for TRESR and fourteen clinical trial sites for ATTACC in North America and Europe. We observed initial signs of biological and clinical activity as monotherapy and evaluated multiple doses and schedules. We established the recommended Phase 2 dose as 160 mg once daily 3 days on / 4 days off, given continuously every week with a tolerability and safety profile that is favorable and the dominant on-target toxicity is anemia. Grade 3 anemia was reported at 15% with no grade 4 anemia and other grade 3 or 4 toxicities were at maximum 5%. Clinical responders were seen across multiple genomic alterations and tumor types. Clinical benefit rate reported at the AACR-ASCP-NCI meeting in October 2021 was 49%. In February 2021, we initiated recruitment of patients for the talazoparib combination arm of the trial. In December 2021 we entered the Phase 2 part of the trial with expansion into specific tumor and genotype cohorts. We reported complete safety and efficacy data for the monotherapy dose escalation phase of the trial at AACR in April 2022.

34


 

The designs for our Phase 1/2 clinical trials for camonsertib are summarized in the diagram below.

 

https://cdn.kscope.io/b1da4b78003f62f54ff6e3a200263933-img193244649_21.jpg 

Full Dataset from the TRESR Phase 1/2 Trial Presented at AACR 2022:

In April 2022, we presented comprehensive Phase 1 monotherapy clinical data from the TRESR Phase 1/2 clinical trial, reflecting analysis of 120 patients, of which 99 patients were evaluable for efficacy as of the data cut-off date of February 14, 2022 (excluding one patient evaluated as of March 22, 2022). The trial included 95 patients who received therapeutically active doses or at the recommended Phase 2 dose schedule of three days on / four days off, and reflecting the data cut-off date of February 14, 2022. Monotherapy with camonsertib continued to appear safe and well tolerated. Anemia was the most common treatment-related adverse event and easily manageable. Only 24.2% of all patients in the three days on / four days off schedule experienced Grade 3 anemia, and none experienced Grade 4 anemia. Camonsertib monotherapy resulted in durable clinical benefit across tumor types and genomic alterations, with enriched benefit demonstrated in specific patient subsets. These updated monotherapy results showed a 43% CBR, which was defined as response or treatment duration of at least 16 weeks without progression, an overall response rate of 14%, and a mPFS of 15 weeks in solid tumors across genotypes, with potential best-in-class safety and tolerability. The overall CBR in patients after PARP inhibitor failure was 47%.

We observed camonsertib demonstrated robust activity in patients with ovarian cancer (n=20), demonstrating 75% CBR after dosing with camonsertib, an overall response rate of 25%, and a mPFS of 35 weeks. The ovarian cancer patient population was heavily pretreated and comprised a hard to treat population: of which 90% had previous treatment with PARP inhibitors and 85% were platinum resistant. The responders included one complete response, three partial responses as determined by RECIST 1.1 criteria, and one durable and ongoing CA-125 response in a patient with stable disease.

The TRESR clinical trial comprises the largest set of tumors with detailed genomic analysis evaluated with ATRi monotherapy. Genomic subsets of tumors beyond ATM included tumors harboring alterations in ATR-sensitizing genes, with responses observed in tumors harboring BRCA1/2, SETD2 and RAD51C alterations. In patients with BRCA1/2 mutated tumors (n = 37), response rate was 14% and included two patients with ovarian cancer, and one each with breast cancer, head and neck squamous cell carcinoma, and melanoma. In patients with tumors carrying BRCA1 mutations, the CBR was 48%. In patients with tumors with ATM loss-of-function (LOF) (n = 34), response rate was 9% including one RECIST 1.1 confirmed/unconfirmed response, and two prostate specific antigen responses. An additional patient with pancreatic cancer and ATM LOF had a late response, after the data cut-off date of February 14, 2022, which was after 54 weeks of treatment. The CBR in the patients with ATM LOF was 44% and mPFS was 17 weeks. Sequencing data demonstrated biallelic gene LOF, an emerging biomarker for synthetic lethal therapies, could potentially be leveraged to further enrich for patients most likely to benefit from camonsertib. CBR in patients with biallelic LOF was significantly higher (47%) compared to the CBR in patients with non-biallelic tumors (15%).

35


 

Initial Dataset from the Phase 1/2 TRESR and ATTACC Clinical Trials Presented at AACR 2023:

In a Clinical Trials Plenary Session at the 2023 AACR Annual Meeting, we presented initial clinical data from the Phase 1/2 TRESR and ATTACC clinical trials evaluating camonsertib in combination with three PARP inhibitors - talazoparib, niraparib, and olaparib. The presentation included initial data from the ongoing Phase 1/2 TRESR clinical trial evaluating camonsertib in combination with talazoparib and initial data from the ongoing Phase 1b/2 ATTACC clinical trial evaluating camonsertib in combination with niraparib or olaparib in patients with advanced solid tumors. The clinical trials included 107 patients, of which 90 patients were evaluable for efficacy and treated at least 13 weeks prior to the data cutoff of February 27, 2023. This study population comprised patients with a broad range of historically difficult to treat tumors, including patients with platinum-resistant tumors, patients who had either recurred or progressed during or after treatment with PARP inhibitors, and patients who had developed known BRCA-reversion mutations.

The camonsertib-PARP inhibitor combinations demonstrated durable 48% CBR in patients with unmet medical needs, across tumor types and different genomic alterations, and regardless of PARPi partner or platinum resistance, with a favorable safety and tolerability profile. Patients with platinum-resistant tumors had an overall response rate (ORR) of 12% and CBR of 49%, and benefited similarly to non-platinum-resistant tumors (ORR 13%, CBR 46%). Combination results showed the most benefit in late-line ovarian cancer in 19 patients demonstrating 32% overall response, 58% CBR and mPFS of approximately seven months, with treatment greater than 16 weeks and ongoing in nine patients.

Early ctDNA data showed a strong correlation with the degree of tumor shrinkage and duration of disease control, and provided a mechanistic explanation for the observed durable clinical benefit in heavily pretreated patients, beyond the natural history of the disease. Molecular responses observed in 66% of evaluable patients (31/47) confirmed the antitumor activity of low dose intermittent PARP inhibitor and camonsertib therapy. The molecular response rate (MRR) was significantly higher in patients with clinical benefit (83%) compared to those without (48%; p=0.015), confirming treatment effect. Molecular responses were observed in patients with prior PARPi exposure (57%) and platinum resistance (64%). The camonsertib-PARP inhibitor combinations appeared to be well tolerated. Dose limiting toxicity (DLTs) in 68 patients were related to myelotoxicity only, including Grade 3 or higher anemia of 3%, thrombocytopenia of 6%, neutropenia of 7%, and febrile neutropenia of 3%. No prophylactic growth factors were required when administering the PARP inhibitors at evaluated doses.

The TRESR and ATTACC clinical trials have completed enrollment. FDA endorsed the camonsertib monotherapy recommended dose. Our proposals for drug dose optimization are in line with the principles of FDA's Project Optimus. We are finalizing the camonsertib and PARP inhibitors combination data analysis.

RP-1664, Our First-in-Class, Highly Selective Polo-Like Kinase 4 (PLK4) Inhibitor Program

 

Overview

 

RP-1664 is a first-in-class, highly selective, oral PLK4 inhibitor designed to harness the synthetic lethal relationship with TRIM37 amplification or overexpression in solid tumors. Tumors rely on PLK4 for centriole biogenesis in S-phase of the cell cycle when TRIM37, an E3 ligase that reduces pericentriolar material, is high. Preclinical studies demonstrate that RP-1664 selectively inhibits PLK4 and drives potent synthetic lethality in TRIM37-high tumor models, both in vitro and in vivo. Elevated TRIM37 is a feature found across a range of solid tumors and in approximately 80% of high-grade neuroblastoma. RP-1664 is the only selective PLK4 inhibitor known to be in the clinic. We reported comprehensive preclinical data for RP-1664 in November 2023, including deep tumor growth inhibition and regressions in multiple TRIM37-high solid tumor or neuroblastoma xenograft models. The preclinical evaluation was performed both internally and in collaboration with Children’s Hospital of Philadelphia (CHOP). In February 2024, we dosed the first patient in the LIONS (PLK4 Inhibitor in Advanced Solid Tumors) clinical trial, a multicenter, open-label Phase 1 study to investigate safety, pharmacokinetics, pharmacodynamics, and the preliminary efficacy of RP-1664. After evaluating safety in adult patients with recurrent solid tumors in the LIONS clinical trial, we expect to move into a Phase 1/2 study in high risk, recurrent pediatric neuroblastoma, in which children have limited treatment options and high prevalence of TRIM37-altered tumors.

 

Mechanism of Action

36


 

 

Centrosomes are the main microtubule organizing center of the cell and enable the correct segregation of sister chromatids during cell division. Centrosomes are composed of two centrioles and the pericentriolar material (PCM), both of which can nucleate microtubules that form the mitotic spindle. TRIM37, an E3 ligase, negatively regulates the stability of PCM proteins, causing PCM dysfunction when overexpressed and increasing dependence on centrioles for successful mitosis. PLK4 is a serine/threonine mitotic kinase which is crucial for the duplication of centrioles. PLK4 inhibition results in the loss of centrioles, which is detrimental to cells with high TRIM37 and depleted PCM. Thus the inhibition of PLK4 in the context of TRIM37 amplification or gain is considered synthetic lethal.

 

Two distinct isogenic cell line pairs demonstrated that PLK4 inhibition kills control MCF7 cells, which are TRIM37 high, but not TRIM37-depleted cells that become resistant to PLK4 inhibition. Similarly, RPE1 cells that have been engineered to overexpress TRIM37 were hypersensitive to PLK4 inhibition versus wildtype cells.

 

PLK4 Inhibition is Synthetic Lethal with TRIM37-High Tumors

https://cdn.kscope.io/b1da4b78003f62f54ff6e3a200263933-img193244649_22.jpg 

 

Our Solution, RP-1664

 

We identified PLK4 as a SL target through our SNIPRx screen campaign of TRIM37, based on:

i.
existing third party preclinical support for the potential of PLK4 inhibition to trigger selective mitotic failure as a precision oncology therapy;
ii.
our ability to design a PLK4 inhibitor with enhanced chemical properties, such as potency and selectivity, as determined both in vitro and in vivo; and
iii.
the frequent copy-gain or amplification of TRIM37 and other PCM dysfunction in pediatric neuroblastoma, and in adult solid tumors including breast, lung, uterine, bladder and other cancers.

 

We designed RP-1664 as an oral small molecule PLK4 inhibitor with high potency, selectivity, and bioavailability. RP-1664 has demonstrated strong, dose-dependent anti-tumor activity as monotherapy across preclinical models, both in internal models and in collaboration with CHOP. The LIONS clinical trial of RP-1664 in patients with molecularly selected advanced solid tumors dosed the first patient in February 2024 and is ongoing.

 

Preclinical Data

 

RP-1664 potently and selectively inhibits the kinase domain of PLK4. RP-1664 was shown to inhibit the enzyme with an IC50 of 1nM. Using a cellular target engagement assay, data shows that RP-1664 engages PLK4 with an IC50 of approximately 3nM. We observed less inhibition of other essential mitotic kinases, such as Aurora A and Aurora B, presenting an important selectivity window of over 2000-fold. We also observed that RP-1664 has a favorable ADME profile and safety pharmacology screen.

 

37


 

We tested RP-1664 in different in vivo models, including breast and non-small cell lung cancer CDX and PDX models. We saw a clear dose response with robust monotherapy activity ranging from stasis to regression in this set of models.

 

RP-1664 Monotherapy Activity Across PDX/CDX Models

https://cdn.kscope.io/b1da4b78003f62f54ff6e3a200263933-img193244649_23.jpg 

 

Through a collaboration with Children's Hospital of Philadelphia, we extended our findings demonstrating deep monotherapy regressions in two neuroblastoma CDX models. The collaboration includes testing in up to 16 CDX and PDX models. The first five of six models lead to deep and durable regressions out to six weeks or more of dosing. Further, we observed similar activity across a range of doses and continuous or intermittent schedules.

 

RP-1664 Monotherapy Regressions in 5 of 6 Neuroblastoma Models

https://cdn.kscope.io/b1da4b78003f62f54ff6e3a200263933-img193244649_24.jpg 

 

We also established a set of pharmacodynamic biomarkers downstream of PLK4 inhibition for clinical assessment. These key downstream biomarkers can be confirmed with clinical assays available for the Phase 1 LIONS trial, and include abnormal centrioles, abnormal mitoses, and the upregulation of p21.

 

38


 

Established Pharmacodynamic Biomarkers for Phase 1 LIONS Trial

 

https://cdn.kscope.io/b1da4b78003f62f54ff6e3a200263933-img193244649_25.jpg 

Design of Trial

In February 2024, we initiated our Phase 1 LIONS clinical trial of RP-1664 as a monotherapy and enrolled the first patient. The LIONS clinical trial is a multicenter, open-label Phase 1 study to investigate safety, pharmacokinetics, pharmacodynamics, and the preliminary efficacy of RP-1664. The clinical trial is expected to enroll approximately 80 patients with molecularly selected advanced solid tumors, including those with gain or amplification of TRIM37, among other genetic alterations. The primary endpoints are to determine the safety, tolerability, dose and schedule of RP-1664 and assess any early antitumor activity. During the dose escalation in adults or adolescents with recurrent solid tumors, we hope to efficiently achieve key dose and/or safety milestones in order to progress to the next step in development. We developed a pediatric formulation to facilitate dosing of smaller children and plan to investigate RP-1664 in children with recurrent neuroblastoma. We expect to expand our trial in adults with TRIM37-high status and additional biomarkers of sensitivity to PLK4 inhibition at the RP2D. These two investigations, carefully designed in collaboration with both medical and pediatric oncologists, will give early insights into both the highly biomarker-enriched neuroblastoma and the TRIM37 high adult tumor opportunities. We expect to provide further detail on RP-1664 development beyond the dose finding study later in 2024.

39


 

The designs of our Phase 1 clinical trial and future, prospective clinical trials are summarized in the diagram below.

RP-1664 Phase 1/2 Monotherapy Clinical Development Plan

https://cdn.kscope.io/b1da4b78003f62f54ff6e3a200263933-img193244649_26.jpg 

RP-3467, Our Polymerase Theta (Polθ) Adenosinetriphosphatase (ATPase) Inhibitor Preclinical Program

We are developing a small molecule inhibitor of Polθ ATPase, a SL target associated with BRCA mutations as well as other genomic alterations. This program was initially added to our portfolio through a collaboration with our co-founder, Dr. Agnel Sfeir, now at Memorial Sloan Kettering Cancer Center, who initially published her observations on the SL between BRCA and Polθ in Nature in 2016.

Polymerase theta enzyme (POLQ) is a DNA polymerase enzyme that participates in the repair of double-strand breaks in DNA. Mutations in genes such as BRCA1 and BRCA2 increase the frequency of these breaks, resulting in SL with Polθ. Preclinical studies have shown that inactivation of Polθ both on its own and in combination with PARP inhibitors reduces survival in BRCA-mutated cells, but not in BRCA wild-type cells. BRCA1 and BRCA2 mutations are routinely identified in multiple genetic profiling tests and observed in approximately 1% to 7% of patients with breast and ovarian cancer. However, the frequency of mutations in one of these BRCA genes increases in women with a family history of disease and in certain subpopulations. For example, up to 37% of patients with breast cancer with low estrogen and progesterone receptor expression have BRCA mutations.

Multiple genetic alterations causing homologous recombination deficiency, such as BRCA1 and BRCA2 mutations, have also been shown in clinical trials to be SL with PARP inhibitors in multiple tumors, such as breast and ovarian cancer. While PARP inhibitors have proven effective in BRCA-mutant tumors, no statistically significant survival benefit has been reported in breast or pancreatic cancer to date, highlighting the potential for other SL targets, such as Polθ, to demonstrate meaningful improvement of PARP inhibitor efficacy as a monotherapy or in combination with PARP inhibitors. In 2022, we selected a proposed inhibitor, which we designated as RP-2119, and initiated IND-enabling studies. In February 2023, based on our review of ongoing preclinical studies, we elected to prioritize other Polθ inhibiting compounds in our preclinical development portfolio, which we believe have a higher probability for clinical impact relative to RP-2119.

In November 2023, we revealed preclinical data for our lead Polθ ATPase inhibitor drug candidate, RP-3467. RP-3467 has demonstrated potential best-in-class activity with no signs of additive nor synergistic toxicity in the haematopoetic compartment when combined not only with PARP inhibitors, but importantly with RLT or chemotherapy, offering broad utility as a combination agent that improves outcomes of current therapeutic strategies.

40


 

Complete, sustained regressions in tested PDX models in combination with PARP inhibitors and compelling anti-tumor activity in combination with RLT and chemotherapy were observed in preclinical studies. We expect to initiate a Phase 1 clinical trial of RP-3467 in the second half of 2024.

 

RP-3467 Preclinical Data: Deep and Durable Complete Regressions
in Combination with a PARP Inhibitor and Well Tolerated

 

https://cdn.kscope.io/b1da4b78003f62f54ff6e3a200263933-img193244649_27.jpg 

Intellectual Property

We strive to protect and enhance the proprietary technologies, inventions, and improvements that we believe are important to our business, including seeking, maintaining, and defending patent rights, whether developed internally or licensed from third parties. Our policy is to seek to protect our proprietary position by, among other methods, pursuing and obtaining patent protection in the United States and in jurisdictions outside of the United States related to our proprietary technology, inventions, improvements, platforms, and our product candidates that are important to the development and implementation of our business.

As of December 31, 2023, our patent portfolio relating to our product candidates included six pending U.S. provisional patent applications, consisting of: three applications covering uses of ATR inhibitors; two applications covering uses of CCNE1-SL inhibitors; and one application covering PolQ inhibitors and their use. In addition, our patent portfolio included six pending international applications under the Patent Cooperation Treaty of 1970 (PCT); one covering camonsertib and/or its uses; one covering CCNE1-SL inhibitors, including lunresertib derivatives, and their uses; one covering the manufacture of CCNE1-SL inhibitors, including lunresterib; two covering PolQ inhibitors, including RP-3467, and their uses; and one covering PLK4 inhibitors, including RP-1664, and their uses. Our portfolio also included ten pending U.S. non-provisional patent applications, three having composition of matter claims covering ATR inhibitors, including camonsertib; three having method of treatment claims covering ATR inhibitors, including camonsertib; one having composition of matter claims covering lunresertib; and three having composition of matter claims covering CCNE1-SL inhibitors, including lunresertib derivatives, and their uses.

As of December 31, 2023, two of our six solely owned PCT applications have method of treatment and use claims covering camonsertib. Any application, if issued, claiming priority to either of these PCT applications is expected to expire in 2042, not including any patent term adjustment. Any patent issuing in our solely owned, pending U.S. non-provisional patent application having composition of matter and method of treatment and use claims covering camonsertib and its use is expected to expire in 2039, not including any patent term adjustment. Any patent issuing in our solely owned, pending U.S. non-provisional patent application having method of treatment and use claims covering certain uses of camonsertib is expected to expire in 2040, not including any patent term adjustment. Any U.S. patent, if issued, claiming priority to any one of the U.S. provisional patent applications covering uses of camonsertib is expected to expire in 2043.

As of December 31, 2023, one of our ten solely owned, pending U.S. non-provisional patent applications has a composition of matter claim covering lunresertib. Any patent issuing in this application is expected to expire in 2041,

41


 

not including any patent term adjustment. Three of our ten solely owned, pending U.S. non-provisional patent applications have composition of matter claims covering CCNE1-SL inhibitors. Any patent issuing in any of these applications would be expected to expire in 2042 or 2043, not accounting for any potentially favorable patent term adjustment. Any U.S. patent, if issued, claiming priority to the PCT application covering CCNE1-SL inhibitors, is expected to expire in 2043, not including any potentially favorable patent term adjustment. Any U.S. patent, if issued, claiming priority to any one of the U.S. provisional patent applications covering uses of CCNE1-SL inhibitors, including lunresertib, is expected to expire in 2044, not including any potentially favorable patent term adjustment. Any U.S. patent, if issued, claiming priority to the PCT application covering methods of making CCNE1-SL inhibitors, including lunresertib, is expected to expire in 2043, not including any potentially favorable patent term adjustment. Any U.S. patent, if issued, claiming priority to the either of the PCT applications covering PolQ inhibitors, including RP-3467, and their use is expected to expire in 2042, not including any potentially favorable patent term adjustment. Any U.S. patent, if issued, claiming priority to the U.S. provisional application covering PolQ inhibitors, including RP-3467, and their use is expected to expire in 2044, not including any potentially favorable patent term adjustment. Any U.S. patent, if issued, claiming priority to the PCT application covering PLK4 inhibitors, including RP-1664, and their use, is expected to expire in 2043, not including any potentially favorable patent term adjustment.

As of December 31, 2023, our patent portfolio also included two co-owned, pending U.S. non-provisional applications covering uses of CCNE1-SL inhibitors, including lunresertib. Any U.S. patent, if issued, claiming priority to the PCT applications is expected to expire in 2041 or 2042, respectively, not including any patent term adjustment.

Individual patents extend for varying periods depending on the date of filing of the patent application or the date of patent issuance and the legal term of patents in the countries in which they are obtained. Generally, patents issued for regularly filed applications in the United States are granted a term of 20 years from the earliest effective non-provisional filing date. In addition, in certain instances, a patent term can be extended to recapture a portion of the U.S. Patent and Trademark Office (USPTO) delay in issuing the patent as well as a portion of the term effectively lost as a result of the FDA regulatory review period. However, as to the FDA component, the restoration period cannot be longer than five years and the total patent term including the restoration period must not exceed 14 years following FDA approval. The duration of foreign patents varies in accordance with provisions of applicable local law, but typically is also 20 years from the earliest effective filing date. However, the actual protection afforded by a patent varies on a product-by-product basis, from country to country and depends upon many factors, including the type of patent, the scope of its coverage, the availability of regulatory-related extensions, the availability of legal remedies in a particular country and the validity and enforceability of the patent.

The PCT is an international patent law treaty that provides a unified procedure for filing patent applications to protect inventions in each of its contracting states. Thus, a single PCT application can be converted into a patent application in any of the PCT-contracting states, and is considered a simple, cost-effective means for seeking patent protection in numerous regions or countries. This nationalization (converting into an application in any of the contracting states) typically occurs 18 months after the PCT application filing date. An applicant must undertake prosecution within the allotted time in each of the contracting states or on a regional basis if it determines to undertake patent issuance in protection in such country or territory. Pursuant to its PCT application, the Company expects to pursue patent protection in the United States.

In addition, we rely upon trade secrets and know-how and continuing technological innovation to develop and maintain our competitive position. We seek to protect our proprietary information, in part, using confidentiality agreements with our collaborators, employees and consultants and invention assignment agreements with our employees. We also have confidentiality agreements or invention assignment agreements with our collaborators and consultants. These agreements are designed to protect our proprietary information and, in the case of the invention assignment agreements, to grant us ownership of technologies that are developed through a relationship with a third party. These agreements may be breached, and we may not have adequate remedies for any breach. In addition, our trade secrets may otherwise become known or be independently discovered by competitors. To the extent that our collaborators, employees, and consultants use intellectual property owned by others in their work for us, disputes may arise as to the rights in related or resulting know-how and inventions.

Our commercial success will also depend in part on not infringing upon the proprietary rights of third parties. It is uncertain whether the issuance of any third-party patent would require us to alter our development or commercial

42


 

strategies, or our product candidates or processes, obtain licenses or cease certain activities. Our breach of any license agreements or failure to obtain a license to proprietary rights that we may require to develop or commercialize our future product candidates may have an adverse impact on us. For more information, please see “Risk Factors—Risks Related to Intellectual Property.”

Collaborations and License Agreements

Collaboration and Worldwide License Agreement with Roche

In June 2022, we announced a worldwide license and collaboration agreement with Hoffmann-La Roche Inc. and F. Hoffmann-La Roche Ltd (collectively, Roche), or the Roche Agreement for the development and commercialization of camonsertib and specified other ATR inhibitors for the treatment of tumors with specific synthetic-lethal genomic alterations. Under the Roche Agreement, Roche assumed all subsequent development of camonsertib with the potential to expand development into additional tumor indications and multiple combination studies.

Under the terms of the Roche Agreement, we received a $125 million upfront payment in July 2022 and were eligible to receive up to $1.172 billion in potential clinical, regulatory, commercial and sales milestones, of which a $40 million milestone was received in the first quarter of 2024 upon dosing of the first patient in the camonsertib-based arm of the Roche TAPISTRY trial, as well as royalties on global net sales ranging from high-single-digits to high-teens. We received $5.6 million in October 2022 for the transfer of clinical trial material on hand to Roche, as agreed to pursuant to the Roche Agreement. In December 2022 and April 2023, we received additional payments of $4.0 million each, negotiated with Roche for revisions to the clinical development plan under the Roche Agreement. We further negotiated an additional payment of $4.0 million for revisions to the clinical development plan under the Roche Agreement, of which $2.1 million was recorded as collaboration revenue receivable at December 31, 2023. Since inception of the Roche camonsertib collaboration, we have earned a cumulative total of $182.6 million, including the upfront payment, the milestone payment, as well as additional reimbursements from Roche.

The Roche Agreement also provided our company with the ability to opt-in to a 50/50 U.S. co-development and profit share arrangement, including participation in U.S. co-promotion if U.S. regulatory approval was received, that was exercisable prior to the commencement of the first pivotal clinical trial of camonsertib. If we would have chosen to exercise the co-development and profit share option, we would have continued to be eligible to receive certain clinical, regulatory, commercial and sales milestone payments, in addition to full ex-U.S. royalties. Royalties were payable by Roche on a product by product and country by country basis until the later of 12 years following the first commercial sale of a licensed product in such country or the expiration of certain exclusivity rights.

The Roche Agreement was subsequently amended in October 2022 to extend the timeline to negotiate in good faith the parties’ rights and obligations with respect to certain clinical trials and to clarify indications included in the development plan that are subject to milestones.

On February 7, 2024, we received written notice from Roche of their election to terminate for convenience the Roche camonsertib collaboration. The termination will become effective in May 2024, at which time we will regain global development and commercialization rights for camonsertib from Roche.

Collaboration and License Agreement with Bristol-Myers Squibb Company

In May 2020, we entered into a collaboration and license agreement (the BMS Agreement), with Bristol-Myers Squibb Company (Bristol-Myers Squibb), pursuant to which we and Bristol-Myers Squibb agreed to collaborate in the research and development of potential new product candidates for the treatment of cancer.

We provided Bristol-Myers Squibb access to a selected number of our existing early SNIPRx screening campaigns and novel campaigns. We were responsible for carrying out early-stage research activities directed to identifying and validating potential targets for licensing by Bristol-Myers Squibb, in accordance with a mutually agreed upon research plan. The collaboration consisted of programs directed to both druggable targets and to targets commonly considered undruggable by traditional small molecule approaches. In the event that Bristol-Myers Squibb

43


 

elected to obtain an exclusive license for the subsequent development, manufacture and commercialization of a program, Bristol-Myers Squibb would then be solely responsible for all such worldwide activities. The research collaboration was overseen by a joint steering committee through completion of all research activities.

The BMS Agreement was subsequently amended in July, September and November 2020 to expand our collaboration with Bristol-Myers Squibb. We amended the BMS Agreement to, among other things: (i) include additional campaigns to the list of Existing Repare Campaigns (as such term is defined in the BMS Agreement) from which Bristol-Myers Squibb could select campaigns under the BMS agreement, and (ii) enable unblinding of a Bristol-Myers Squibb alliance manager in order to streamline the collaboration and selection process. The BMS Agreement was further amended in May 2023 to extend review periods for specified targets.

Under the terms of the BMS Agreement, Bristol-Myers Squibb paid us an initial upfront fee payment of $50.0 million. In connection with entering into the BMS Agreement, we also entered into a warrant agreement with an affiliate of Bristol-Myers Squibb pursuant to which we issued a warrant for total proceeds of $15.0 million, which was automatically exercised into 750,000 common shares upon closing of our IPO at which time the warrants were cancelled.

For each of the targets in the collaboration, we were entitled to receive, on a program-by-program basis, option exercise fees ranging in the low six figures depending on the nature of the applicable program. Bristol-Myers Squibb had the right to retain rights to certain back-up programs in exchange for a one-time payment in the low eight figures per program. Additionally, we were entitled to receive additional fees ranging in the low to mid seven figures upon the selection of certain programs beyond a specified limit.

In October 2021, we received notification from Bristol-Myers Squibb of their option exercise for two druggable targets directed at a single synthetic lethal lesion, pursuant to the terms of the BMS Agreement and in May 2023, they exercised their option for a druggable target directed at another synthetic lethal lesion. Bristol-Myers Squibb also triggered a further development election for one of its previously optioned druggable targets in May 2023.

Under the BMS Agreement, we are entitled to receive up to $3.0 billion in total milestones across all potential programs. Such milestones consist of $301.0 million in total milestones per program, including $176.0 million in the aggregate for certain specified research, development, and regulatory milestones and $125.0 million in the aggregate for certain specified commercial milestones. We are also entitled to a tiered percentage royalty on annual net sales ranging from high-single digits to low-double digits, subject to certain specified reductions. Royalties are payable by Bristol-Myers Squibb on a licensed product-by-licensed product and country-by-country basis until the later of the expiration of the last valid claim covering the licensed product in such country, expiration of all applicable regulatory exclusivities in such country for such licensed product and the tenth anniversary of the first commercial sale of such licensed product in such country.

On a program-by-program basis, prior to the earlier of such program ceasing to be included under the BMS Agreement and expiration of the last to expire royalty term for such program, we, alone and with third parties, are prohibited from researching, developing, manufacturing and commercializing products that are directed to the applicable target for such program.

We also have provided Bristol-Myers Squibb with certain, limited rights to first negotiate with us if we determine to divest, license, or collaborate with others regarding certain existing programs, including if we received an unsolicited offer to do so. The right to first negotiation expressly excludes any potential Change of Control transaction (as such term is contractually defined in the BMS Agreement).

The BMS Agreement will expire on a licensed product-by-licensed product and country-by-country basis on expiration of the applicable royalty term and in its entirety upon expiration of the last royalty term. Either party may terminate the BMS Agreement earlier upon an uncured material breach of the agreement by the other party, or the insolvency of the other party. Additionally, Bristol-Myers Squibb may terminate the BMS Agreement for any or no

44


 

reason on a program-by-program basis upon specified written notice. We completed the discovery portion of the BMS Agreement in November 2023.

Research Services, License and Collaboration Agreement with Ono Pharmaceutical Co.

All payments by Ono to us are presented in U.S. dollars. Future payments as disclosed in this summary have been converted to U.S. dollars at the December 31, 2023 exchange rate of $1.00 = [140.85] Japanese yen.

In January 2019, we entered into a research services, license and collaboration agreement (the Ono Agreement) with Ono Pharmaceutical Co., Ltd. (Ono), pursuant to which we and Ono agreed to collaborate in the research of potential product candidates targeting Polθ and the development of our small molecule Polθ ATPase inhibitor program. We were primarily responsible for carrying out research activities to identify a product candidate for the program, to be licensed to Ono, in accordance with a mutually agreed upon research plan until the first submission of an IND in the United States or Japan. In the event that Ono elected to collaborate on the subsequent development and commercialization of a proposed product candidate, Ono would then be responsible for such activities in Japan, South Korea, Taiwan, Hong Kong, Macau and certain other Southeast Asian countries, and we would be responsible for such activities in the rest of the world. The collaboration was overseen by a joint research committee through development candidate selection and a joint steering committee thereafter. Except as set forth below, each party bore its own expenses in connection with research, development, and commercialization activities under the Ono Agreement.

In October 2021, we entered into an amendment to the Ono Agreement whereby the Research Term, as defined in the Ono Agreement, was extended by one year at no additional cost to us. In January 2023, we and Ono entered into a second amendment to the Ono Agreement whereby the Research Term was extended until July 31, 2023. The Ono Agreement expired in July 2023, thereby returning our Polθ ATPase inhibitor program, RP-3467, to be wholly-owned by us.

Under the terms of the Ono Agreement, Ono paid us an initial upfront fee payment of ¥110 million (approximately $1.0 million). Additionally, in connection with the research activities to be conducted by us pursuant to the Ono Agreement, Ono paid us an initial upfront research service payment of ¥790 million (approximately $7.1 million) and agreed to make research service payments up to an aggregate of ¥750 million (approximately $5.3 million) upon (i) certain specified research triggers and (ii) the election by Ono to collaborate on the development and commercialization of a proposed product candidate. In October 2021 and December 2022, the Company achieved specified research triggers amounting to ¥100 million ($0.9 million) and ¥200 million ($1.5 million), respectively, as research service payments provided for in the Ono Agreement. Upon election by Ono to collaborate on a proposed product candidate, Ono would have been responsible for a specified percentage of research and development costs for the IND-enabling studies of the selected product candidate.

Under the Ono Agreement, we were also entitled to receive up to ¥5.11 billion (approximately $36.3 million) in the aggregate for certain specified development and regulatory milestones, ¥12.1 billion (approximately $85.9 million) in the aggregate for certain specified commercial milestones and a tiered percentage royalty on annual net sales in Ono’s territory ranging from high-single digits to low teens, subject to certain specified reductions. Royalties were payable by Ono on a licensed product-by-licensed product and country-by-country basis until the later of the expiration of the last valid claim covering the licensed product in such country and the tenth anniversary of the first commercial sale of such licensed product in such country.

License Agreement with New York University

In December 2016, we entered into a license agreement with New York University pursuant to which we obtained a worldwide, royalty-bearing, exclusive license under certain current and/or future patents and know-how of New York University to research, develop and commercialize products that are covered by such licensed patents or otherwise modulate Polθ. Upon initial entry into the license agreement, we issued New York University 60,211 common shares in December 2016 as consideration for the license.

In July 2018, we subsequently amended and restated our license agreement with NYU, which we refer to, as amended and restated, as the NYU Agreement. Pursuant to the terms of the NYU Agreement, we are obligated to use

45


 

reasonable diligence in connection with the research, development, and commercialization of the licensed products (as such term is defined in the NYU Agreement), including specified minimum annual spends on research and development.

Under the terms of the NYU Agreement, we are obligated to pay New York University annual license maintenance fees in the low five figures that are creditable against any milestone payments payable in such year. Additionally, in connection with development, regulatory and commercial activities, we have agreed to make milestone payments of (i) $2.6 million in the aggregate for a product covered by a licensed patent that achieves specified development and sales milestones for the first indication, (ii) $1.3 million in the aggregate for a product covered by a licensed patent that achieves specified development and sales milestones for a second indication, (iii) $575,000 in the aggregate for a product covered by a licensed patent that achieves specified development and sales milestones for each of a third and fourth indication, (iv) $1.3 million in the aggregate for a product that is not covered by a licensed patent that achieves specified development and sales milestones for the first indication, (v) $650,000 in the aggregate for a product that is not covered by a licensed patent that achieves specified development and sales milestones for a second indication, (vi) $287,500 in the aggregate for a product that is not covered by a licensed patent that achieves specified development and sales milestones for each of a third and fourth indication. We have the right to reduce these milestone payments by a specified amount of any milestones payable to a third party for a license required for the commercialization of a product candidate.

We are also obligated to pay New York University a low single digit royalty on net sales of any product covered by a licensed patent and a lower single digit royalty on net sales of any product that is not covered by a licensed patent, in each case subject to reduction by a specified amount of any royalties payable to a third party for a license to unblocking intellectual property. Moreover, we are obligated to pay New York University a percentage of any non-royalty consideration received by us from a sublicensee ranging in the low double digits.

The Ono Agreement was considered a sublicensee under the terms of the NYU Agreement. Accordingly, we have paid New York University a specified percentage of the approximately $1.0 million initial upfront fee payment we received from Ono.

Upon the expected initiation of a Phase 1 clinical trial of RP-3467 in the second half of 2024, a milestone payment of $0.1 million to New York University would be triggered under the terms of the NYU Agreement.

Payments in respect of net sales or sublicense in a country shall remain in force on a product-by-product, country-by-country basis, with respect to (i) products that are not covered by a licensed patent, for ten years from the date of first commercial sale in such country and (ii) products that are covered by a licensed patent, until the expiration date of the last to expire of the licensed patents covering such product or its manufacture or use in the applicable country.

The NYU Agreement expires on the date of expiration of all royalty obligations. Either party may terminate the NYU Agreement earlier upon an uncured material breach of NYU Agreement by the other party or the insolvency of the other party.

Sales and Marketing

Given our stage of development, we have not yet established a commercial organization or distribution capabilities. We have established a wholly-owned U.S. subsidiary, Repare Therapeutics USA Inc., a Delaware corporation with operations in Cambridge, Massachusetts, to support our clinical development program and our potential commercialization efforts in the United States.

Manufacturing

We currently rely, and expect to continue to rely for the foreseeable future, on third-party contract manufacturing organizations (CMOs) to produce our product candidates for preclinical and clinical testing, as well as for future commercial manufacture of any products that we may commercialize.

46


 

We require all of our CMOs to conduct manufacturing activities in compliance with current good manufacturing practice (cGMP) requirements. We have assembled a team of experienced employees and consultants to provide the necessary technical, quality, and regulatory oversight over our CMOs. Currently, we have manufacturing and supply agreements with our CMOs for the manufacture of lunresertib, RP-1664, and our preclinical candidates, including the synthesis of the active pharmaceutical ingredient (API), as well as drug product.

All of our product candidates are small molecules and are manufactured in synthetic processes from available starting materials. The chemistry underlying our product candidates appears amenable to scale up and does not currently require unusual equipment in the manufacturing process. We expect to continue to develop product candidates that can be produced cost-effectively at contract manufacturing facilities.

We plan to continue to rely on third-party manufacturers for any future trials and commercialization of lunresertib, camonsertib, RP-1664 and any future product candidates, if approved. We anticipate that these CMOs will have capacity to support commercial scale production, but we do not have any formal agreements in place at this time given our early stages of development. If needed, we believe we can identify and establish additional CMOs to provide API and finished drug product without significant disruption to our business or clinical development timelines.

Competition

The biotechnology and pharmaceutical industries are characterized by the rapid evolution of technologies and understanding of disease etiology, intense competition, and a strong emphasis on intellectual property. We believe that our approach, strategy, scientific capabilities, know-how and experience provide us with competitive advantages. However, we expect substantial competition from multiple sources, including major pharmaceutical, specialty pharmaceutical, and existing or emerging biotechnology companies, academic research institutions and governmental agencies and public and private research institutions worldwide. Many of our competitors, either alone or with their collaborations, have significantly greater financial resources and expertise in research and development, manufacturing, preclinical testing, conducting clinical trials, obtaining regulatory approvals, and marketing approved products than we do. Smaller or early-stage companies may also prove to be significant competitors, particularly through collaborative arrangements with large and established companies. These competitors also compete with us in recruiting and retaining qualified scientific and management personnel and establishing clinical trial sites and patient enrollment in clinical trials, as well as in acquiring technologies complementary to, or necessary for, our programs. As a result, our competitors may discover, develop, license, or commercialize products before or more successfully than we do.

We face competition from segments of the pharmaceutical, biotechnology and other related markets that pursue the development of precision oncology therapies for patients with genetically-defined cancers. Several biopharmaceutical companies, including Loxo Oncology, Inc. (part of Eli Lilly and Company), Blueprint Medicines Corporation, SpringWorks Therapeutics, Inc., Black Diamond Therapeutics, Inc., Deciphera Pharmaceuticals, Inc., Tango Therapeutics, Inc., Zentalis Pharmaceuticals, Inc., Turning Point Therapeutics, Inc. (acquired by Bristol-Myers Squibb), and Exelixis, Inc. are developing precision oncology medicines. In addition, we may face competition from companies developing product candidates that are based on SL, including AstraZeneca, GlaxoSmithKline, Pfizer, Bayer, Merck Serono, Schrodinger, Inc., Exelixis, Inc., Artios Pharma Ltd., IDEAYA Biosciences, Inc, Impact Therapeutics, Aprea Therapeutics, Shanghai De Novo Pharmatech, Tide Pharmaceutical, Acrivon Therapeutics, Biocity Biopharma, Oric Pharmaceuticals, Schrodinger, Treadwell Therapeutics, Varsity Pharma, Breakpoint Therapeutics, Rhizen Pharmaceuticals AG, Simcere Pharmaceutical, and Shouyao Holdings.

Furthermore, we also face competition more broadly across the oncology market for cost-effective and reimbursable cancer treatments. The most common methods of treating patients with cancer are surgery, radiation, and drug therapy, including chemotherapy, hormone therapy, biologic therapy, such as monoclonal and bispecific antibodies, immunotherapy, cell-based therapy and targeted therapy, or a combination of any such methods. There are a variety of available drug therapies marketed for cancer. In many cases, these drugs are administered in combination to enhance efficacy. While our product candidates, if any are approved, may compete with these existing drugs and other therapies, to the extent they are ultimately used in combination with or as an adjunct to these therapies, our product candidates may not be competitive with them. Some of these drugs are branded and subject to patent protection, and others are available on a generic basis. Insurers and other third-party payors may also encourage the use of generic products or specific branded products. As a result, obtaining market acceptance of, and gaining

47


 

significant share of the market for, any of our product candidates that we successfully introduce to the market may pose challenges. In addition, many companies are developing new oncology therapeutics, and we cannot predict what the standard of care will be as our product candidates progress through clinical development.

With respect to our initial product candidate, camonsertib, several companies are developing ATR inhibitors with multiple monotherapy and/or combination trials ongoing, including AstraZeneca (AZD6738), Bayer (BAY1895344), Merck Serono (M4344, M6620, M1774) and most recently, Artios Pharma (ATR0380), Aprea Therapeutics/Atrin Pharmaceuticals (ATRN-119), Biocity Biopharmaceutics (SC0245), Impact Therapeutics (IMP9064), Shanghai De Novo Pharmatech (DN020198), and Tide Pharmaceutical. The intensity of trials with ATR inhibitors as monotherapy and in combination with immune-oncology compounds, chemotherapy and radiation, as well as other DDR inhibitors significantly increased over the last several years.

With respect to our PKMYT1 inhibitor product candidate, lunresertib, while we are not aware of any other clinical-stage PKMYT1 inhibitors, Acrivon Therapeutics, Exelixis, Inc, Schrodinger, and Psivant have disclosed PKMYT1 inhibitor programs in preclinical development.

With respect to our PLK4 inhibitor product candidate, RP-1664, Exelixis, Inc. and Oric Pharmaceuticals have disclosed PLK4 inhibitor programs in early preclinical development, and Treadwell Therapeutics has a non-selective PLK4 inhibitor program in the clinic.

For our preclinical Polθ ATPase inhibitor program, RP-3467, Artios Pharma, IDEAYA Biosciences (in collaboration with GlaxoSmithKline plc), Varsity Pharma, Breakpoint Therapeutics, Rhizen Pharmaceuticals AG, and Simcere Pharmaceutical have Polθ programs in various stages of clinical and preclinical development.

We could see a reduction or elimination in our commercial opportunity if our competitors develop and commercialize drugs that are safer, more effective, have fewer or less severe side effects, are more convenient to administer, are less expensive or with a more favorable label than our product candidates. Our competitors also may compete for available patient pool, slowing our accrual in trials, obtain FDA or other regulatory approval for their drugs more rapidly than we may obtain approval for ours, which could result in our competitors establishing a strong market position before we are able to enter the market. The key competitive factors affecting the success of all of our product candidates, if approved, are likely to be their efficacy, safety, convenience, price, the level of generic competition and the availability of reimbursement from government and other third-party payors.

Government Regulation

The FDA and comparable regulatory agencies in state and local jurisdictions and in foreign countries impose substantial requirements upon the clinical development, manufacture, and marketing of pharmaceutical products. These agencies and other federal, state, and local entities regulate research and development activities and the testing, manufacture, quality control, safety, effectiveness, labeling, storage, packaging, recordkeeping, tracking, approval, import, export, distribution, advertising, and promotion of our products.

U.S. Government Regulation of Drug Products

In the United States, the FDA regulates drugs under the Federal Food, Drug, and Cosmetic Act (FDCA), and its implementing regulations. The process of obtaining regulatory approvals and the subsequent compliance with applicable federal, state, local and foreign statutes and regulations requires the expenditure of substantial time and financial resources. Failure to comply with the applicable U.S. requirements at any time during the product development process, approval process or after approval, may subject an applicant to a variety of administrative or judicial sanctions, such as the FDA’s refusal to approve a pending New Drug Application (NDA), withdrawal of an approval, imposition of a clinical hold, issuance of warning letters, product recalls, product seizures, total or partial suspension of production or distribution, injunctions, fines, refusals of government contracts, restitution, disgorgement or civil or criminal penalties.

48


 

The process required by the FDA before product candidates may be marketed in the United States generally involves the following:

nonclinical laboratory and animal tests that must be conducted in accordance with good laboratory practices (GLPs);
submission to the FDA of an investigational new drug application (IND), which must become effective before clinical trials may begin;
approval by an independent institutional review board (IRB) for each clinical site or centrally before each trial may be initiated;
adequate and well-controlled human clinical trials to establish the safety and efficacy of the proposed product candidate for its intended use, performed in accordance with good clinical practices (GCPs);
submission to the FDA of an NDA and payment of user fees;
satisfactory completion of an FDA advisory committee review, if applicable;
pre-approval inspection of manufacturing facilities and selected clinical investigators for their compliance with cGMP and GCPs;
satisfactory completion of FDA audits of clinical trial sites to assure compliance with GCPs and the integrity of the clinical data;
FDA review and approval of an NDA to permit commercial marketing for particular indications for use; and
compliance with any post-approval requirements, including the potential requirement to implement a Risk Evaluation and Mitigation Strategy (REMS), and the potential requirement to conduct post-approval studies.

The testing and approval process requires substantial time, effort, and financial resources.

Preclinical Studies

Preclinical studies include laboratory evaluation of drug substance chemistry, pharmacology, toxicity, and drug product formulation, as well as animal studies to assess potential safety and efficacy. Prior to commencing the first clinical trial with a product candidate, a sponsor must submit the results of the preclinical tests and preclinical literature, together with manufacturing information, analytical data and any available clinical data or literature, among other required information, to the FDA as part of an IND. Some preclinical studies may continue even after the IND is submitted. The IND automatically becomes effective 30 days after receipt by the FDA, unless the FDA, within the 30-day time period, raises safety concerns or questions about the conduct of the clinical trial and imposes a clinical hold. In such a case, the IND sponsor and the FDA must resolve any outstanding concerns before the clinical trial can begin. As a result, submission of an IND may not result in FDA authorization to commence a clinical trial.

Clinical Trials

Clinical trials involve the administration of the investigational new drug to human subjects under the supervision of qualified investigators in accordance with GCP requirements. A separate submission to the existing IND must be made for each successive clinical trial conducted during product development, as well as amendments to previously submitted clinical trials. Further, an independent IRB for each institution participating in the clinical trial must review and approve the plan for any clinical trial, its informed consent form, and other communications to study subjects before the clinical trial commences at that site. The IRB must continue to oversee the clinical trial while it is being conducted, including any changes to the study plans.

Regulatory authorities, an IRB or the sponsor may suspend or discontinue a clinical trial at any time on various grounds, including a finding that the subjects are being exposed to an unacceptable health risk, the clinical trial is not being conducted in accordance with the FDA’s or the IRB’s requirements, or if the drug has been associated with unexpected serious harm to subjects. Some studies also include a data safety monitoring board, which receives special

49


 

access to unblinded data during the clinical trial and may advise the sponsor to halt the clinical trial if it determines that there is an unacceptable safety risk for subjects or other grounds, such as no demonstration of efficacy.

In general, for purposes of NDA approval, human clinical trials are typically conducted in three sequential phases that may overlap.

Phase 1—Studies are initially conducted to test the product candidate for safety, dosage tolerance, structure-activity relationships, mechanism of action, absorption, metabolism, distribution and excretion in healthy volunteers or subjects with the target disease or condition. If possible, Phase 1 clinical trials may also be used to gain an initial indication of product effectiveness.
Phase 2—Controlled studies are conducted with groups of subjects with a specified disease or condition to provide enough data to evaluate the preliminary efficacy, optimal dosages and dosing schedule and expanded evidence of safety. Multiple Phase 2 clinical trials may be conducted to obtain information prior to beginning larger and more expansive Phase 3 clinical trials.
Phase 3—These clinical trials are generally undertaken in larger subject populations to provide statistically significant evidence of clinical efficacy and to further test for safety in an expanded subject population at multiple clinical trial sites. These clinical trials are intended to establish the overall risk/benefit ratio of the product and provide an adequate basis for product labeling. These clinical trials may be done at trial sites outside the United States as long as the global sites are also representative of the U.S. population and the conduct of the study at global sites comports with FDA regulations and guidance, such as compliance with GCPs.

The FDA may require, or companies may pursue, additional clinical trials after a product is approved. These so-called Phase 4 studies may be made a condition to be satisfied after approval. The results of Phase 4 studies can confirm the effectiveness of a product candidate and can provide important safety information.

Clinical trials must be conducted under the supervision of qualified investigators in accordance with GCP requirements, which include the requirements that all research subjects provide their informed consent in writing for their participation in any clinical trial, and the review and approval of the study by an IRB. Investigators must also provide information to the clinical trial sponsors to allow the sponsors to make specified financial disclosures to the FDA. Clinical trials are conducted under protocols detailing, among other things, the objectives of the trial, the trial procedures, the parameters to be used in monitoring safety and the efficacy criteria to be evaluated and a statistical analysis plan. Information about some clinical trials, including a description of the trial and trial results, must be submitted within specific timeframes to the National Institutes of Health for public dissemination on their ClinicalTrials.gov website. Progress reports detailing the results of the clinical trials must be submitted at least annually to the FDA and more frequently if serious adverse events occur.

The manufacture of investigational drugs for the conduct of human clinical trials is subject to cGMP requirements. Investigational drugs and active pharmaceutical ingredients imported into the United States are also subject to regulation by the FDA relating to their labeling and distribution. Further, the export of investigational drug products outside of the United States is subject to regulatory requirements of the receiving country as well as U.S. export requirements under the FDCA. Progress reports detailing the results of the clinical trials must be submitted at least annually to the FDA and the IRB and more frequently if serious adverse effects occur.

Concurrent with clinical trials, companies usually complete additional animal studies and must also develop additional information about the chemistry and physical characteristics of the product candidate as well as finalize a process for manufacturing the product in commercial quantities in accordance with cGMP requirements. The manufacturing process must be capable of consistently producing quality batches of the product candidate and, among other things, must develop methods for testing the identity, strength, quality, and purity of the final product. Additionally, appropriate packaging must be selected and tested, and stability studies must be conducted to demonstrate that the product candidate does not undergo unacceptable deterioration over its shelf life.

50


 

Special FDA Expedited Review and Approval Programs

The FDA has various programs, including fast track designation, breakthrough therapy designation, accelerated approval, and priority review, which are intended to expedite or simplify the process for the development and FDA review of drugs that are intended for the treatment of serious or life-threatening diseases or conditions and demonstrate the potential to address unmet medical needs. The purpose of these programs is to provide important new drugs to patients earlier than under standard FDA review procedures.

Under the fast track program, the sponsor of a new drug candidate may request that FDA designate the drug candidate for a specific indication as a fast track drug concurrent with, or after, the filing of the IND for the drug candidate. To be eligible for a fast track designation, the FDA must determine, based on the request of a sponsor, that a product is intended to treat a serious or life threatening disease or condition and demonstrates the potential to address an unmet medical need. The FDA will determine that a product will fill an unmet medical need if it will provide a therapy where none exists or provide a therapy that may be potentially superior to existing therapy based on efficacy or safety factors. Fast track designation provides additional opportunities for interaction with the FDA’s review team and may allow for rolling review of NDA components before the completed application is submitted, if the sponsor provides a schedule for the submission of the sections of the NDA, the FDA agrees to accept sections of the NDA and determines that the schedule is acceptable, and the sponsor pays any required user fees upon submission of the first section of the NDA. However, the FDA’s time period goal for reviewing an application does not begin until the last section of the NDA is submitted. The FDA may decide to rescind the fast track designation if it determines that the qualifying criteria no longer apply.

In addition, a sponsor can request breakthrough therapy designation for a drug if it is intended, alone or in combination with one or more other drugs, to treat a serious or life-threatening disease or condition, and preliminary clinical evidence indicates that the drug may demonstrate substantial improvement over existing therapies on one or more clinically significant endpoints, such as substantial treatment effects observed early in clinical development. Drugs designated as breakthrough therapies are eligible for intensive guidance from the FDA on an efficient drug development program, organizational commitment to the development and review of the product including involvement of senior managers, and, like fast track products, are also eligible for rolling review of the NDA. Both fast track and breakthrough therapy products may be eligible for accelerated approval and/or priority review, if relevant criteria are met.

Under the FDA’s accelerated approval regulations, the FDA may approve a drug for a serious or life threatening illness that provides meaningful therapeutic benefit to patients over existing treatments based upon a surrogate endpoint that is reasonably likely to predict clinical benefit, or on a clinical endpoint that can be measured earlier than irreversible morbidity or mortality, that is reasonably likely to predict an effect on irreversible morbidity or mortality or other clinical benefit, taking into account the severity, rarity, or prevalence of the condition and the availability or lack of alternative treatments. A drug candidate approved on this basis is subject to rigorous post marketing compliance requirements, including the completion of Phase 4 or post approval clinical trials to confirm the effect on the clinical endpoint. Failure to conduct required post approval studies and regularly update FDA on their progress, or confirm a clinical benefit during post marketing studies, will allow the FDA to withdraw the drug from the market on an expedited basis. All promotional materials for drug candidates approved under accelerated approval regulations are subject to prior review by the FDA.

Once an NDA is submitted for a product intended to treat a serious condition, the FDA may assign a priority review designation if FDA determines that the product, if approved, would provide a significant improvement in safety or effectiveness. A priority review means that the goal for the FDA to review an application is six months, rather than the standard review of ten months under the Prescription Drug User Fee Act (PDUFA) guidelines. Under the current PDUFA performance goals, these six and ten month review periods are measured from the 60-day filing date rather than the receipt date for NDAs for new molecular entities, which typically adds approximately two months to the timeline for review from the date of submission.

Even if a product qualifies for one or more of these programs, the FDA may later decide that the product no longer meets the conditions for qualification or decide that the time period for FDA review or approval will not be shortened. In addition, the manufacturer of an investigational drug for a serious or life-threatening disease is required to make available, such as by posting on its website, its policy on responding to requests for expanded access.

51


 

Furthermore, fast track designation, breakthrough therapy designation, accelerated approval and priority review do not change the standards for approval and may not ultimately expedite the development or approval process.

NDA Submission and Review by the FDA

Assuming successful completion of the required clinical and preclinical testing, among other items, the results of product development, including chemistry, manufacture and controls, nonclinical studies and clinical trials are submitted to the FDA, along with proposed labeling, as part of an NDA. The submission of an NDA requires payment of a substantial user fee to the FDA. These user fees must be filed at the time of the first submission of the application, even if the application is being submitted on a rolling basis. Fee waivers or reductions are available in some circumstances.

In addition, under the Pediatric Research Equity Act, an NDA or supplement to an NDA for a new active ingredient, indication, dosage form, dosage regimen or route of administration must contain data that are adequate to assess the safety and efficacy of the drug for the claimed indications in all relevant pediatric subpopulations, and to support dosing and administration for each pediatric subpopulation for which the product is safe and effective.

The FDA may, on its own initiative or at the request of the applicant, grant deferrals for submission of some or all pediatric data until after approval of the product for use in adults or full or partial waivers from the pediatric data requirements.

The FDA must refer applications for drugs that contain active ingredients, including any ester or salt of the active ingredients, that have not previously been approved by the FDA to an advisory committee or provide in an action letter a summary of the reasons for not referring it to an advisory committee. The FDA may also refer drugs which present difficult questions of safety, purity, or potency to an advisory committee. An advisory committee is typically a panel that includes clinicians and other experts who review, evaluate, and make a recommendation as to whether the application should be approved and under what conditions. The FDA is not bound by the recommendations of an advisory committee, but it considers such recommendations carefully when making decisions.

The FDA reviews applications to determine, among other things, whether a product is safe and effective for its intended use and whether the manufacturing controls are adequate to assure and preserve the product’s identity, strength, quality and purity. Before approving an NDA, the FDA will inspect the facility or facilities where the product is manufactured. The FDA will not approve an application unless it determines that the manufacturing processes and facilities, including contract manufacturers and subcontracts, are in compliance with cGMP requirements and adequate to assure consistent production of the product within required specifications. Additionally, before approving an NDA, the FDA will typically inspect one or more clinical trial sites to assure compliance with GCPs.

Once the FDA receives an application, it has 60 days to review the NDA to determine if it is substantially complete to permit a substantive review, before it accepts the application for filing. Once the submission is accepted for filing, the FDA begins an in-depth review of the NDA. Under the goals and policies agreed to by the FDA under PDUFA, the FDA has set the review goal of 10 months from the 60-day filing date to complete its initial review of a standard NDA for a new molecular entity (NME), and make a decision on the application. For priority review applications, the FDA has set the review goal of reviewing NME NDAs within six months of the 60-day filing date. Such deadlines are referred to as the PDUFA date. The PDUFA date is only a goal and the FDA does not always meet its PDUFA dates. The review process and the PDUFA date may also be extended if the FDA requests or the NDA sponsor otherwise provides additional information or clarification regarding the submission during the review period that amends the original application.

Once the FDA’s review of the application is complete, the FDA will issue either a Complete Response Letter (CRL) or approval letter. A CRL indicates that the review cycle of the application is complete, and the application is not ready for approval. A CRL generally contains a statement of specific conditions that must be met in order to secure final approval of the NDA and may require additional clinical or preclinical testing, or other information or analyses in order for the FDA to reconsider the application in the future. Even with the submission of additional information, the FDA ultimately may decide that the application does not satisfy the regulatory criteria for approval. If and when those conditions have been met to the FDA’s satisfaction, the FDA may issue an approval letter. An approval letter authorizes commercial marketing of the drug with specific prescribing information for specific indications.

52


 

The FDA may delay or refuse approval of an NDA if applicable regulatory criteria are not satisfied, require additional testing or information and/or require post-marketing testing and surveillance to monitor safety or efficacy of a product, or impose other conditions, including distribution restrictions or other risk management mechanisms. For example, the FDA may require a REMS as a condition of approval or following approval to mitigate any identified or suspected serious risks and ensure safe use of the drug. The FDA may prevent or limit further marketing of a product, or impose additional post-marketing requirements, based on the results of post-marketing studies or surveillance programs. After approval, some types of changes to the approved product, such as adding new indications, manufacturing changes and additional labeling claims, are subject to further testing requirements, FDA notification and FDA review and approval. Further, should new safety information arise, additional testing, product labeling or FDA notification may be required.

If regulatory approval of a product is granted, such approval may entail limitations on the indicated uses for which such product may be marketed or may include contraindications, warnings, or precautions in the product labeling, which has resulted in a boxed warning. A boxed warning is the strictest warning put in the labeling of prescription drugs or drug products by the FDA when there is reasonable evidence of an association of a serious hazard with the drug. The FDA also may not approve the inclusion of all labeling claims sought by an applicant. Once approved, the FDA may withdraw the product approval if compliance with pre- and post-marketing regulatory standards is not maintained or if problems occur after the product reaches the marketplace. In addition, the FDA may require Phase 4 post-marketing studies to monitor the effect of approved products and may limit further marketing of the product based on the results of these post-marketing studies.

U.S. Post-Approval Requirements

Any products manufactured or distributed by us pursuant to FDA approvals are subject to continuing regulation by the FDA, including periodic reporting, product sampling and distribution, advertising, promotion, drug shortage reporting, compliance with any post-approval requirements imposed as a conditional of approval such as Phase 4 clinical trials, REMS and surveillance, recordkeeping and reporting requirements, including adverse experiences.

After approval, most changes to the approved product, such as adding new indications or other labeling claims are subject to prior FDA review and approval. There also are continuing, annual program fee requirements for approved products, as well as new application fees for supplemental applications with clinical data. Drug manufacturers and their subcontractors are required to register their establishments with the FDA and certain state agencies and to list their drug products and are subject to periodic announced and unannounced inspections by the FDA and these state agencies for compliance with cGMPs and other requirements, which impose procedural and documentation requirements.

Changes to the manufacturing process are strictly regulated and often require prior FDA approval before being implemented, or FDA notification. FDA regulations also require investigation and correction of any deviations from cGMPs and specifications and impose reporting and documentation requirements upon the sponsor and any third-party manufacturers that the sponsor may decide to use. Accordingly, manufacturers must continue to expend time, money, and effort in the area of production and quality control to maintain cGMP compliance.

Later discovery of previously unknown problems with a product, including adverse events of unanticipated severity or frequency, or with manufacturing processes, or failure to comply with regulatory requirements, may result in withdrawal of marketing approval, mandatory revisions to the approved labeling to add new safety information or other limitations, imposition of post-market studies or clinical trials to assess new safety risks, or imposition of distribution or other restrictions under a REMS program, among other consequences.

The FDA closely regulates the marketing and promotion of drugs. A company can make only those claims relating to safety and efficacy that are consistent with the FDA approved labeling. Physicians, in their independent professional medical judgement, may prescribe legally available products for uses that are not described in the product’s labeling and that differ from those tested by us and approved by the FDA. However, manufacturers and third parties acting on their behalf are prohibited from marketing or promoting drugs in a manner inconsistent with the approved labeling. The FDA and other agencies actively enforce the laws and regulations prohibiting the promotion of off-label uses and a company that is found to have improperly promoted off-label uses may be subject to significant liability.

53


 

Failure to comply with any of the FDA’s requirements could result in significant adverse enforcement actions. These include a variety of administrative or judicial sanctions, such as refusal to approve pending applications, license suspension or revocation, withdrawal of an approval, imposition of a clinical hold or termination of clinical trials, warning letters, untitled letters, modification of promotional materials or labeling, product recalls, product seizures or detentions, refusal to allow imports or exports, total or partial suspension of production or distribution, debarment, injunctions, fines, consent decrees, corporate integrity agreements, refusals of government contracts and new orders under existing contracts, exclusion from participation in federal and state healthcare programs, restitution, disgorgement or civil or criminal penalties, including fines and imprisonment. It is also possible that failure to comply with the FDA’s requirements relating to the promotion of prescription drugs may lead to investigations alleging violations of federal and state healthcare fraud and abuse and other laws, as well as state consumer protection laws. Any of these sanctions could result in adverse publicity, among other adverse consequences.

U.S. Marketing Exclusivity

The FDA provides periods of non-patent regulatory exclusivity, which provides the holder of an approved NDA limited protection from new competition in the marketplace for the innovation represented by its approved drug for a period of three or five years following the FDA’s approval of the NDA. Five years of exclusivity are available to new chemical entities (NCEs). An NCE is a drug that contains no active moiety that has been approved by the FDA in any other NDA. An active moiety is the molecule or ion, excluding those appended portions of the molecule that cause the drug to be an ester, salt, including a salt with hydrogen or coordination bonds, or other noncovalent, or not involving the sharing of electron pairs between atoms, derivatives, such as a complex (i.e., formed by the chemical interaction of two compounds), chelate (i.e., a chemical compound), or clathrate (i.e., a polymer framework that traps molecules), of the molecule, responsible for the therapeutic activity of the drug substance. During the exclusivity period, the FDA may not accept for review or approve an Abbreviated New Drug Application (ANDA) a 505(b)(2) NDA submitted by another company that contains the previously approved active moiety. An ANDA or 505(b)(2) application, however, may be submitted one year before NCE exclusivity expires if a Paragraph IV certification is filed.

Regulation outside the United States

We will be subject to similar foreign laws and regulations concerning the development of our product candidates outside of the United States.

Other Healthcare Laws and Regulations

Our business activities, including but not limited to, research, sales, promotion, distribution, medical education and other activities are subject to regulation by numerous regulatory and law enforcement authorities in the United States in addition to the FDA, including the Department of Justice, the Department of Health and Human Services (HHS) and its various divisions, including Centers for Medicare & Medicaid Services (CMS), and the Health Resources and Services Administration, the Department of Veterans Affairs, the Department of Defense and state and local governments. Our business activities must comply with numerous healthcare laws and regulations, including those described below.

The federal Anti-Kickback Statute prohibits, among other things, any person or entity, from knowingly and willfully offering, paying, soliciting or receiving any remuneration, directly or indirectly, overtly or covertly, in cash or in kind, to induce or reward, or in return for, the referral of an individual for, or purchasing, leasing, ordering, or arranging for the purchase, lease or order of, any good, facility, item or service reimbursable under Medicare, Medicaid or other federal healthcare programs. The Anti-Kickback Statute has been interpreted to apply to arrangements between pharmaceutical manufacturers on the one hand and prescribers, purchasers, and formulary managers on the other hand. The term remuneration has been interpreted broadly to include anything of value. There are a number of statutory exceptions and regulatory safe harbors protecting some common activities from prosecution. The exceptions and safe harbors are drawn narrowly and require strict compliance in order to offer protection. Practices that involve remuneration that may be alleged to be intended to induce prescribing, purchasing, or recommending may be subject to scrutiny if they do not qualify for an exception or safe harbor. Failure to meet all of the requirements of a particular applicable statutory exception or regulatory safe harbor does not make the conduct per se illegal under the federal Anti-Kickback Statute. Instead, the legality of the arrangement will be evaluated on a case-by-case basis based on a

54


 

cumulative review of all of its facts and circumstances. Additionally, the Patient Protection and Affordable Care Act of 2010, as amended by the Health Care and Education Reconciliation Act of 2010 (collectively the ACA), amended the intent requirement of the federal Anti-Kickback Statute, and other healthcare criminal fraud statutes, so that a person or entity no longer needs to have actual knowledge of the federal Anti-Kickback Statute, or the specific intent to violate it, to have violated the statute. The ACA also provided that a violation of the federal Anti-Kickback Statute is grounds for the government or a whistleblower to assert that a claim for payment of items or services resulting from such violation constitutes a false or fraudulent claim for purposes of the federal civil False Claims Act (FCA).

The federal civil and criminal false claims laws, including the FCA, and civil monetary penalties laws prohibit, among other things, any person or entity from knowingly presenting, or causing to be presented, a false claim for payment to, or approval by, the U.S. federal government, including the Medicare and Medicaid programs, or knowingly making, using, or causing to be made or used a false record or statement material to a false or fraudulent claim or to avoid, decrease or conceal an obligation to pay money to the federal government. As a result of a modification made by the Fraud Enforcement and Recovery Act of 2009, a claim includes “any request or demand” for money or property presented to the U.S. government. In addition, manufacturers can be held liable under the FCA even when they do not submit claims directly to government payors if they are deemed to “cause” the submission of false or fraudulent claims. The FCA also permits a private individual acting as a “whistleblower” to bring actions on behalf of the federal government alleging violations of the FCA and to share in any monetary recovery. FCA liability is potentially significant in the healthcare industry because the statute provides for treble damages and mandatory penalties. Government enforcement agencies and private whistleblowers have investigated pharmaceutical companies for or asserted liability under the FCA for a variety of alleged promotional and marketing activities, such as providing free products to customers with the expectation that the customers would bill federal programs for the products; providing consulting fees and other benefits to physicians to induce them to prescribe products; engaging in promotion for “off-label” uses; and submitting inflated best price information to the Medicaid Rebate Program.

The federal Health Insurance Portability and Accountability Act of 1996 (HIPAA) created additional federal criminal statutes that prohibits, among other things, knowingly and willfully executing, or attempting to execute, a scheme to defraud any healthcare benefit program or obtain, by means of false or fraudulent pretenses, representations or promises, any of the money or property owned by, or under the custody or control of, any healthcare benefit program, regardless of whether the payor is public or private, knowingly and willfully embezzling or stealing from a health care benefit program, willfully obstructing a criminal investigation of a health care offense and knowingly and willfully falsifying, concealing or covering up by any trick, scheme or device a material fact or making any materially false, fictitious or fraudulent statements in connection with the delivery of, or payment for, healthcare benefits, items or services relating to healthcare matters. Additionally, the ACA amended the intent requirement of some of these criminal statutes under HIPAA so that a person or entity no longer needs to have actual knowledge of the statute, or the specific intent to violate it, to have committed a violation.

Additionally, the federal Open Payments program pursuant to the Physician Payments Sunshine Act, created under Section 6002 of the ACA and its implementing regulations, requires certain manufacturers of drugs, devices, biologicals and medical supplies for which payment is available under Medicare, Medicaid or the Children’s Health Insurance Program (with specified exceptions) to report annually information related to specified payments or other transfers of value provided to physicians (defined to include doctors, dentists, optometrists, podiatrists and chiropractors), other healthcare professionals (such as physicians assistants and nurse practitioners), and teaching hospitals, or to entities or individuals at the request of, or designated on behalf of, the physicians and teaching hospitals and to report annually specified ownership and investment interests held by physicians and their immediate family members. Failure to submit timely, accurately and completely the required information for all payments, transfers of value and ownership or investment interests may result in civil monetary penalties.

In addition, we may be subject to data privacy and security regulation by both the federal government and the states in which we conduct our business. HIPAA, as amended by the Health Information Technology for Economic and Clinical Health Act (HITECH), and their implementing regulations, impose requirements relating to the privacy, security and transmission of individually identifiable health information held by covered entities and their business associates and covered subcontractors. Among other things, HITECH makes HIPAA’s security standards directly applicable to business associates, defined as independent contractors or agents of covered entities that create, receive, maintain, or transmit protected health information in connection with providing a service for or on behalf of a covered entity. HITECH also created new tiers of civil monetary penalties, amended HIPAA to make civil and criminal

55


 

penalties directly applicable to business associates, and gave state attorneys general new authority to file civil actions for damages or injunctions in federal courts to enforce the federal HIPAA laws and seek attorneys’ fees and costs associated with pursuing federal civil actions.

Many states have also adopted laws similar to each of the above federal laws, which may be broader in scope and apply to items or services reimbursed by any third-party payor, including commercial insurers. We may also be subject to state laws that require pharmaceutical companies to comply with the pharmaceutical industry’s voluntary compliance guidelines and the relevant compliance guidance promulgated by the federal government, and/or state laws that require drug manufacturers to report information related to payments and other transfers of value to physicians and other healthcare providers or marketing expenditures and pricing information, state and local laws that require the registration of pharmaceutical sales representatives, and state laws governing the privacy and security of health information in certain circumstances, many of which differ from each other in significant ways and may not have the same effect, thus complicating compliance efforts.

Ensuring that our internal operations and business arrangements with third parties comply with applicable healthcare laws and regulations will likely be costly. It is possible that governmental authorities will conclude that our business practices do not comply with current or future statutes, regulations or case law involving applicable fraud and abuse or other healthcare laws and regulations. If our operations were found to be in violation of any of these laws or any other governmental regulations that may apply to us, we may be subject to significant civil, criminal and administrative penalties, damages, fines, disgorgement, imprisonment, possible exclusion from government funded healthcare programs, contractual damages, reputational harm, diminished profits and future earnings, additional reporting obligations and oversight if we become subject to a corporate integrity agreement or other agreement to resolve allegations of non-compliance with these laws, and curtailment of our operations, any of which could substantially disrupt our operations. If the physicians or other providers or entities with whom we expect to do business are found not to be in compliance with applicable laws, they may be subject to significant criminal, civil or administrative sanctions, including exclusions from government funded healthcare programs.

Coverage and Reimbursement

Our ability to commercialize any products successfully will also depend in part on the extent to which coverage and adequate reimbursement for the procedures utilizing our product candidates, performed by health care providers, once approved, will be available from government health administration authorities, private health insurers and other organizations. Government authorities and other third-party payors, such as private health insurers and health maintenance organizations, determine which procedures, and the products utilized in such procedures, they will cover and establish reimbursement levels. Assuming coverage is obtained for procedures utilizing a given product by a third-party payor, the resulting reimbursement payment rates may not be adequate or may require co-payments that patients find unacceptably high. Patients who undergo procedures for the treatment of their conditions, and their treating physicians, generally rely on third-party payors to reimburse all or part of the costs associated with the procedures which utilize our products. Treating physicians are unlikely to use and order our products unless coverage is provided and the reimbursement is adequate to cover all or a significant portion of the cost of the procedures which utilize our products. Therefore, coverage and adequate reimbursement for procedures which utilize new products is critical to the acceptance of such new products. Coverage decisions may depend upon clinical and economic standards that disfavor new products when more established or lower cost therapeutic alternatives are already available or subsequently become available.

Government authorities and other third-party payors are developing increasingly sophisticated methods of cost containment, such as including price controls, restrictions on coverage and reimbursement and requirements for substitution of less expensive products and procedures. Government and other third-party payors are increasingly challenging the prices charged for health care products and procedures, examining the cost effectiveness of procedures, and the products used in such procedures, in addition to their safety and efficacy, and limiting or attempting to limit both coverage and the level of reimbursement. Further, no uniform policy requirement for coverage and reimbursement exists among third-party payors in the United States, which causes significant uncertainty related to the insurance coverage and reimbursement of newly approved products, and the procedures which may utilize such newly approved products. Therefore, coverage and reimbursement can differ significantly from payor to payor and health care provider to health care provider. As a result, the coverage determination process is often a time-consuming and costly process that requires the provision of scientific and clinical support for the use of new products to each

56


 

payor separately, with no assurance that coverage and adequate reimbursement will be applied consistently or obtained in the first instance.

There may be significant delays in obtaining coverage and reimbursement for newly approved products, and coverage may be more limited than the purposes for which the product is approved by the FDA. Moreover, eligibility for coverage and reimbursement does not imply that a product, or the procedures which utilize such product, will be paid for in all cases or at a rate which the health care providers who purchase those products will find cost effective. Additionally, we expect pricing pressures in connection with the sale of any of our product candidates due to the trend toward managed healthcare, the increasing influence of health maintenance organizations, and additional legislative changes.

We cannot be sure that coverage and reimbursement will be available for any product that we commercialize, or the procedures which utilize such product, and, if reimbursement is available, what the level of reimbursement will be. Coverage and reimbursement may impact the demand for, or the price of, any product candidate for which we obtain marketing approval. If coverage and reimbursement are not available or reimbursement is available only to limited levels, we may not successfully commercialize any product candidate for which we obtain marketing approval.

Healthcare Reform Measures

The United States and some foreign jurisdictions are considering or have enacted a number of legislative and regulatory proposals designed to change the healthcare system. Among policy-makers and payors in the United States and elsewhere, there is significant interest in promoting changes in healthcare systems with the stated goals of containing healthcare costs, improving quality and/or expanding access. In the United States, the pharmaceutical industry has been a particular focus of these efforts and has been significantly affected by major legislative initiatives.

For example, the pharmaceutical industry in the United States has been affected by the passage of ACA, which, among other things: imposed new fees on entities that manufacture or import certain branded prescription drugs; expanded pharmaceutical manufacturer obligations to provide discounts and rebates to certain government programs; implemented a licensure framework for follow-on biologic products; expanded health care fraud and abuse laws; revised the methodology by which rebates owed by manufacturers to the state and federal government under the Medicaid Drug Rebate Program are calculated for certain drugs and biologics, including products that are inhaled, infused, instilled, implanted or injected; imposed an additional rebate similar to an inflation penalty on new formulations of drugs; extended the Medicaid Drug Rebate Program to utilization of prescriptions of individuals enrolled in Medicaid managed care organizations; expanded the 340B program which caps the price at which manufacturers can sell covered outpatient pharmaceuticals to specified hospitals, clinics and community health centers; and provided incentives to programs that increase the federal government’s comparative effectiveness research.

There have been executive, judicial and Congressional challenges to certain aspects of the ACA. For example, on June 17, 2021 the U.S. Supreme Court dismissed a challenge on procedural grounds that argued the ACA is unconstitutional in its entirety because the “individual mandate” was repealed by Congress. Prior to the U.S. Supreme Court ruling, on January 28, 2021, President Biden issued an executive order to initiate a special enrollment period for purposes of obtaining health insurance coverage through the ACA marketplace. The executive order also instructs certain governmental agencies to review and reconsider their existing policies and rules that limit access to healthcare, including among others, reexamining Medicaid demonstration projects and waiver programs that include work requirements, and policies that create unnecessary barriers to obtaining access to health insurance coverage through Medicaid or the ACA. Further, on August 16, 2022, President Biden signed the Inflation Reduction Act of 2022 (IRA) into law, which among other things, extends enhanced subsidies for individuals purchasing health insurance coverage in ACA marketplaces through plan year 2025. The IRA also eliminates the “donut hole” under the Medicare Part D program beginning in 2025 by significantly lowering the beneficiary maximum out-of-pocket cost and creating a new manufacturer discount program. It is possible that the ACA will be subject to judicial or Congressional challenges in the future. It is unclear how any such challenges and additional healthcare reform measures of the Biden administration will impact the ACA.

Other legislative changes have been proposed and adopted in the United States since the ACA was enacted. In August 2011, the Budget Control Act of 2011, among other things, included aggregate reductions of Medicare

57


 

payments to providers of 2.0% per fiscal year, which went into effect in April 2013, and due to subsequent legislative amendments will remain in effect through 2032, unless additional U.S. Congressional action is taken. On March 11, 2021, President Biden signed the American Rescue Plan Act of 2021 into law, which eliminates the statutory Medicaid drug rebate cap, currently set at 100% of a drug’s average manufacturer price, for single source and innovator multiple source drugs, beginning January 1, 2024. In addition, in January 2013, President Obama signed into law the American Taxpayer Relief Act of 2012, which, among other things, reduced Medicare payments to several categories of healthcare providers and increased the statute of limitations period for the government to recover overpayments to providers from three to five years. Additionally, the Medicare Access and CHIP Reauthorization Act of 2015 (MACRA) ended the use of the statutory formula for clinician payment and established a quality payment incentive program, also referred to as the Quality Payment Program. This program provides clinicians with two ways to participate, including through the Advanced Alternative Payment Models (APMs) and the Merit-based Incentive Payment System (MIPS). In November 2019, CMS issued a final rule finalizing the changes to the Quality Payment Program. Under both APMs and MIPS, performance data collected each performance year will affect Medicare payments in later years, including potentially reducing payments. Any reduction in reimbursement from Medicare or other government programs may result in a similar reduction in payments from private payors.

In addition, there has been particular and increasing legislative and enforcement interest in the United States with respect to drug pricing practices in recent years, particularly with respect to drugs that have been subject to relatively large price increases over relatively short time periods. Specifically, there have been several recent U.S. Congressional inquiries, Presidential executive orders and proposed and enacted federal and state legislation designed to, among other things, bring more transparency to product pricing, review the relationship between pricing and manufacturer patient programs, reduce the cost of prescription drugs under Medicare and reform government program reimbursement methodologies for pharmaceutical products. At the federal level, in July 2021, the Biden administration released an executive order, “Promoting Competition in the American Economy,” with multiple provisions aimed at prescription drugs. In response to Biden’s executive order, on September 9, 2021, HHS released a Comprehensive Plan for Addressing High Drug Prices that outlines principles for drug pricing reform and sets out a variety of potential legislative policies that Congress could pursue to advance these principles. In addition, the IRA, among other things, (1) directs HHS to negotiate the price of certain single-source drugs and biologics covered under Medicare and (2) imposes rebates under Medicare Part B and Medicare Part D to penalize price increases that outpace inflation. These provisions take effect progressively starting in fiscal year 2023. On August 29, 2023, HHS announced the list of the first ten drugs that will be subject to price negotiations, although the Medicare drug price negotiation program is currently subject to legal challenges. In response to the Biden administration’s October 2022 executive order, on February 14, 2023, HHS released a report outlining three new models for testing by the CMS Innovation Center which will be evaluated on their ability to lower the cost of drugs, promote accessibility, and improve quality of care. It is unclear whether the models will be utilized in any health reform measures in the future. Further, on December 7, 2023, the Biden administration announced an initiative to control the price of prescription drugs through the use of march-in rights under the Bayh-Dole Act. On December 8, 2023, the National Institute of Standards and Technology published for comment a Draft Interagency Guidance Framework for Considering the Exercise of March-In Rights which for the first time includes the price of a product as one factor an agency can use when deciding to exercise march-in rights. While march-in rights have not previously been exercised, it is uncertain if that will continue under the new framework. It is unclear whether this executive order or similar policy initiatives will be implemented in the future. In addition, individual states in the United States have become increasingly active in passing legislation and implementing regulations designed to control pharmaceutical product pricing, including price or patient reimbursement constraints, discounts, restrictions on certain product access and marketing cost disclosure and transparency measures, and, in some cases, designed to encourage importation from other countries and bulk purchasing. For example, on January 5, 2024, the FDA approved Florida’s Section 804 Importation Program (SIP) proposal to import certain drugs from Canada for specific state healthcare programs. It is unclear how this program will be implemented, including which drugs will be chosen, and whether it will be subject to legal challenges in the United States or Canada. Other states have also submitted SIP proposals that are pending review by the FDA. Any such approved importation plans, when implemented, may result in lower drug prices for products covered by those programs. In the future, there will likely continue to be proposals relating to the reform of the U.S. healthcare system, some of which could further limit coverage and reimbursement of products.

58


 

The Foreign Corrupt Practices Act

The Foreign Corrupt Practices Act (FCPA) prohibits any U.S. individual or business from paying, offering or authorizing payment or offering of anything of value, directly or indirectly, to any foreign official, political party or candidate for the purpose of influencing any act or decision of the foreign entity in order to assist the individual or business in obtaining or retaining business. The FCPA also obligates companies whose securities are listed in the United States to comply with accounting provisions requiring the companies to maintain books and records that accurately and fairly reflect all transactions of the companies, including international subsidiaries, and to devise and maintain an adequate system of internal accounting controls for international operations.

Employees and Human Capital Resources

As of February 16, 2024, we had 179 full-time employees, including 66 who hold an M.D. or Ph.D. degree. Of these full-time employees, 143 were primarily engaged in research and development activities and 36 were primarily engaged in management or general and administrative activities. None of our employees is represented by a labor union and we consider our employee relations to be good. We are committed to strict policies and procedures to maintain a safe work environment. The health and safety of our employees, patients and communities are of primary concern.

Our Core Values; Culture Drivers

Our core values are as follow:

Patients come first.
Respect and trust are core.
We are empathetic and aim to bring out the best in each other.
We are open, direct, and authentic.
We embrace risk and thrive because of our courage to dream.

Our culture is reflected in our five culture drivers: results, resilience, collaboration, transformation and innovation. Through our core values and culture drivers, our employees work to meaningfully improve the lives of cancer patients through our science.

Our Focus and Commitment to Culture, Competitive Compensation and Employee Benefits

We rely on highly skilled and innovative professionals to conduct our research, development and business activities. Our ability to attract, retain and motivate employees is critical to the continued success of our business and it is our goal to offer competitive compensation and benefits, a collaborative and inclusive work environment, ongoing skills development initiatives, attractive career advancement opportunities, and a culture that rewards innovation and exceptional execution.

We are dedicated to building a talented team and strive to offer competitive compensation packages. In addition to competitive base salaries, the other competitive benefits that we provide to all employees include annual equity and cash incentive plans, comprehensive healthcare and insurance benefits, retirement benefits and an employee share purchase plan. The principal purposes of these employee benefits are to attract, retain and reward top talent in order to support our business objectives, assist in the achievement of our strategic goals and align the interests of employees with the interests of our shareholders. Beyond compensation and benefits, we believe that continued growth and development are essential to the professional well-being of our team. We seek to develop our employee talent within the organization through access to training, continuous learning programs, lunch & learn sessions, tuition reimbursement and other development initiatives. As our organization and capabilities grow, we aim to ensure we have provided our team members with the guidance and resources they need to develop as professionals and to support our business.

During the past three years, our employee turnover has remained consistently below average for the life sciences industry generally. We continually assess employee turnover, recruitment initiatives, employee engagement, compensation and benefits programs and other matters relevant to human capital management, and we review results with our Board of Directors on a periodic basis.

59


 

Corporate Information

We were incorporated under the Canada Business Corporations Act on September 6, 2016. Immediately prior to completion of our initial public offering on June 23, 2020, we were continued as a corporation under the Business Corporations Act (Québec) (QBCA). Our principal executive offices are located at 7171 Frederick-Banting, Building 2, Suite 270, St-Laurent, Quebec, H4S 1Z9 and our telephone number is 857-412-7018. In June 2017, we incorporated our wholly-owned subsidiary, Repare Therapeutics USA Inc., a Delaware corporation, which is located at 101 Main Street, Suite 1650, Cambridge, Massachusetts 02142.

Available Information

We maintain an internet website at www.reparerx.com and make available free of charge through our website our Annual Reports on Form 10-K, Quarterly Reports on Form 10-Q, Current Reports on Form 8-K and amendments to those reports filed or furnished pursuant to Sections 13(a) and 15(d) of the Exchange Act of 1934 (the “Exchange Act”). We make these reports available through our website as soon as reasonably practicable after we electronically file such reports with, or furnish such reports to, the Securities and Exchange Commission (the “SEC”). You can review our electronically filed reports and other information that we file with the SEC on the SEC’s web site at http://www.sec.gov and on SEDAR at http://www.sedarplus.com. In addition, we regularly use our website to post information regarding our business, product development programs and governance, and we encourage investors to use our website, specifically the sections title “Investors & Media” as a source of information about us.

The information on our website is not incorporated by reference into this Annual Report on Form 10-K and should not be considered to be part of this Annual Report on Form 10-K. Our website address is included in this Annual Report on Form 10-K as an inactive technical reference only.

60


 

Item 1A. Risk Factors.

Investing in our common shares involves a high degree of risk. You should carefully consider the risks described below, as well as the other information in this Annual Report, including our consolidated financial statements and the related notes and “Management’s Discussion and Analysis of Financial Condition and Results of Operations,” before deciding whether to invest in our common shares. The occurrence of any of the events or developments described below could harm our business, financial condition, results of operations and prospects. In such an event, the market price of our common shares could decline and you may lose all or part of your investment.

Risks Related to Our Financial Position and Capital Needs

Our limited operating history may make it difficult for you to evaluate the success of our business to date and to assess our future viability.

We are a clinical-stage biopharmaceutical company founded in 2016, and our operations to date have focused primarily on raising capital, organizing and staffing our company, conducting discovery and research activities, identifying potential synthetic lethal (SL) gene pairs, establishing and protecting our intellectual property portfolio including for our proprietary SNIPRx platform, developing and progressing our product candidates through preclinical studies and clinical development, including continuing our open-label Phase 1/2 clinical trials of camonsertib, our ongoing Phase 1 clinical trials of lunresertib, our ongoing Phase 1 clinical trial evaluating RP-1664, and establishing arrangements with third parties for the manufacture of initial quantities of our product candidates and component materials. We do not have any product candidates approved for sale and have not generated any revenue from product sales. Additionally, as an organization, we have not yet demonstrated an ability to successfully complete clinical development, obtain regulatory approvals, manufacture a commercial-scale product, or arrange for a third party to do so on our behalf, or conduct sales and marketing activities necessary for successful commercialization. Consequently, any predictions about our future success or viability may not be as accurate as they could be if we had a longer operating history.

We may encounter unforeseen expenses, difficulties, complications, delays and other known or unknown factors in achieving our business objectives. In time, we will need to transition from a company with a research and development focus to a company capable of supporting commercial activities. We may not be successful in such a transition.

Additionally, we expect our financial condition and operating results to continue to fluctuate from quarter to quarter and year to year due to a variety of factors, many of which are beyond our control. Accordingly, you should not rely upon the results of any quarterly or annual periods as indications of future operating performance.

We have incurred significant operating losses since inception and anticipate that we will continue to incur substantial operating losses for the foreseeable future and may never achieve or maintain profitability.

Investment in biopharmaceutical product development is a highly speculative undertaking and entails substantial upfront capital expenditures and significant risk that any potential product candidate will fail to demonstrate adequate efficacy or an acceptable safety profile, gain regulatory approval and become commercially viable. We have no products approved for commercial sale and have not generated any product revenue to date, and we are devoting substantially all of our financial resources and efforts to research and development of our product candidates including camonsertib, lunresertib, RP-1664, as well as to enhancing our SNIPRx platform. To date, we have primarily funded our operations through sales of equity securities, including our IPO in June 2020 and our follow-on offering in November 2021, as well as upfront payments from collaboration and research agreements.

We have incurred significant operating losses since our inception in 2016. Our net loss was $93.8 million, and $29.0 million for the years ended December 31, 2023 and 2022, respectively. As of December 31, 2023, we had an accumulated deficit of $333.1 million. We expect to continue to incur significant expenses and increasing operating

61


 

losses for the foreseeable future. It could be several years, if ever, before we have a commercialized drug. We anticipate that our expenses will increase substantially if, and as, we:

continue our ongoing and planned development of our product candidates, including our ongoing open-label Phase 1/2 clinical trials of camonsertib, Phase 1 clinical trials of lunresertib and Phase 1 clinical trial evaluating RP-1664;
initiate preclinical studies and clinical trials for any additional product candidates that we may pursue in the future, including our earlier-stage programs;
seek to identify novel SL targets, develop small molecule inhibitors of these targets, nominate and develop additional product candidates and further expand our clinical product pipeline;
seek regulatory approvals for any product candidates that successfully complete clinical trials;
build a portfolio of product candidates through the discovery, development, or acquisition or in-license of drugs, product candidates or technologies;
establish a sales, marketing, manufacturing and distribution capability to commercialize any product candidate for which we may obtain marketing approval;
maintain, protect and expand our intellectual property portfolio;
acquire or in-license other product candidates and technologies;
hire additional clinical, regulatory and scientific personnel;
add operational, financial and management information systems and personnel, including personnel to support our product development and planned future commercialization efforts; and
incur additional legal, accounting and other expenses associated with operating as a public company, particularly since we are now an accelerated filer and are no longer a smaller reporting company starting with the filing of our first Quarterly Report on Form 10-Q in 2024.

To become and remain profitable, we must succeed in developing and eventually commercializing products that generate significant revenue. This will require us to be successful in a range of challenging activities, including completing clinical trials of any product candidates that we may pursue, obtaining regulatory approval, procuring commercial-scale manufacturing, marketing, and selling any products for which we may obtain regulatory approval, as well as discovering or acquiring and then developing additional product candidates. We are only in the preliminary stages of some of these activities. We may never succeed in these activities and, even if we do, may never generate revenues that are significant enough to achieve profitability.

Because of the numerous risks and uncertainties associated with drug development, we are unable to accurately predict the timing or amount of expenses or when, or if, we will be able to achieve profitability. Our expenses could increase beyond our expectations if we are required by the U.S. Food and Drug Administration (FDA), the EMA, or other regulatory authorities to perform studies in addition to those we currently expect, or if there are any delays in the initiation and completion of our clinical trials or the development of camonsertib, lunresertib, RP-1664, or any future product candidates.

Even if we do achieve profitability, we may not be able to sustain or increase profitability on a quarterly or annual basis. Our failure to become and remain profitable would decrease the value of our common shares and could impair our ability to raise capital, maintain our research and development efforts, expand our business, or continue our operations. A decline in the value of our common shares could also cause you to lose all or part of your investment.

We will require substantial additional funding to finance our operations. If we are unable to raise capital when needed, we could be forced to delay, reduce, or terminate certain of our product development programs or other operations.

To date, we have primarily funded our operations through sales of equity securities, including our IPO in June 2020 and our follow-on offering in November 2021, as well as upfront payments from collaboration and research

62


 

agreements. We expect to spend substantial amounts to advance our product candidates into clinical development and to complete the clinical development of, seek regulatory approvals for and commercialize our product candidates, if approved. We will require additional capital, which we may raise through equity offerings, debt financings, marketing and distribution arrangements and other collaborations, milestone and royalty payments under our current or future strategic alliances and licensing arrangements or other sources to enable us to complete the development and potential commercialization of our product candidates. Furthermore, we have incurred and will continue to incur additional costs associated with operating as a public company. Adequate additional financing may not be available to us on acceptable terms, or at all. Weakness and volatility in the capital markets and the economy in general could limit our access to capital markets and increase our costs of borrowing. Our failure to raise capital as and when needed would have a negative effect on our financial condition and our ability to pursue our business strategy. In addition, attempting to secure additional financing may divert the time and attention of our management from day-to-day activities and harm our product candidate development efforts. If we are unable to raise capital when needed or on acceptable terms, we would be forced to delay, reduce, or eliminate certain of our research and development programs.

As of December 31, 2023, our cash and cash equivalents and marketable securities on hand was $223.6 million. In February 2024, we received a $40 million milestone payment from Roche upon dosing of the first patient with camonsertib in Roche’s TAPISTRY trial. We believe that our cash, cash equivalents and marketable securities, will enable us to fund our operating expenses and capital expenditure requirements into mid-2026. However, we will need to obtain substantial additional funding in connection with our continuing operations and planned activities. Our future capital requirements will depend on many factors, including:

the continuation of our ongoing and planned development of our product candidates, including our ongoing Phase 1 clinical trials of lunresertib and our ongoing Phase 1 clinical trial evaluating RP-1664;
the timing, costs, progress and results of our ongoing clinical trials, including our ongoing Phase 1 clinical trials of lunresertib and our ongoing Phase 1 clinical trial evaluating RP-1664;
the progress of preclinical development and possible clinical trials of our current earlier-stage programs;
the scope, progress, results and costs of our research programs and preclinical development of other product candidates that we may pursue;
the development requirements of other product candidates that we may pursue;
our headcount growth and associated costs as we expand our research and development and establish a commercial infrastructure;
the timing and amount of milestone and royalty payments that we are required to make or eligible to receive under our current or future collaboration agreements;
the cost of establishing a sales, marketing and distribution infrastructure to commercialize any product candidates for which we may obtain marketing approval;
the outcome, timing and cost of meeting regulatory requirements established by the FDA, EMA and other regulatory authorities;
the costs and timing of future commercialization activities, including product manufacturing, marketing, sales and distribution, for any of our product candidates for which we receive marketing approval;
the cost of expanding, maintaining and enforcing our intellectual property portfolio, including filing, prosecuting, defending and enforcing our patent claims and other intellectual property rights;
the cost of defending potential intellectual property disputes, including patent infringement actions brought by third parties against us or any of our product candidates;
the effect of competing technological and market developments;
the cost and timing of completion of commercial-scale manufacturing activities;
the extent to which we partner our programs, acquire or in-license other product candidates and technologies or enter into additional strategic collaborations;

63


 

the revenue, if any, received from commercial sales of camonsertib, lunresertib, RP-1664 and any future product candidates for which we or our collaborators receive marketing approval;
the addition of equipment and physical infrastructure to support our research and development; and
the costs of operating as a public company.

Identifying potential product candidates and conducting preclinical testing and clinical trials is a time-consuming, expensive, and uncertain process that takes years to complete, and we may never generate the necessary data or results required to obtain regulatory approval and achieve product sales. In addition, camonsertib, lunresertib, RP-1664 and any future product candidates, if approved, may not achieve commercial success. Our commercial revenues, if any, will be derived from sales of products that we do not expect to be commercially available for several years, if at all. Accordingly, we will need to continue to rely on additional financing to achieve our business objectives. Adequate additional financing may not be available to us on acceptable terms, or at all. In addition, we may seek additional capital due to favorable market conditions or strategic considerations even if we believe we have sufficient funds for our current or future operating plans. If we are unable to raise capital when needed or on attractive terms, we could be forced to delay, reduce, or altogether terminate our research and development programs or future commercialization efforts.

Raising additional capital will cause dilution to our shareholders, restrict our operations, or require us to relinquish rights to our product candidates.

Until such time, if ever, as we can generate substantial product revenue, we expect to finance our cash needs through public or private equity or debt financings, third-party funding, marketing, and distribution arrangements, as well as other collaborations, strategic alliances and licensing arrangements, or any combination of these approaches. We do not have any committed external source of funds. To the extent that we raise additional capital through the sale of equity or convertible debt securities, your ownership interest will be diluted, and the terms of these securities may include liquidation or other preferences that adversely affect your rights as a shareholder. Debt and equity financings, if available, may involve agreements that include covenants limiting or restricting our ability to take specific actions, such as redeeming our shares, making investments, incurring additional debt, making capital expenditures, declaring dividends or placing limitations on our ability to acquire, sell or license intellectual property rights.

If we raise additional capital through future collaborations, strategic alliances, or third-party licensing arrangements, we may have to relinquish certain valuable rights to our intellectual property, future revenue streams, research programs or product candidates, or grant licenses on terms that may not be favorable to us. If we are unable to raise additional capital when needed, we may be required to delay, limit, reduce or terminate our clinical development or future commercialization efforts, or grant rights to develop and market product candidates that we would otherwise develop and market ourselves.

Risks Related to the Development of Our Product Candidates

We are very early in our development efforts. If we are unable to advance our product candidates into and through clinical development, obtain regulatory approval and ultimately commercialize any of our product candidates, or experience significant delays in doing so, our business will be materially harmed.

We have no products approved for sale and our initial clinical product candidates, camonsertib lunresertib and RP-1664, are still in the early stages of clinical development and will require additional clinical development, regulatory review and approval in each jurisdiction in which we intend to market it, access to sufficient commercial manufacturing capacity, and significant sales and marketing efforts before we can generate any revenue from product sales. Our ability to generate product revenues, which we do not expect will occur for many years, if ever, will depend heavily on the successful clinical development and eventual commercialization, by us or our collaborators of camonsertib, lunresertib, RP-1664 and one or more of our other product candidates. The success of our product candidates will depend on several factors, including the following:

successful completion of preclinical studies, including the identification of clinical candidates for each of our preclinical programs;
approval of investigational new drug (IND) applications for our planned or future clinical trials;

64


 

acceptance by the FDA, EMA or foreign regulatory authority of our development strategy;
successful initiation of clinical trials;
successful patient enrollment in and completion of clinical trials;
safety, tolerability and efficacy profiles for our product candidates that are satisfactory to the FDA, EMA or any foreign regulatory authority for marketing approval;
the extent of any required post-marketing approval commitments to applicable regulatory authorities;
obtaining and maintaining patent and trade secret protection and regulatory exclusivity for our product candidates;
making arrangements with third-party manufacturers, or establishing manufacturing capabilities, for both clinical and commercial supplies of our product candidates, if any product candidates are approved;
establishing sales, marketing and distribution capabilities and launching commercial sales of our products, if and when approved, whether alone or in collaboration with others;
acceptance of our products, if and when approved, by patients, the medical community and third-party payors;
effectively competing with other cancer therapies;
obtaining and maintaining third-party coverage and adequate reimbursement and patients’ willingness to pay out-of-pocket in the absence of such coverage and adequate reimbursement; and
maintaining a continued acceptable safety profile of products following approval.

There is no guarantee that the results obtained in current preclinical studies, our ongoing open-label Phase 1/2 clinical trials of camonsertib, our ongoing Phase 1 clinical trials of lunresertib, our ongoing Phase 1 clinical trial evaluating RP-1664 or any future clinical trials of any product candidate will be sufficient to obtain regulatory approval or marketing authorization for such product candidate.

Many of these risks are beyond our control, including the risks related to clinical development, the regulatory submission process, potential threats to our intellectual property rights and the manufacturing, marketing, and sales efforts of any future collaborator. If we are unable to develop, receive regulatory approval for, or successfully commercialize our current or future product candidates, or if we experience delays as a result of any of these risks or otherwise, our business could be materially harmed.

Our business substantially depends upon the successful development of product candidates generated through the application of our SNIPRx platform, and in particular, our initial product candidates, camonsertib, lunresertib, and RP-1664. If we or our collaborators are unable to obtain regulatory approval for, and successfully commercialize, products developed through the application of our SNIPRx platform, our business may be materially harmed.

Our initial clinical product candidates, camonsertib, lunresertib and RP-1664, were developed through the application of our SNIPRx platform. All of our product candidates to date were derived based on the same principle of SL. As such, negative results in the development of camonsertib, lunresertib or RP-1664 may also impact our ability to obtain regulatory approval for our other product candidates, either at all or within anticipated timeframes because, although other product candidates may target different indications, the underlying technology platform, manufacturing process and development process is the same for all of our product candidates. Accordingly, a failure in any one program may decrease trust in our technology and affect the ability to obtain regulatory approval to continue or conduct clinical programs for other product candidates. If camonsertib, lunresertib or RP-1664 shows unexpected adverse events or a lack of efficacy in the indications they are intended to treat, or if we or our collaborators experience other regulatory or developmental issues, our development plans and business could be significantly harmed.

65


 

We have limited experience as a company in conducting clinical trials.

We have limited experience as a company in conducting clinical trials. We began our first clinical trial of camonsertib in July 2020, our first clinical trial of lunresertib in April 2021 and our first clinical trial of RP-1664 in February 2024. In part because of this lack of experience, we cannot be certain that our clinical trials will begin or be completed on time, if at all. Large-scale clinical trials would require significant additional financial and management resources and reliance on third-party clinical investigators, contract research organizations (CROs), and consultants. Relying on third-party clinical investigators, CROs and consultants may force us to encounter delays that are outside of our control. We may be unable to identify and contract with sufficient investigators, CROs and consultants on a timely basis or at all. There can be no assurance that we will be able to negotiate and enter into any master services agreement with CROs, as necessary, on terms that are acceptable to us on a timely basis or at all.

We may not be able to file INDs or IND amendments to commence additional clinical trials on the timelines we expect, and even if we are able to, the FDA may not permit us to proceed.

We have filed INDs for camonsertib, lunresertib and RP-1664, but we may not be able to file INDs for our other product candidates on the timelines we expect. For example, we may experience manufacturing delays or other delays with IND-enabling studies. Moreover, we cannot be sure that submission of an IND will result in the FDA allowing further clinical trials to begin, or that, once begun, issues will not arise that suspend or terminate clinical trials. Additionally, even if such regulatory authorities agree with the design and implementation of the clinical trials set forth in an IND, we cannot guarantee that such regulatory authorities will not change their requirements in the future. These considerations also apply to new clinical trials we may submit as amendments to existing INDs or to a new IND. Any failure to file INDs on the timelines we expect or to obtain regulatory approvals for our trials may prevent us from completing our clinical trials or commercializing our products on a timely basis, if at all.

The successful development of targeted therapeutics, including our portfolio of SL small molecule inhibitors, as well as any related diagnostics, is highly uncertain.

Successful development of targeted therapeutics, such as our portfolio of SL small molecule inhibitors, as well as any related diagnostics, is highly uncertain and is dependent on numerous factors, many of which are beyond our control. Our SNIPRx platform is based on new technologies and methods relating to precision target and biomarker identification, screening, and validation. While we believe our clinical development approach will eventually provide validation of our SNIPRx platform, we have not, to date, sought regulatory approval for any therapeutics developed through our platform. As such, it is difficult to accurately predict the developmental challenges we may incur for our current and future product candidates as we proceed through product discovery, identification, preclinical studies, and clinical trials.

Our SNIPRx platform is novel and may not be effective at identifying SL targets for product candidates. We therefore cannot provide any assurance that we will be able to successfully identify additional novel targets or product candidates, advance any of these additional product candidates or diagnostics for their associated biomarkers through the development process. Most of our proposed targets are unproven in clinical trials and there is no guarantee that the preclinical data will translate into a clinical relevance of such novel biomarkers and targets.

Targeted therapeutics that appear promising in the early phases of development may fail to reach the market for several reasons, including:

research or preclinical studies may show our targeted small molecule inhibitors or antagonists to be less effective than desired or to have harmful or problematic side effects or toxicities;
failure to accurately identify, validate or develop clinically relevant biomarkers for our targeted therapeutic product candidates;
trial results may show our targeted therapeutic small molecule inhibitors to be less effective than expected based on preclinical studies (e.g., a clinical trial could fail to meet its primary endpoint(s)) or to have unacceptable side effects or toxicities;
the failure to receive the necessary regulatory approvals or a delay in receiving such approvals. Among other things, such delays may be caused by slow enrollment in clinical trials, patients dropping out of

66


 

trials, length of time to achieve trial endpoints, additional time requirements for data analysis, preparation of IND applications, discussions with the FDA, an FDA request for additional preclinical or clinical data, or unexpected safety or manufacturing issues;
manufacturing costs, formulation issues, pricing or reimbursement issues, or other factors that may make our targeted therapeutic small molecule inhibitors uneconomical;
the size of the patient population that have disease with the appropriate biomarkers for which we are developing our product candidates may not be large enough to support commercial viability of our product candidates, if approved;
proprietary rights of others and their competing products and technologies that may prevent our targeted therapeutic small molecule inhibitors, or the diagnostics for biomarkers associated with such small molecule inhibitors, from being commercialized;
the development of alternative treatments or evolution in the standard of care for our targets may make our drugs less attractive; and
our approach of using any of our product candidates in combination with other agents, including standard of care agents, may not materialize due to overlapping toxicity, high cost or an inability to replicate preclinical results in clinical trials.

As a result of these factors, it is more difficult for us to predict the time and cost of product candidate development, and we cannot predict whether the application of our SNIPRx platform will result in the identification, development, and regulatory approval of any products.

We may incur unexpected costs or experience delays in completing, or ultimately be unable to complete, the development and commercialization of our product candidates.

We may not commercialize, market, promote or sell any product candidate without obtaining marketing approval from the FDA, EMA, or other comparable regulatory authority, and we may never receive such approvals. It is impossible to predict when or if any of our product candidates will prove effective or safe in humans and will receive regulatory approval. Before obtaining marketing approval from regulatory authorities for the sale of our product candidates, we must complete preclinical development and then conduct extensive clinical trials to demonstrate the safety and efficacy of our product candidates in humans. Clinical testing is expensive, difficult to design and implement, can take many years to complete and is uncertain as to outcome. Competing clinical trials for the same populations targeted as ours may limit our enrollment, or the results of competitors with similar technologies and products may falsely undermine the potential of our SNIPRx platform. A failure of one or more clinical trials can occur at any stage of testing. Moreover, preclinical and clinical data are often susceptible to varying interpretations and analyses, and many companies that have believed their product candidates performed satisfactorily in preclinical studies and clinical trials have nonetheless failed to obtain marketing approval of their products.

We or our collaborators may experience numerous unforeseen events prior to, during, or as a result of, clinical trials that could delay or prevent our ability to receive marketing approval or commercialize camonsertib, lunresertib, RP-1664 and any future product candidates, including:

delays in reaching a consensus with regulatory authorities on design or implementation of our clinical trials;
regulators or institutional review boards (IRBs) may not authorize us or our investigators to commence a clinical trial or conduct a clinical trial at a prospective trial site;
delays in reaching agreement on acceptable terms with prospective CROs and clinical trial sites;
the number of patients required for clinical trials of our product candidates may be larger than we anticipate, enrollment in these clinical trials may be slower than we anticipate, patients may drop out of these clinical trials at a higher rate than we anticipate or fail to return for post-treatment follow-up or we may fail to recruit suitable patients to participate in a trial;

67


 

delays in our combination trials due to lack of access to the drugs with which we are testing our product candidates;
clinical trials of our product candidates may produce negative or inconclusive results;
imposition of a clinical hold by regulatory authorities as a result of a serious adverse event, concerns with a class of product candidates or after an inspection of our clinical trial operations, trial sites or manufacturing facilities;
occurrence of serious adverse events associated with the product candidate that are viewed to outweigh its potential benefits;
external business disruptions affecting the initiation, patient enrollment, development and operation of our clinical trials, including a public health emergency, such as the COVID-19 pandemic;
changes in regulatory requirements and guidance that require amending or submitting new clinical protocols; or
we may decide, or regulators may require us, to conduct additional clinical trials or abandon product development programs.

Any inability to successfully complete preclinical and clinical development could result in additional costs to us or impair our ability to generate revenue from future drug sales or other sources. In addition, if we make manufacturing or formulation changes to our product candidates, we may need to conduct additional testing to bridge our modified product candidate to earlier versions. Clinical trial delays could also shorten any periods during which we may have the exclusive right to commercialize our product candidates, if approved, or allow our competitors to bring competing drugs to market before we do, which could impair our ability to successfully commercialize our product candidates and may harm our business, financial condition, results of operations and prospects.

Additionally, if the results of our clinical trials are inconclusive or if there are safety concerns or serious adverse events associated with our product candidates, we may:

be delayed in obtaining marketing approval, if at all;
obtain approval for indications or patient populations that are not as broad as intended or desired;
obtain approval with labeling that includes significant use or distribution restrictions or safety warnings;
be subject to additional post-marketing testing requirements;
be required to perform additional clinical trials to support approval or be subject to additional post-marketing testing requirements;
have regulatory authorities withdraw, or suspend, their approval of the drug or impose restrictions on its distribution in the form of a modified risk evaluation and mitigation strategy (REMS);
be subject to the addition of labeling statements, such as warnings or contraindications;
be sued; or
experience damage to our reputation.

Our product development costs will also increase if we experience delays in testing or obtaining marketing approvals. We do not know whether any of our preclinical studies or clinical trials will begin as planned, need to be restructured or be completed on schedule, if at all.

Clinical trials are very expensive, time consuming and difficult to design and implement.

Our product candidates will require clinical testing before we are prepared to submit a new drug application (NDA) or equivalent application required in another jurisdiction for regulatory approval. We cannot predict with any certainty if or when we might submit an NDA or equivalent application required in another jurisdiction for regulatory approval for any of our product candidates or whether any such application will be approved by the FDA or other

68


 

comparable regulatory authority, as applicable. Human clinical trials are very expensive and difficult to design and implement, in part because they are subject to rigorous regulatory requirements. For instance, the FDA or other comparable regulatory authority may not agree with our proposed endpoints for any future clinical trial of our product candidates, which may delay the commencement of our clinical trials. In addition, we may not succeed in developing and validating disease-relevant clinical endpoints based on insights regarding biological pathways for the diseases we are studying. The clinical trial process is also time consuming. We estimate that the successful completion of clinical trials for camonsertib, lunresertib, RP-1664 and any future product candidates will take several years to complete. Furthermore, failure can occur at any stage, and we could encounter problems that cause us to abandon or repeat clinical trials.

Success in preclinical studies or earlier clinical trials may not be indicative of results in future clinical trials and we cannot assure you that any ongoing, planned or future clinical trials will lead to results sufficient for the necessary regulatory approvals.

We initiated our first clinical trial, an open-label Phase 1/2 clinical trial of camonsertib, in the third quarter of 2020, initiated a Phase 1 clinical trial of lunresertib in the second quarter of 2021, and initiated a Phase 1 clinical trial of RP-1664 in the first quarter of 2024. Success in preclinical testing and earlier clinical trials does not ensure that later clinical trials will generate the same results or otherwise provide adequate data to demonstrate the efficacy and safety of a product candidate. Preclinical tests and Phase 1 and Phase 2 clinical trials are primarily designed to test safety, to study pharmacokinetics and pharmacodynamics and to understand the side effects of product candidates at various doses and schedules. Success in preclinical studies and earlier clinical trials does not ensure that later efficacy trials will be successful, nor does it predict final results. Frequently, product candidates that have shown promising results in early clinical trials have subsequently suffered significant setbacks in later clinical trials. In addition, the design of a clinical trial can determine whether its results will support approval of a product and flaws in the design of a clinical trial may not become apparent until the clinical trial is well advanced. We have limited experience designing clinical trials and may be unable to design and execute a clinical trial to support regulatory approval. There is a high failure rate for drugs and biologic products proceeding through clinical trials. Many companies in the pharmaceutical and biotechnology industries have suffered significant setbacks in late-stage clinical trials even after achieving promising results in preclinical testing and earlier-stage clinical trials. These setbacks have been caused by, among other things, preclinical findings made while clinical trials were underway or safety or efficacy observations made in clinical trials, including previously unreported adverse events.

In addition, differences in trial design between early-stage clinical trials and later-stage clinical trials make it difficult to extrapolate the results of earlier clinical trials to later clinical trials. The early trials will be single arm and not comparing the results with existing (or new) standard of care. Moreover, clinical data are often susceptible to varying interpretations and analyses, and many companies that have believed their product candidates performed satisfactorily in clinical trials have nonetheless failed to obtain marketing approval of their products or had to withdraw the product after comparator or later stage trials delivered results. The changing regulatory landscape may require larger and randomized trials that will take a longer time to perform.

Additionally, some of our trials may be open-label studies, where both the patient and investigator know whether the patient is receiving the investigational product candidate or an existing approved drug, introducing bias in early interpretation of the results. Most typically, open-label clinical trials test only the investigational product candidate and sometimes do so at different dose levels. Open-label clinical trials are subject to various limitations that may exaggerate any therapeutic effect as patients in open-label clinical trials are aware when they are receiving treatment. In addition, open-label clinical trials may be subject to an “investigator bias” where those assessing and reviewing the physiological outcomes of the clinical trials are aware of which patients have received treatment and may interpret the information of the treated group more favorably given this knowledge. Therefore, it is possible that positive results observed in open-label trials will not be replicated in later placebo-controlled trials. Further, as our trials are in patients who encountered multiple therapy failures previously, interpretation of results may be biased both towards lesser activity and at the same time towards a population that is able to tolerate and possibly benefit from novel therapies. Hence interpretation of any results from this population may not directly translate to our eventual pivotal trial population that will likely be more homogenous and less pretreated.

Data obtained from preclinical and clinical activities are subject to varying interpretations, which may delay, limit, or prevent regulatory approval. Moreover, as the development of the SL pair, ATM-ATR, is still early, any

69


 

clinical validation of the SL approach to treating cancer may or may not validate our approach. In addition, we may experience regulatory delays or rejections as a result of many factors, including due to changes in regulatory policy during the period of our product candidate development. Any such delays could negatively impact our business, financial condition, results of operations and prospects.

Interim, “top-line” and preliminary data from our clinical trials that we announce or publish from time to time may change as more patient data become available and are subject to audit and verification procedures that could result in material changes in the final data.

From time to time, we may publish interim, “top-line” or preliminary data from our ongoing and planned clinical trials. Interim data from clinical trials that we may complete are subject to the risk that one or more of the clinical outcomes may materially change as patient enrollment continues and more patient data become available. Preliminary or “top-line” data also remain subject to audit and verification procedures that may result in the final data being materially different from the preliminary data we previously published. As a result, interim and preliminary data should be viewed with caution until the final data are available. Differences between preliminary or interim data and final data could significantly harm our business prospects and may cause the trading price of our common shares to fluctuate significantly.

The regulatory approval processes of the FDA and comparable foreign regulatory authorities are lengthy, time consuming and inherently unpredictable, and if we are ultimately unable to obtain regulatory approval for our product candidates, on a timely basis or at all, our business will be substantially harmed.

The length of time necessary to complete clinical trials and to submit an application for marketing approval for a decision by a regulatory authority may be difficult to predict for targeted therapeutic small molecule inhibitors, in large part because of the limited regulatory history associated with them. The clinical trial requirements of the FDA and other comparable foreign regulatory authorities and the criteria these regulators use to determine the safety and efficacy of a product candidate vary substantially according to the type, complexity, novelty and intended use and market of the product candidate. There is a limited history of multi-tumor indications, and any regulatory approvals may be conditioned upon confirmatory trials with clinical endpoints such as survival. Such trials are not only more expensive to conduct but take several years to complete. Increasing pressure from reimbursement bodies may result in poor (or no) acceptance of early trials for reimbursement. Except for certain PARP inhibitors, no products based on SL have been approved to date by regulators. As a result, the regulatory approval process for product candidates such as ours is uncertain and may be more expensive and take longer than the approval process for product candidates based on other, better known or more extensively studied technologies. It is difficult to determine how long it will take or how much it will cost to obtain regulatory approvals for our product candidates in either the United States or other comparable regions of the world or how long it will take to commercialize our product candidates. Delay or failure to obtain, or unexpected costs in obtaining, the regulatory approval necessary to bring a potential product candidate to market would adversely affect our business, financial condition, results of operations and prospects.

Our product candidates could fail to receive regulatory approval for many reasons, including the following:

the FDA or comparable foreign regulatory authorities may disagree with the design or implementation of our clinical trials;
we may be unable to demonstrate to the satisfaction of the FDA or comparable foreign regulatory authorities that a product candidate is safe and effective for its proposed indication;
the results of clinical trials may not meet the level of statistical significance required by the FDA or comparable foreign regulatory authorities for approval;
we may be unable to demonstrate that a product candidate’s clinical and other benefits outweigh its safety risks;
the FDA or comparable foreign regulatory authorities may disagree with our interpretation of data from preclinical studies or clinical trials;

70


 

the data collected from clinical trials of our product candidates may not be sufficient to support the submission of an NDA to the FDA or other submission or to obtain regulatory approval in the United States or elsewhere;
the FDA or comparable foreign regulatory authorities may fail to approve the manufacturing processes or facilities of third-party manufacturers with which we contract for clinical and commercial supplies; and
the approval policies or regulations of the FDA or comparable foreign regulatory authorities may significantly change in a manner rendering our clinical data insufficient for approval.

Prior to obtaining approval to commercialize a product candidate in the United States or elsewhere, we or our collaborators must demonstrate with substantial evidence from well-controlled clinical trials, and to the satisfaction of the FDA or comparable foreign regulatory agencies, that such product candidates are safe and effective for their intended uses. Results from nonclinical studies and clinical trials can be interpreted in different ways. Even if we believe the nonclinical or clinical data for our product candidates are promising, such data may not be sufficient to support approval by the FDA or comparable foreign regulatory authorities. The FDA may also require us to conduct additional preclinical studies or clinical trials for our product candidates either prior to or post-approval, or it may object to elements of our clinical development program. Depending on the extent of these or any other studies required by the FDA or comparable foreign regulatory authorities, approval of any regulatory approval applications that we submit may be delayed by several years, or may require us to expend significantly more resources than we have available.

Of the large number of potential products in development, only a small percentage successfully complete the FDA or comparable foreign regulatory approval processes and are commercialized. The lengthy approval process as well as the unpredictability of future clinical trial results may result in our failing to obtain regulatory approval to market our product candidates, which would significantly harm our business, results of operations and prospects.

In addition, even if we were to obtain approval, regulatory authorities may approve any of our product candidates for fewer or more limited indications than we request, may impose significant limitations in the form of narrow indications, warnings, or a post-marketing risk management strategy such as a REMS or the equivalent in another jurisdiction. Regulatory authorities may not approve the price we intend to charge for our products, may grant approval contingent on the performance of costly post-marketing clinical trials, or may approve a product candidate with a label that does not include the labeling claims necessary or desirable for the successful commercialization of that product candidate. Any of the foregoing scenarios could materially harm the commercial prospects for our product candidates.

Synthetic lethality represents an emerging class of precision medicine targets, and negative perceptions of the efficacy, safety, or tolerability of this class of targets, including any that we develop, could adversely affect our ability to conduct our business, advance our product candidates or obtain regulatory approvals.

Aside from PARP inhibitors, such as Lynparza, Rubraca, Zejula and Talzenna, no small molecule inhibitor therapeutics for SL in DNA damage have been approved to date by the FDA or other comparable regulators. Adverse events in future clinical trials of our product candidates or in clinical trials of others developing similar products and the resulting publicity, as well as any other adverse events in the field of SL, or other products that are perceived to be similar to SL, such as those related to gene therapy or gene editing, could result in a decrease in the perceived benefit of one or more of our programs, increased regulatory scrutiny, decreased confidence by patients and CROs in our product candidates, and less demand for any product that we may develop. Our pipeline of SL small molecule inhibitor product candidates could result in a greater quantity of reportable adverse events or other reportable negative clinical outcomes, manufacturing reportable events or material clinical events that could lead to clinical delays or holds by the FDA or applicable regulatory authority or other clinical delays, any of which could negatively impact the perception of one or more of our SL programs, as well as our business as a whole. In addition, responses by U.S. federal or foreign governments to negative public perception may result in new legislation or regulations that could limit our ability to develop any product candidates or commercialize any approved products, obtain, or maintain regulatory approval, or otherwise achieve profitability. More restrictive statutory regimes, government regulations, or negative public opinion would have an adverse effect on our business, financial condition, results of operations, and prospects, and may delay or impair the development of our product candidates and commercialization of any approved products or demand for any products we may develop.

71


 

We may not be successful in applying our SNIPRx platform to discover SL targets with therapeutic and commercial potential or in the discovery and development of commercially viable product candidates for us or our collaborators.

Our scientific approach focuses on applying our proprietary SNIPRx platform to identify SL targets across the human genome. Our drug discovery team then chooses targets identified by SNIPRx and develops potent and selective inhibitors of these targets. We use these inhibitors to further validate our SL findings before advancing them into clinical development.

We believe the results of our SNIPRx screen campaigns suggest that our platform is capable of identifying high quality product candidates, but past success in identifying potential product candidates does not assure future success for us with our internal drug discovery programs. Our SNIPRx platform is novel, and we may not succeed in applying our SNIPRx platform to identify targets for product candidates. We therefore cannot provide any assurance that we or our collaborators will be able to successfully identify additional product candidates or advance any of these additional product candidates. In addition, others may have discovered and prosecuted targets that we believe are undiscovered. As a result of these factors, it is more difficult for us to predict the time and cost of product candidate development, and we cannot predict whether the application of our SNIPRx platform will result in the identification, development, and regulatory approval of any products. In addition, we may not succeed in applying our STEP2 screens to expand the potential patient populations that can be treated with our product candidates.

Efforts to identify, acquire or in-license, and then develop product candidates require substantial technical, financial, and human resources, whether or not any product candidates are ultimately identified. We apply our SNIPRx technology and STEP2 screening in our efforts to discover potential precision targets for which our product candidates may be developed. Our efforts may initially show promise in identifying potential product candidates, yet fail to yield product candidates for clinical development, approved products, or commercial revenues for many reasons, including the following:

the methodology used may not be successful in identifying potential product candidates;
competitors may develop alternatives that render any product candidates we develop obsolete;
any product candidates we develop may nevertheless be covered by third parties’ patents or other exclusive rights;
a product candidate may be shown to have harmful side effects or other characteristics that indicate it is unlikely to be effective or otherwise does not meet applicable regulatory criteria;
a product candidate may not be capable of being produced in commercial quantities at an acceptable cost, or at all; and
a product candidate may not be accepted as safe and effective by physicians, patients, the medical community or third-party payors.

Difficulty in enrolling patients could delay or prevent clinical trials of our product candidates. We may find it difficult to enroll patients in our ongoing and planned clinical trials with the genomic alterations that these trials are designed to target.

Identifying and qualifying patients to participate in clinical trials of our product candidates is critical to our success. The timing of completion of our clinical trials depends in part on the speed at which we can recruit patients to participate in testing our product candidates, and we may experience delays in our clinical trials if we encounter difficulties in enrollment. We may not be able to initiate or continue clinical trials for our product candidates if we are unable to locate and enroll a sufficient number of eligible patients to participate in these trials as required by the FDA or similar regulatory authorities outside the United States. In particular, because we are focused on patients with specific genomic alterations identified by our STEP2 screens, our ability to enroll eligible patients may be limited or may result in slower enrollment than we anticipate. Certain genes identified by our STEP2 screens may not yet be included in commercially available panels or CLIA-validated panels used in large academic centers. We cannot be certain how many patients will have each of the genomic alterations that the applicable product candidate is designed to target or that the number of patients enrolled for each mutation will suffice for regulatory approval and inclusion

72


 

of each such mutation in the approved label. We may be unsuccessful in our efforts to work with our clinical partners to identify patients who are eligible for our clinical trials.

In addition, some of our competitors have ongoing clinical trials for product candidates that treat the same or similar populations as our product candidates, and patients who would otherwise be eligible for our clinical trials may instead enroll in clinical trials of our competitors’ product candidates.

We are engaging third parties to develop patient selection tools for use in our clinical trials, but such third parties may not be successful in developing such tools, furthering the difficulty in identifying patients with the targeted genomic alterations for our clinical trials and risking enrollment into our trials. Next Generation Sequencing panels may not include genes required for screening for our clinical trials or may not be broadly commercially available. The optimal method of diagnosis is not yet known and the availability of third party payment for diagnostic tests may limit our clinical trials as well. Further, if we are unable to include patients with the targeted genomic alterations, this could compromise our ability to seek participation in FDA’s expedited review and development programs or otherwise seek to accelerate clinical development and regulatory timelines.

The enrollment of patients further depends on many factors, including:

the risks and benefits of the product candidate under trial;
the availability and efficacy of competing therapies and clinical trials;
the availability of genetic sequencing information for patient tumors so that we can identify patients with the targeted genomic alterations;
the patient referral practices of physicians;
the proximity of patients to clinical trial sites;
the design of the clinical trial;
our ability to recruit clinical trial investigators with the appropriate competencies and experience;
the ability of any current or future license partner to execute on its development commitments and responsibilities for any product candidate to which it has acquired development rights in a given geography;
our ability to obtain and maintain patient consents;
reporting of the preliminary results of any of our clinical trials; and
the risk that patients enrolled in clinical trials will drop out of the clinical trials before clinical trial completion.

Our clinical trials will compete with other clinical trials for product candidates that are in the same therapeutic areas as our product candidates, and this competition will reduce the number and types of patients available to us because some patients who might have opted to enroll in our clinical trials may instead opt to enroll in a clinical trial being conducted by one of our competitors. Since the number of qualified clinical investigators is limited, we expect to conduct some of our clinical trials at the same clinical trial sites that some of our competitors use, which will reduce the number of patients who are available for our clinical trials at such clinical trial sites. Moreover, because our product candidates represent a departure from more commonly used methods for cancer treatment and because our product candidates have not been tested in humans before, potential patients and their doctors may be inclined to use conventional therapies, such as chemotherapy, rather than enroll patients in any future clinical trial.

If we experience delays in the completion of, or termination of, any clinical trial of our product candidates, the commercial prospects of our product candidates will be harmed, and our ability to generate product revenue from any of these product candidates could be delayed or prevented.

73


 

Our product candidates may cause undesirable side effects or have other properties that could delay or prevent their regulatory approval, limit the commercial potential or result in significant negative consequences following any potential marketing approval.

Serious adverse events or undesirable side effects caused by our product candidates could cause us or regulatory authorities to interrupt, delay or halt clinical trials and could result in a more restrictive label or the delay or denial of regulatory approval by the FDA, EMA, or other authorities. Results of our clinical trials could reveal a high and unacceptable severity and prevalence of side effects, toxicities, or unexpected characteristics, including death.

If unacceptable side effects or deaths arise in the development of our product candidates, we, the IRBs at the institutions in which our studies are conducted, the FDA or any comparable foreign regulatory authority could suspend or terminate our clinical trials or the FDA or other regulatory authorities could order us to cease clinical trials or deny approval of our product candidates for any or all targeted indications. Undesirable side effects or deaths in clinical trials with our product candidates may cause the FDA or comparable foreign regulatory authorities to place a clinical hold on the associated clinical trials, to require additional studies, or otherwise to delay or deny approval of our product candidates for any or all targeted indications. Treatment-related side effects could also affect patient recruitment or the ability of enrolled patients to complete the trial or result in potential product liability claims. In addition, these side effects may not be appropriately recognized or managed by the treating medical staff. We expect to have to train medical personnel using our product candidates to understand the side effect profiles for our clinical trials and upon any commercialization of any of our product candidates. Inadequate training in recognizing or managing the potential side effects of our product candidates could result in patient injury or death. Any of these occurrences may harm our business, financial condition, and prospects significantly.

If any of our product candidates receives marketing approval, and we or others later identify undesirable side effects caused by any such product, including during any long-term follow-up observation period recommended or required for patients who receive treatment using our products, a number of potentially significant negative consequences could result, including:

regulatory authorities may suspend, limit or withdraw approvals of such product, or seek an injunction against its manufacture and distribution;
we may be required to recall a product or change the way such product is administered to patients;
additional restrictions may be imposed on the marketing of the particular product or the manufacturing processes for the product;
regulatory authorities may require additional warnings on the label, such as a boxed warning or contraindication, or issue safety alerts, Dear Healthcare Provider letters, press releases or other communications containing warnings or other safety information about the product;
we may be required to implement a REMS or create a medication guide outlining the risks of such side effects for distribution to patients;
the product could become less competitive;
a strategic collaborator for the product may choose to terminate its agreement and compromise our ability to commercialize such product in the collaborator’s geography;
we may be subject to fines, injunctions, or the imposition of civil or criminal penalties;
we could be sued and held liable for harm caused to patients; and
our reputation may suffer.

Any of these events could prevent us from achieving or maintaining market acceptance of the particular product candidate, if approved, and could significantly harm our business, results of operations and prospects.

74


 

We may in the future conduct clinical trials for product candidates outside the United States, and the FDA and comparable foreign regulatory authorities may not accept data from such trials.

We currently expect, and may in the future choose, to conduct one or more clinical trials outside the United States, including in Europe. The acceptance of study data from clinical trials conducted outside the United States or another jurisdiction by the FDA or comparable foreign regulatory authority may be subject to certain conditions or may not be accepted at all. In cases where data from foreign clinical trials are intended to serve as the basis for marketing approval in the United States, the FDA will generally not approve the application on the basis of foreign data alone unless (i) the data are applicable to the U.S. population and U.S. medical practice; and (ii) the trials were performed by clinical investigators of recognized competence and pursuant to good clinical practice, or GCP, regulations. Additionally, the FDA’s clinical trial requirements, including sufficient size of patient populations and statistical powering, must be met. Many foreign regulatory authorities have similar approval requirements. In addition, such foreign trials would be subject to the applicable local laws of the foreign jurisdictions where the trials are conducted. Results for our clinical trials may differ by jurisdiction as a result of varying standards of care or local restrictions on reimbursement from third-party payors for clinical trials, thereby affecting the willingness of the FDA or any comparable foreign regulatory authority to accept such data. There can be no assurance that the FDA or any comparable foreign regulatory authority will accept data from trials conducted outside of the United States or the applicable jurisdiction. If the FDA or any comparable foreign regulatory authority does not accept such data, it would result in the need for additional trials, which could be costly and time-consuming, and which may result in product candidates that we may develop not receiving approval for commercialization in the applicable jurisdiction.

If it is determined that companion diagnostics are needed, we may be unable to successfully develop companion diagnostics for biomarkers that enable patient selection, or experience significant delays in doing so, we may not realize the full commercial potential of our product candidates.

A key component of our strategy includes the use of diagnostic tools to guide patient selection of our product candidates. In some cases, a diagnostic tool may be commercially available, for example, on a tumor-profiling panel. If not already commercially available, we may be required to seek collaborations with diagnostic companies for the development of diagnostics for biomarkers associated with our product candidates. We may have difficulty in establishing or maintaining such development relationships, and we will face competition from other companies in establishing these collaborations. Furthermore, even if a diagnostic is commercially available, we may not be able to obtain reimbursement for its use without obtaining regulatory approval.

There are also several risks associated with biomarker identification and validation. We, in collaboration with any diagnostic partners, may not be able to identify predictive biomarkers or pharmacodynamic biomarkers for one or more of our programs. We may not be able to validate potential biomarkers (e.g., certain genomic alterations) or their functional relevance preclinically in relevant in vitro or in vivo models. Data analytics and information from databases that we rely on for identifying or validating some of our biomarker-target relationships may not accurately reflect potential patient populations or may be based on incorrect methodology. Potential biomarkers, even if validated preclinically, may not be functionally validated in human clinical trials.

If it is determined that companion diagnostics are needed, we may, in collaboration with these parties, be unable to successfully develop companion diagnostics for our product candidates, or experience delays in doing so, which may adversely affect the development of our product candidates. The development of companion diagnostic products requires a significant investment of working capital, and may not result in any future income. This could require us to raise additional funds, which could dilute our current investors or impact our ability to continue our operations in the future.

There are also risks associated with diagnostics that are commercially available, including that we may not have access to reliable supply for such diagnostics.

The failure to obtain required regulatory approvals for any companion diagnostic tests that may be required and that we may pursue may prevent or delay approval of our product candidates. Moreover, the commercial

75


 

success of any of our product candidates may be tied to the regulatory approval, market acceptance and continued availability of a companion diagnostic.

The FDA and other comparable regulatory authorities regulate in vitro companion diagnostics as medical devices that will likely be subject to clinical trials in conjunction with the clinical trials for our product candidates, and which will require regulatory clearance or approval prior to commercialization. If it is determined that companion diagnostics are needed, we plan to collaborate with third parties for the development, testing and manufacturing of these companion diagnostics, the application for and receipt of any required regulatory clearances or approvals, and the commercial supply of these companion diagnostics. Our third-party collaborators may fail to obtain the required regulatory clearances or approvals, which could prevent or delay approval of our product candidates. In addition, the commercial success of any of our product candidates may be tied to and dependent upon the receipt of required regulatory clearances or approvals of the companion diagnostic.

For example, the genomic alterations our compounds are addressing, such as ATM loss and CCNE1 amplification, are uncommon genetic alterations in tumors, or their subsets and their prognostic significance has not been fully validated for the patient populations that we are targeting. Such development risk contributes to the costs that we may need to bear in validating the alterations as well as the optimal method of diagnostic screening for our clinical trial populations.

Even if a companion diagnostic is approved, we will rely on the continued ability of any third-party collaborator to make the companion diagnostic commercially available to us on reasonable terms in the relevant geographies. Market acceptance of the companion diagnostic may be low as a result of the cost and complexity of utilizing such companion diagnostic. Furthermore, if commercial tumor profiling panels are not able to be updated to include additional tumor-associated genes, or if clinical oncologists do not incorporate molecular or genetic sequencing into their clinical practice, we may not be successful in developing or commercializing our existing product candidates or any future product candidates.

We intend to pursue the development of certain of our product candidates in combination with other therapies, and regulatory approval, safety or supply issues with these other therapies may delay or prevent the development and approval of our product candidates.

We have explored and may continue to explore the use of our product candidates in combination with other therapies, including those that are not yet approved. For example, our ongoing Phase 1 MYTHIC clinical trial is evaluating camonsertib in combination with lunresertib. If we choose to develop a product candidate for use in combination with an approved therapy, we are subject to the risk that the FDA or comparable foreign regulatory authorities could revoke approval of, or that safety, efficacy, manufacturing, or supply issues could arise with, the therapy used in combination with our product candidate. If the therapies we use in combination with our product candidates are replaced as the standard of care, the FDA or comparable foreign regulatory authorities may require us to conduct additional clinical trials, or we may not be able to obtain adequate reimbursement from third-party payors. The occurrence of any of these risks could result in our product candidates, if approved, being removed from the market or being less successful commercially.

Where we develop a product candidate for use in combination with a therapy that has not been approved by the FDA or comparable foreign regulatory authorities, we will not be able to market our product candidate for use in combination with such an unapproved therapy, unless and until the unapproved therapy receives regulatory approval. These unapproved therapies face the same risks described with respect to our product candidates currently in development, including serious adverse effects and delays in their clinical trials. In addition, other companies may also develop their products or product candidates in combination with the unapproved therapies with which we are developing our product candidates for use in combination. Any setbacks in these companies’ clinical trials, including the emergence of serious adverse effects, may delay or prevent the development and approval of our product candidates.

If the FDA or comparable foreign regulatory authorities do not approve or revoke their approval of, or if safety, efficacy, manufacturing, or supply issues arise with, therapies we choose to evaluate in combination with any of our product candidates, we may be unable to obtain regulatory approval of or to commercialize such product candidates in combination with these therapies.

76


 

Risks Related to the Commercialization of Our Product Candidates

We have never commercialized a product candidate and may experience delays or unexpected difficulties in obtaining regulatory approval for our current or future product candidates for our initial or potential additional indications.

We have never obtained regulatory approval for, or commercialized, a drug. It is possible that the FDA may refuse to accept any or all of our planned NDAs for substantive review or may conclude after review of our data that our application is insufficient to obtain regulatory approval for any product candidates. If the FDA does not approve any of our planned NDAs, it may require that we conduct additional costly clinical, nonclinical, or manufacturing validation studies before it will reconsider our applications. Depending on the extent of these or any other FDA-required studies, approval of any NDA or other application that we submit may be significantly delayed, possibly for several years, or may require us to expend more resources than we have available. Any failure or delay in obtaining regulatory approvals would prevent us from commercializing our current or future product candidates, generating revenues, and achieving and sustaining profitability. It is also possible that additional studies, if performed and completed, may not be considered sufficient by the FDA to approve any NDA or other application that we submit. If any of these outcomes occur, we may be forced to abandon the development of our product candidates, which would materially adversely affect our business and could potentially cause us to cease operations. We face similar risks for our applications in foreign jurisdictions.

We currently have no marketing and sales organization and have no experience as a company in marketing products. If we are unable to establish marketing and sales capabilities or enter into agreements with third parties to market and sell our product candidates, if approved, we may not be able to generate product revenue.

We currently have no sales, marketing or distribution capabilities and have no experience in marketing products. We intend to develop an in-house marketing organization and sales force, which will require significant capital expenditures, management resources and time. We will have to compete with other pharmaceutical and biotechnology companies to recruit, hire, train, and retain marketing and sales personnel.

If we are unable or decide not to establish internal sales, marketing, and distribution capabilities, we will pursue arrangements with third-party sales, marketing, and distribution collaborators regarding the sales and marketing of our products, if approved. However, there can be no assurance that we will be able to establish or maintain such arrangements on favorable terms or if at all, or if we are able to do so, that these third-party arrangements will provide effective sales forces or marketing and distribution capabilities. Any revenue we receive will depend upon the efforts of such third parties, which may not be successful. We may have little or no control over the marketing and sales efforts of such third parties and our revenue from product sales may be lower than if we had commercialized our product candidates ourselves. We also face competition in our search for third parties to assist us with the sales and marketing efforts of our product candidates.

There can be no assurance that we will be able to develop in-house sales and distribution capabilities or establish or maintain relationships with third-party collaborators to commercialize any product in the United States or overseas.

Due to our limited resources and access to capital, we must, and have in the past decided to, prioritize development of certain product candidates over other potential product candidates. These decisions may prove to have been wrong and may adversely affect our ability to develop our own programs, our attractiveness as a commercial partner and may ultimately have an impact on our commercial success.

Because we have limited resources and access to capital to fund our operations, we must decide which product candidates to pursue and the amount of resources to allocate to each. Our decisions concerning the allocation of research, collaboration, management, and financial resources toward particular proprietary molecules in our library, product candidates or therapeutic areas may not lead to the development of viable commercial products and may divert resources away from better opportunities. Similarly, our decisions to delay, terminate or collaborate with third parties in respect of certain product development programs may also prove not to be optimal and could cause us to miss valuable opportunities. If we make incorrect determinations regarding the market potential of our product candidates or misread trends in the biopharmaceutical industry, in particular for our lead product candidate, our business, financial condition and results of operations could be materially adversely affected.

77


 

Even if we obtain regulatory approval of our product candidates, the products may not gain market acceptance among physicians, patients, hospitals, cancer treatment centers and others in the medical community.

The use of precision medicines as a potential cancer treatment is a recent development and may not become broadly accepted by physicians, patients, hospitals, cancer treatment centers and others in the medical community. Various factors will influence whether our product candidates are accepted in the market, including:

the clinical indications for which our product candidates are approved;
physicians, hospitals, cancer treatment centers and patients considering our product candidates as a safe and effective treatment;
the potential and perceived advantages of our product candidates over current or future alternative treatments;
our ability to demonstrate the advantages of our product candidates over other cancer medicines;
the prevalence and severity of any side effects;
the prevalence and severity of any side effects for other precision medicines and public perception of other precision medicines;
product labeling or product insert requirements of the FDA or comparable foreign regulatory authorities;
limitations or warnings contained in the labeling approved by the FDA or comparable foreign regulatory authorities;
the timing of market introduction of our product candidates as well as competitive products;
the cost of treatment, including with respect to diagnostic tools for our product candidates, and the availability of testing for patient selection;
the pricing of our products, if approved, and the availability of adequate coverage and reimbursement by third-party payors and government authorities;
the willingness of patients to pay out-of-pocket in the absence of coverage or adequate reimbursement by third-party payors and government authorities;
relative convenience and ease of administration, including as compared to alternative treatments and competitive therapies; and
the effectiveness of our sales and marketing efforts.

If our product candidates are approved for commercialization but fail to achieve market acceptance among physicians, patients, hospitals, cancer treatment centers or others in the medical community, we will not be able to generate significant revenue.

In addition, although our product candidates differ in certain ways from other precision medicine approaches, serious adverse events or deaths in other clinical trials involving precision medicines, even if not ultimately attributable to our product or product candidates, could result in increased government regulation, unfavorable public perception and publicity, potential regulatory delays in the testing or licensing of our product candidates, stricter labeling requirements for those product candidates that are licensed, and a decrease in demand for any such product candidates.

Even if our products achieve market acceptance, we may not be able to maintain that market acceptance over time if new products or technologies are introduced that are more favorably received than our products, are more cost effective or render our products obsolete.

78


 

The market opportunities for our product candidates may be relatively small as it will be limited to those patients who are ineligible for or have failed prior treatments and our estimates of the prevalence of our target patient populations may be inaccurate.

Cancer therapies are sometimes characterized as first line, second line, or third line, and the FDA often approves new therapies initially only for a particular line of use. When cancer is detected early enough, first line therapy is sometimes adequate to cure the cancer or prolong life without a cure. Whenever first line therapy, usually chemotherapy, antibody drugs, tumor-targeted small molecules, hormone therapy, radiation therapy, surgery, or a combination of these, proves unsuccessful, second line therapy may be administered. Second line therapies often consist of more chemotherapy, radiation, antibody drugs, tumor-targeted small molecules, or a combination of these. Third line therapies can include chemotherapy, antibody drugs and small molecule tumor-targeted therapies, more invasive forms of surgery and new technologies. We expect to initially seek approval of our product candidates in most instances at least as a second or third line therapy. Subsequently, for those product candidates that prove to be sufficiently safe and beneficial, if any, we would expect to seek approval as a second line therapy and potentially as a first line therapy, but there is no guarantee that our product candidates, even if approved as a second or third or subsequent line of therapy, would be approved for an earlier line of therapy, and, prior to any such approvals, we may have to conduct additional clinical trials.

We rely on various sources, including published literature and public or proprietary databases, to ascertain an estimate of the number of patients having particular genomic alterations, such as mutations, deletions or fusions. The determinable prevalence may vary depending on the source and quality of the underlying data and in some cases, insufficient data or poorly curated data may impact our ability to accurately estimate the prevalence of our target patient populations for each indication and in the aggregate across multiple indications both in the clinical trial setting, as well as in the commercial setting, if our product is approved. If the market opportunities for our product candidates are smaller than we estimate, our business, financial position, results of operations and prospects may be harmed. In addition, upon treatment with our product candidates, patients may have or develop resistance to our product candidates, reducing the addressable patient population and duration of treatment.

We face substantial competition, which may result in others developing or commercializing drugs before or more successfully than us.

The biopharmaceutical industry is characterized by intense competition and rapid innovation. Our competitors may be able to develop other compounds or drugs that are able to achieve similar or better results. Our potential competitors include major multinational pharmaceutical companies, established biotechnology companies, specialty pharmaceutical companies and universities and other research institutions. Many of our competitors have substantially greater financial, technical, and other resources, such a larger research and development team and experienced marketing and manufacturing organizations and well-established sales forces. Smaller or early-stage companies may also prove to be significant competitors, particularly as they develop novel approaches to treating disease indications that our product candidates are also focused on treating. Established pharmaceutical companies may also invest heavily to accelerate discovery and development of novel therapeutics or to in-license novel therapeutics that could make the product candidates that we develop obsolete. Mergers and acquisitions in the biotechnology and pharmaceutical industries may result in even more resources being concentrated in our competitors. Competition may increase further as a result of advances in the commercial applicability of technologies and greater availability of capital for investment in these industries. Our competitors, either alone or with collaborative partners, may succeed in developing, acquiring, or licensing on an exclusive basis drug or biologic products that are more effective, safer, more easily commercialized or less costly than our product candidates or may develop proprietary technologies or secure patent protection that we may need for the development of our technologies and products. We believe the key competitive factors that will affect the development and commercial success of our product candidates are efficacy, safety, tolerability, reliability, convenience of use, price, and reimbursement.

We face competition from segments of the pharmaceutical, biotechnology and other related markets that pursue the development of precision oncology therapies for patients with genetically-defined cancers. Several biopharmaceutical companies, including Loxo Oncology, Inc. (part of Eli Lilly and Company), Blueprint Medicines Corporation, SpringWorks Therapeutics, Inc., Black Diamond Therapeutics, Inc., Deciphera Pharmaceuticals, Inc., Tango Therapeutics, Inc., Zentalis Pharmaceuticals, Inc., Turning Point Therapeutics, Inc. (acquired by Bristol-Myers Squibb), and Exelixis, Inc. are developing precision oncology medicines. In addition, we may face competition from

79


 

companies developing product candidates that are based on SL, including AstraZeneca, GlaxoSmithKline, Pfizer, Bayer, Merck Serono, Schrodinger, Inc., Exelixis, Inc., Artios Pharma Ltd., IDEAYA Biosciences, Inc, Impact Therapeutics, Aprea Therapeutics, Shanghai De Novo Pharmatech, Tide Pharmaceutical, Acrivon Therapeutics, Biocity Biopharma, Oric Pharmaceuticals, Schrodinger, Treadwell Therapeutics, Varsity Pharma, Breakpoint Therapeutics, Rhizen Pharmaceuticals AG, Simcere Pharmaceutical, and Shouyao Holdings.

We anticipate that we will continue to face intense and increasing competition as new treatments enter the market and advanced technologies become available. There can be no assurance that our competitors are not currently developing, or will not in the future develop, products that are equally or more effective or are more economically attractive than any of our current or future product candidates. Competing products may gain faster or greater market acceptance than our products, if any, and medical advances or rapid technological development by competitors may result in our product candidates becoming non-competitive or obsolete before we are able to recover our research and development and commercialization expenses. If we or our product candidates do not compete effectively, it may have a material adverse effect on our business, financial condition, and results of operations.

If we obtain approval to commercialize any products outside of the United States, a variety of risks associated with international operations could adversely affect our business.

If any of our product candidates are approved for commercialization, we may seek to enter into agreements with third parties to market them in certain jurisdictions outside the United States. We expect that we would be subject to additional risks related to international pharmaceutical operations, including:

different regulatory requirements for drug approvals and rules governing drug commercialization in foreign countries;
reduced protection for intellectual property rights;
foreign reimbursement, pricing and insurance regimes;
unexpected changes in tariffs, export controls, sanctions, trade barriers and regulatory requirements;
economic weakness, including inflation, or political instability in particular foreign economies and markets;
foreign currency fluctuations, which could result in increased operating expenses and reduced revenues, and other obligations incident to doing business in another country;
business interruptions resulting from geopolitical actions, including war, such as the military conflict involving Russia and Ukraine as well as the Middle-East conflicts, and terrorism, natural disasters including earthquakes, typhoons, floods and fires, or from economic or political instability, or public health emergencies, boycotts, curtailment of trade and other business restrictions;
greater difficulty with enforcing our contracts;
potential noncompliance with the U.S. Foreign Corrupt Practices Act, the U.K. Bribery Act 2010 and similar anti-bribery and anticorruption laws in other jurisdictions; and
production shortages resulting from any events affecting raw material supply or manufacturing capabilities abroad.

As an organization, we have no prior experience in these areas. In addition, there are complex regulatory, tax, labor and other legal requirements imposed by individual countries in Europe with which we may need to comply. If we are unable to successfully manage the challenges of international expansion and operations, our business and operating results could be harmed.

Coverage and adequate reimbursement may not be available for our product candidates, which could make it difficult for us to sell profitably or at all, if approved.

Market acceptance and sales of any product candidates that we commercialize, if approved, will depend in part on the extent to which reimbursement for these drugs and related treatments will be available from third-party payors,

80


 

including government health administration authorities, managed care organizations and other private health insurers. Our ability to commercialize any products successfully will also depend in part on the extent to which coverage and adequate reimbursement for the procedures utilizing our product candidates, performed by health care providers, once approved, will be available from government health administration authorities, private health insurers and other organizations. Government authorities and other third-party payors, such as private health insurers and health maintenance organizations, determine which procedures, and the products utilized in such procedures, they will cover and establish reimbursement levels. Assuming coverage is obtained for procedures utilizing a given product by a third-party payor, the resulting reimbursement payment rates may not be adequate or may require co-payments that patients find unacceptably high. Patients who undergo procedures for the treatment of their conditions, and their treating physicians, generally rely on third-party payors to reimburse all or part of the costs associated with the procedures which utilize our products. Treating physicians are unlikely to use and order our products unless coverage is provided and the reimbursement is adequate to cover all or a significant portion of the cost of the procedures which utilize our products. Therefore, coverage and adequate reimbursement for procedures which utilize new products is critical to the acceptance of such new products. Coverage decisions may depend upon clinical and economic standards that disfavor new products when more established or lower cost therapeutic alternatives are already available or subsequently become available.

While no uniform policy for coverage and reimbursement exists in the United States, third-party payors often rely upon Medicare coverage policy and payment limitations in setting their own coverage and reimbursement policies. However, decisions regarding the extent of coverage and amount of reimbursement to be provided for any product candidates that we develop will be made on a payor-by-payor basis. Therefore, one payor’s determination to provide coverage for a drug does not assure that other payors will also provide coverage, and adequate reimbursement, for the drug. Additionally, a third-party payor’s decision to provide coverage for a therapy does not imply that an adequate reimbursement rate will be approved. Each payor determines whether or not it will provide coverage for a therapy, what amount it will pay the manufacturer for the therapy, and on what tier of its formulary it will be placed. The position on a payor’s list of covered drugs, or formulary, generally determines the co-payment that a patient will need to make to obtain the therapy and can strongly influence the adoption of such therapy by patients and physicians. Patients who are prescribed treatments for their conditions and providers prescribing such services generally rely on third-party payors to reimburse all or part of the associated healthcare costs. Patients are unlikely to use our products unless coverage is provided and reimbursement is adequate to cover a significant portion of the cost of our products.

Third-party payors have attempted to control costs by limiting coverage and the amount of reimbursement for particular medications. We cannot be sure that coverage and reimbursement will be available for any drug that we commercialize and, if reimbursement is available, what the level of reimbursement will be. Inadequate coverage and reimbursement may impact the demand for, or the price of, any drug for which we obtain marketing approval. Additionally, we or our collaborators may develop companion diagnostic tests for use with our product candidates. Companion diagnostic tests require coverage and reimbursement separate and apart from the coverage and reimbursement for their companion pharmaceutical or biological products. Similar challenges to obtaining coverage and reimbursement, applicable to pharmaceutical products, will apply to companion diagnostics. If coverage and adequate reimbursement are not available, or are available only to limited levels, we may not be able to successfully commercialize any product candidates that we develop.

81


 

Even if we are successful in obtaining regulatory approval, commercial success of any approved products will also depend in large part on the availability of insurance coverage and adequate reimbursement from third-party payors, including government payors, such as the Medicare and Medicaid programs, and managed care organizations, which may be affected by existing and future healthcare reform measures designed to reduce the cost of healthcare. Third-party payors could require us to conduct additional studies, including post-marketing studies related to the cost-effectiveness of a product, to qualify for reimbursement, which could be costly and divert our resources. If government and other healthcare payors were not to provide adequate insurance coverage and reimbursement levels for any of our products once approved, market acceptance and commercial success would be limited.

We may become exposed to costly and damaging liability claims, either when testing our product candidates in the clinic or at the commercial stage, and our product liability insurance may not cover all damages from such claims.

We are exposed to potential product liability and professional indemnity risks that are inherent in the research, development, manufacturing, marketing and use of biopharmaceutical products. Currently, we have no products that have been approved for commercial sale; however, the current and future use of product candidates by us and our collaborators in clinical trials, and the potential sale of any approved products in the future, may expose us to liability claims. These claims might be made by patients who use the product, healthcare providers, pharmaceutical companies, our collaborators, or others selling such products. Any claims against us, regardless of their merit, could be difficult and costly to defend and could materially adversely affect the market for our product candidates or any prospects for commercialization of our product candidates. Although the clinical trial process is designed to identify and assess potential side effects, it is always possible that a product, even after regulatory approval, may exhibit unforeseen side effects. If any of our product candidates were to cause adverse side effects during clinical trials or after approval of the product candidate, we may be exposed to substantial liabilities. Physicians and patients may not comply with any warnings that identify known potential adverse effects and patients who should not use our product candidates. Regardless of the merits or eventual outcome, liability claims may result in:

decreased demand for our products due to negative public perception;
injury to our reputation;
withdrawal of clinical trial participants or difficulties in recruiting new trial participants;
initiation of investigations by regulators;
costs to defend or settle the related litigation;
a diversion of management’s time and our resources;
substantial monetary awards to trial participants or patients;
product recalls, withdrawals or labeling, marketing or promotional restrictions;
loss of revenues from product sales; and
the inability to commercialize any of our product candidates, if approved.

Although we believe we maintain adequate product liability insurance for our product candidates, it is possible that our liabilities could exceed our insurance coverage. We intend to expand our insurance coverage to include the sale of commercial products if we obtain marketing approval for any of our product candidates. However, we may not be able to maintain insurance coverage at a reasonable cost or obtain insurance coverage that will be adequate to satisfy any liability that may arise. If a successful product liability claim or series of claims is brought against us for uninsured liabilities or in excess of insured liabilities, our assets may not be sufficient to cover such claims and our business operations could be impaired.

Should any of the events described above occur, this could have a material adverse effect on our business, financial condition, and results of operations.

82


 

Risks Related to Regulatory Matters

Even if we obtain FDA approval for any of our product candidates in the United States, we may never obtain approval for or commercialize any of them in any other jurisdiction, which would limit our ability to realize their full market potential.

In order to market any products in any particular jurisdiction, we must establish and comply with numerous and varying regulatory requirements on a country-by-country basis regarding safety and efficacy.

Approval by the FDA in the United States does not ensure approval by regulatory authorities in other countries or jurisdictions. However, the failure to obtain approval in one jurisdiction may negatively impact our ability to obtain approval elsewhere. In addition, clinical trials conducted in one country may not be accepted by regulatory authorities in other countries, and regulatory approval in one country does not guarantee regulatory approval in any other country.

Approval processes vary among countries and can involve additional product testing and validation and additional administrative review periods. Seeking foreign regulatory approval could result in difficulties and increased costs for us and require additional preclinical studies or clinical trials which could be costly and time consuming. Regulatory requirements can vary widely from country to country and could delay or prevent the introduction of our products in those countries. We do not have any product candidates approved for sale in any jurisdiction, including in international markets, and we do not have experience in obtaining regulatory approval in international markets. If we fail to comply with regulatory requirements in international markets or to obtain and maintain required approvals, or if regulatory approvals in international markets are delayed, our target market will be reduced and our ability to realize the full market potential of any product we develop will be unrealized.

Even if we receive regulatory approval of any product candidates, we will be subject to ongoing regulatory obligations and continued regulatory review, which may result in significant additional expense, and we may be subject to penalties if we fail to comply with regulatory requirements or experience unanticipated problems with our product candidates.

If any of our product candidates are approved, they will be subject to ongoing regulatory requirements for manufacturing, labeling, packaging, storage, advertising, promotion, sampling, record-keeping, conduct of post-marketing studies and submission of safety, efficacy, and other post-market information, including both federal and state requirements in the United States and requirements of comparable foreign regulatory authorities. In addition, we will be subject to continued compliance with cGMP and GCP requirements for any clinical trials that we conduct post-approval.

Manufacturers and manufacturers’ facilities are required to comply with extensive FDA and comparable foreign regulatory authority requirements, including ensuring that quality control and manufacturing procedures conform to cGMP regulations. As such, we and our contract manufacturers will be subject to continual review and inspections to assess compliance with cGMP and adherence to commitments made in any NDA, other marketing application, and previous responses to inspection observations. Accordingly, we and others with whom we work must continue to expend time, money, and effort in all areas of regulatory compliance, including manufacturing, production, and quality control.

Any regulatory approvals that we receive for our product candidates may be subject to limitations on the approved indicated uses for which the product may be marketed or to the conditions of approval, or contain requirements for potentially costly post-marketing testing, including Phase 4 clinical trials and surveillance to monitor the safety and efficacy of the product candidate. The FDA may also require a REMS program as a condition of approval of our product candidates, which could entail requirements for long-term patient follow-up, a medication guide, physician communication plans or additional elements to ensure safe use, such as restricted distribution methods, patient registries and other risk minimization tools. Comparable foreign regulatory authorities may also have programs similar to REMS. In addition, if the FDA or a comparable foreign regulatory authority approves our product candidates, we will have to comply with requirements including submissions of safety and other post-marketing information and reports and registration.

83


 

The FDA may impose consent decrees or withdraw approval if compliance with regulatory requirements and standards is not maintained or if problems occur after the product reaches the market. Later discovery of previously unknown problems with our product candidates, including adverse events of unanticipated severity or frequency, or with our third-party manufacturers or manufacturing processes, or failure to comply with regulatory requirements, may result in revisions to the approved labeling to add new safety information; imposition of post-market studies or clinical trials to assess new safety risks; or imposition of distribution restrictions or other restrictions under a REMS program. Other potential consequences include, among other things:

restrictions on the marketing or manufacturing of our products, withdrawal of the product from the market or voluntary or mandatory product recalls;
fines, warning letters or holds on clinical trials;
refusal by the FDA to approve pending applications or supplements to approved applications filed by us or suspension or revocation of license approvals;
product seizure or detention or refusal to permit the import or export of our product candidates; and
injunctions or the imposition of civil or criminal penalties.

The FDA strictly regulates marketing, labeling, advertising, and promotion of products that are placed on the market. Products may be promoted only for the approved indications and in accordance with the provisions of the approved label. The FDA and other agencies actively enforce the laws and regulations prohibiting the promotion of off-label uses and a company that is found to have improperly promoted off-label uses may be subject to significant liability. However, physicians may, in their independent medical judgment, prescribe legally available products for off-label uses. The FDA does not regulate the behavior of physicians in their choice of treatments, but the FDA does restrict manufacturer’s communications on the subject of off-label use of their products. The policies of the FDA and of comparable foreign regulatory authorities may change and additional government regulations may be enacted that could prevent, limit, or delay regulatory approval of our product candidates. We cannot predict the likelihood, nature or extent of government regulation that may arise from future legislation or administrative action, either in the United States or abroad. If we are slow or unable to adapt to changes in existing requirements or the adoption of new requirements or policies, or if we are not able to maintain regulatory compliance, we may lose any marketing approval that we may have obtained and we may not achieve or sustain profitability.

Our relationships with customers, physicians, and third-party payors are subject, directly or indirectly, to federal and state healthcare fraud and abuse laws, false claims laws, transparency, health information privacy and security laws, and other healthcare laws and regulations. If we are unable to comply, or have not fully complied, with such laws, we could face substantial penalties.

Healthcare providers and third-party payors in the United States and elsewhere will play a primary role in the recommendation and prescription of any product candidates for which we obtain marketing approval. Our current and future arrangements with healthcare professionals, principal investigators, consultants, customers, and third-party payors subject us to various federal and state fraud and abuse laws and other healthcare laws that may constrain the business or financial arrangements and relationships through which we research, sell, market, and distribute our product candidates, if we obtain marketing approval. Such laws include:

the U.S. federal Anti-Kickback Statute, which prohibits, among other things, persons or entities from knowingly and willfully soliciting, offering, receiving or providing any remuneration (including any kickback, bribe, or certain rebate), directly or indirectly, overtly or covertly, in cash or in kind, to induce or reward, or in return for, either the referral of an individual for, or the purchase, lease, order or recommendation of, any good, facility, item or service, for which payment may be made, in whole or in part, under U.S. federal and state healthcare programs such as Medicare and Medicaid. A person or entity does not need to have actual knowledge of the statute or specific intent to violate it in order to have committed a violation;
the U.S. federal civil and criminal false claims laws, including the civil False Claims Act, which can be enforced by private individuals on behalf of the government through civil whistleblower or qui tam actions, and civil monetary penalties laws prohibit, among other things, individuals or entities from knowingly presenting, or causing to be presented, to the U.S. federal government, claims for payment or

84


 

approval that are false or fraudulent, knowingly making, using or causing to be made or used, a false record or statement material to a false or fraudulent claim, or from knowingly making a false statement to avoid, decrease or conceal an obligation to pay money to the U.S. federal government. Manufacturers can be held liable under the False Claims Act even when they do not submit claims directly to government payors if they are deemed to “cause” the submission of false or fraudulent claims. In addition, the government may assert that a claim including items and services resulting from a violation of the U.S. federal Anti-Kickback Statute constitutes a false or fraudulent claim for purposes of the civil False Claims Act;
the Health Insurance Portability and Accountability Act (HIPAA), which created additional federal civil and criminal liability for, among other things, knowingly and willfully executing, or attempting to execute, a scheme to defraud any healthcare benefit program, or knowingly and willfully falsifying, concealing or covering up a material fact or making any materially false statement, in connection with the delivery of, or payment for, healthcare benefits, items or services. Similar to the U.S. federal Anti-Kickback Statute, a person or entity does not need to have actual knowledge of the statute or specific intent to violate it in order to have committed a violation;
HIPAA, as amended by the Health Information Technology for Economic and Clinical Health Act (HITECH) and their implementing regulations, which impose certain obligations, including mandatory contractual terms, with respect to safeguarding the privacy, security and transmission of individually identifiable health information without appropriate authorization by covered entities subject to the rule, such as health plans, healthcare clearinghouses and certain healthcare providers and their business associates, independent contractors of a covered entity that perform certain services involving the use or disclosure of individually identifiable health information, as well as their covered subcontractors. HITECH also created new tiers of civil monetary penalties, amended HIPAA to make civil and criminal penalties directly applicable to business associates, and gave state attorneys general new authority to file civil actions for damages or injunctions in federal courts to enforce the federal HIPAA laws and seek attorneys’ fees and costs associated with pursuing federal civil actions;
the Federal Food, Drug, and Cosmetic Act, which prohibits, among other things, the adulteration or misbranding of drugs, biologics and medical devices;
the U.S. Public Health Service Act, which prohibits, among other things, the introduction into interstate commerce of a biological product unless a biologics license is in effect for that product;
the U.S. Physician Payments Sunshine Act and its implementing regulations, which require certain manufacturers of drugs, devices, biologics and medical supplies that are reimbursable under Medicare, Medicaid, or the Children’s Health Insurance Program, with specific exceptions, to report annually to the Centers for Medicare & Medicaid Services (CMS) information related to certain payments and other transfers of value to physicians (currently defined to include doctors, dentists, optometrists, podiatrists and chiropractors), other healthcare professionals (such as physicians assistants and nurse practitioners), and teaching hospitals, as well as ownership and investment interests held by physicians and their immediate family members;
analogous U.S. state laws and regulations, including: state anti-kickback and false claims laws, which may apply to our business practices, including but not limited to, research, distribution, sales and marketing arrangements and claims involving healthcare items or services reimbursed by any third-party payor, including private insurers; state laws that require pharmaceutical companies to comply with the pharmaceutical industry’s voluntary compliance guidelines and the relevant compliance guidance promulgated by the U.S. federal government, or otherwise restrict payments that may be made to healthcare providers and other potential referral sources; state laws and regulations that require drug manufacturers to file reports relating to drug pricing and marketing information, which requires tracking gifts and other remuneration and items of value provided to healthcare professionals and entities; state and local laws that require the registration of pharmaceutical sales representatives; and state laws governing the privacy and security of health information in certain circumstances, many of which differ from each other in significant ways and often are not preempted by HIPAA, thus complicating compliance efforts; and
analogous laws in other jurisdictions including, but not limited to, laws relating to interactions with government officials, privacy laws, transparency laws, laws relating to reimbursement, competition,

85


 

consumer protection laws, laws relating to the marketing of health products and other healthcare-related laws.

In addition, we are also subject to federal and state consumer protection and unfair competition laws, which broadly regulate marketplace activities and activities that potentially harm customers.

Ensuring that our business arrangements with third parties comply with applicable healthcare laws and regulations will likely be costly. It is possible that governmental authorities will conclude that our business practices may not comply with current or future statutes, regulations or case law involving applicable fraud and abuse or other healthcare laws and regulations. If our operations are found to be in violation of any of these laws or any other governmental regulations that may apply to us, we may be subject to significant civil, criminal and administrative penalties, damages, fines, disgorgement, imprisonment, exclusion from participating in government funded healthcare programs, such as Medicare and Medicaid, additional reporting requirements and oversight if we become subject to a corporate integrity agreement or similar agreement to resolve allegations of non-compliance with these laws, contractual damages, reputational harm and the curtailment or restructuring of our operations.

If the physicians or other providers or entities with whom we expect to do business are found not to be in compliance with applicable laws, they may be subject to significant criminal, civil or administrative sanctions, including exclusions from government funded healthcare programs. Even if resolved in our favor, litigation or other legal proceedings relating to healthcare laws and regulations may cause us to incur significant expenses and could distract our technical and management personnel from their normal responsibilities. In addition, there could be public announcements of the results of hearings, motions or other interim proceedings or developments. If securities analysts or investors perceive these results to be negative, it could have a substantial adverse effect on the price of our common shares. Such litigation or proceedings could substantially increase our operating losses and reduce the resources available for development, manufacturing, sales, marketing, or distribution activities. Uncertainties resulting from the initiation and continuation of litigation or other proceedings relating to applicable healthcare laws and regulations could have a material adverse effect on our ability to compete in the marketplace.

Enacted and future healthcare legislation may increase the difficulty and cost for us to progress our clinical programs and obtain marketing approval of and commercialize our product candidates and may affect the prices we may set.

In the United States and other jurisdictions, there have been, and we expect there will continue to be, a number of legislative and regulatory changes and proposed changes to the healthcare system that could affect our future results of operations. For example, in March 2010, the Patient Protection and Affordable Care Act (ACA) was enacted, which substantially changed the way healthcare is financed by both governmental and private insurers. The ACA, among other things, increased the minimum level of Medicaid rebates payable by manufacturers of brand name drugs; required collection of rebates for drugs paid by Medicaid managed care organizations; required manufacturers to participate in a coverage gap discount program, under which they must agree to offer point-of-sale discounts (increased to 70 percent, effective as of January 1, 2019) off negotiated prices of applicable brand drugs to eligible beneficiaries during their coverage gap period, as a condition for the manufacturer’s outpatient drugs to be covered under Medicare Part D; imposed a non-deductible annual fee on pharmaceutical manufacturers or importers who sell certain “branded prescription drugs” to specified federal government programs, implemented a new methodology by which rebates owed by manufacturers under the Medicaid Drug Rebate Program are calculated for drugs that are inhaled, infused, instilled, implanted, or injected expanded the types of entities eligible for the 340B drug discount program; expanded eligibility criteria for Medicaid programs; created a new Patient-Centered Outcomes Research Institute to oversee, identify priorities in, and conduct comparative clinical effectiveness research, along with funding for such research; and established a Center for Medicare Innovation at CMS to test innovative payment and service delivery models to lower Medicare and Medicaid spending, potentially including prescription drug spending.

There have been judicial, Congressional and executive branch challenges to certain aspects of the ACA. For example, on June 17, 2021, the U.S. Supreme Court dismissed a challenge on procedural grounds that argued the ACA is unconstitutional in its entirety because the “individual mandate” was repealed by Congress. Moreover, prior to the U.S. Supreme Court ruling, on January 28, 2021, President Biden issued an executive order that initiated a special enrollment period for purposes of obtaining health insurance coverage through the ACA marketplace. The executive

86


 

order also instructed certain governmental agencies to review and reconsider their existing policies and rules that limit access to healthcare, including among others, reexamining Medicaid demonstration projects and waiver programs that include work requirements, and policies that create unnecessary barriers to obtaining access to health insurance coverage through Medicaid or the ACA. Further, on August 16, 2022, President Biden signed the Inflation Reduction Act of 2022 (IRA) into law, which among other things, extends enhanced subsidies for individuals purchasing health insurance coverage in ACA marketplaces through plan year 2025. The IRA also eliminates the “donut-hole” under the Medicare Part D program beginning in 2025 by significantly lowering the beneficiary maximum out-of-pocket cost and through a newly established manufacturer discount program. It is possible that the ACA will be subject to judicial or Congressional challenges in the future. It is also unclear how any such challenges and other litigation, and further healthcare reform measures of the Biden administration will impact the ACA and our business.

In addition, other legislative changes have been proposed and adopted in the United States since the ACA was enacted. In August 2011, the Budget Control Act of 2011, among other things, led to aggregate reductions of Medicare payments to providers of 2% per fiscal year. These reductions went into effect in April 2013 and, due to subsequent legislative amendments to the statute will remain in effect until 2032 unless additional action is taken by Congress. On March 11, 2021, President Biden signed the American Rescue Plan Act of 2021 into law, which eliminates the statutory Medicaid drug rebate cap, currently set at 100% of a drug’s average manufacturer price, for single source and innovator multiple source drugs, beginning January 1, 2024. In January 2013, the American Taxpayer Relief Act of 2012 was signed into law, which, among other things, further reduced Medicare payments to several types of providers, including hospitals, imaging centers and cancer treatment centers, and increased the statute of limitations period for the government to recover overpayments to providers from three to five years. These new laws or any other similar laws introduced in the future may result in additional reductions in Medicare and other health care funding, which could negatively affect our customers and accordingly, our financial operations.

Moreover, payment methodologies may be subject to changes in healthcare legislation and regulatory initiatives. For example, CMS may develop new payment and delivery models, such as bundled payment models. In addition, recently there has been heightened governmental scrutiny over the manner in which manufacturers set prices for their marketed products, which has resulted in several U.S. Congressional inquiries and proposed and enacted federal legislation designed to, among other things, bring more transparency to drug pricing, reduce the cost of prescription drugs under Medicare, and review the relationship between pricing and manufacturer patient programs. For example, in July 2021, the Biden administration released an executive order, “Promoting Competition in the American Economy,” with multiple provisions aimed at prescription drugs. In response to Biden’s executive order, on September 9, 2021, the U.S. Department of Health and Human Services (HHS) released a Comprehensive Plan for Addressing High Drug Prices that outlines principles for drug pricing reform and sets out a variety of potential legislative policies that Congress could pursue as well as potential administrative actions HHS can take to advance these principles. In addition, the IRA, among other things, (1) directs HHS to negotiate the price of certain single source drugs and biologics covered under Medicare and (2) imposes rebates under Medicare Part B and Medicare Part D to penalize price increases that outpace inflation. The IRA permits HHS to implement many of these provisions through guidance, as opposed to regulation, for the initial years. HHS has and will continue to issue and update guidance as these programs are implemented. These provisions take effect progressively starting in fiscal year 2023. On August 29, 2023, HHS announced the list of the first ten drugs that will be subject to price negotiations, although the Medicare drug price negotiation program is currently subject to legal challenges. It is currently unclear how the IRA will be implemented, but it is likely to have a significant impact on the pharmaceutical industry. Further, in response to the Biden administration’s October 2022 executive order, on February 14, 2023, HHS released a report outlining three new models for testing by the CMS Innovation Center which will be evaluated on their ability to lower the cost of drugs, promote accessibility, and improve quality of care. Further, on December 7, 2023, the Biden administration announced an initiative to control the price of prescription drugs through the use of march-in rights under the Bayh-Dole Act. On December 8, 2023, the National Institute of Standards and Technology published for comment a Draft Interagency Guidance Framework for Considering the Exercise of March-In Rights which for the first time includes the price of a product as one factor an agency can use when deciding to exercise march-in rights. While march-in rights have not previously been exercised, it is uncertain if that will continue under the new framework. It is unclear whether the models will be utilized in any health reform measures in the future. We expect that additional U.S. federal healthcare reform measures will be adopted in the future, any of which could limit the amounts that the U.S. federal government will pay for healthcare products and services, which could result in reduced demand for our product candidates or additional pricing pressures.

87


 

We may face potential liability if we obtain identifiable patient health information from clinical trials sponsored by us.

Most healthcare providers, including certain research institutions from which we may obtain patient health information, are subject to privacy and security regulations promulgated under HIPAA, as amended by the HITECH. We are not currently classified as a covered entity or business associate under HIPAA and thus are not directly subject to its requirements or penalties. However, any person may be prosecuted under HIPAA’s criminal provisions either directly or under aiding-and-abetting or conspiracy principles. Consequently, depending on the facts and circumstances, we could face substantial criminal penalties if we knowingly receive individually identifiable health information from a HIPAA-covered healthcare provider or research institution that has not satisfied HIPAA’s requirements for disclosure of individually identifiable health information. In addition, in the future, we may maintain sensitive personally identifiable information, including health information, that we receive throughout the clinical trial process, in the course of our research collaborations, and directly from individuals (or their healthcare providers) who may enroll in patient assistance programs if we choose to implement such programs. As such, we may be subject to state laws requiring notification of affected individuals and state regulators in the event of a breach of personal information, which is a broader class of information than the health information protected by HIPAA.

The EU General Data Protection Regulation (GDPR) also confers a private right of action on data subjects and consumer associations to lodge complaints with supervisory authorities, seek judicial remedies, and obtain compensation for damages resulting from violations of the GDPR. In addition, the GDPR includes restrictions on cross-border data transfers. The GDPR may increase our responsibility and liability in relation to personal data that we process where such processing is subject to the GDPR, and we may be required to put in place additional mechanisms to ensure compliance with the GDPR, including as implemented by individual countries. Compliance with the GDPR will be a rigorous and time-intensive process that may increase our cost of doing business or require us to change our business practices, and despite those efforts, there is a risk that we may be subject to fines and penalties, litigation, and reputational harm in connection with our European activities. Further, the United Kingdom’s decision to leave the European Union, referred to as Brexit, has created uncertainty with regard to data protection regulation in the United Kingdom. In particular, it is unclear how data transfers to and from the United Kingdom will be regulated now that the United Kingdom has left the European Union.

Furthermore, certain health privacy laws, data breach notification laws, consumer protection laws and genetic testing laws may apply directly to our operations and/or those of our collaborators and may impose restrictions on our collection, use and dissemination of individuals’ health information. Patients about whom we or our collaborators may obtain health information, as well as the providers who may share this information with us, may have statutory or contractual rights that limit our ability to use and disclose the information. We may be required to expend significant capital and other resources to ensure ongoing compliance with applicable privacy and data security laws. Claims that we have violated individuals’ privacy rights or breached our contractual obligations, even if we are not found liable, could be expensive and time-consuming to defend and could result in adverse publicity that could harm our business.

If we or third-party CMOs, CROs or other contractors or consultants fail to comply with applicable federal, state/provincial or local regulatory requirements, we could be subject to a range of regulatory actions that could affect our or our contractors’ ability to develop and commercialize our therapeutic candidates and could harm or prevent sales of any affected therapeutics that we are able to commercialize, or could substantially increase the costs and expenses of developing, commercializing and marketing our therapeutics. Any threatened or actual government enforcement action could also generate adverse publicity and require that we devote substantial resources that could otherwise be used in other aspects of our business. Increasing use of social media could give rise to liability, breaches of data security or reputational damage.

Additionally, we are subject to state and foreign equivalents of each of the healthcare laws described above, among others, some of which may be broader in scope and may apply regardless of the payor.

88


 

If we or our third-party manufacturers and suppliers fail to comply with environmental, health and safety laws and regulations, we could become subject to fines or penalties or incur costs that could have a material adverse effect on the success of our business.

We are subject to numerous environmental, health and safety laws and regulations, including those governing laboratory procedures and the handling, use, storage, treatment and disposal of hazardous materials and wastes. Our research and development activities involve the use of biological and hazardous materials and produce hazardous waste products. We generally contract with third parties for the disposal of these materials and wastes. We cannot eliminate the risk of contamination or injury from these materials, which could cause an interruption of our commercialization efforts, research and development efforts and business operations, environmental damage resulting in costly clean-up and liabilities under applicable laws and regulations governing the use, storage, handling and disposal of these materials and specified waste products. Although we believe that the safety procedures utilized by our third-party manufacturers for handling and disposing of these materials generally comply with the standards prescribed by these laws and regulations, we cannot guarantee that this is the case or eliminate the risk of accidental contamination or injury from these materials. In such an event, we may be held liable for any resulting damages and such liability could exceed our resources and state or federal or other applicable authorities may curtail our use of certain materials and/or interrupt our business operations. Furthermore, environmental laws and regulations are complex, change frequently and have tended to become more stringent. We cannot predict the impact of such changes and cannot be certain of our future compliance. In addition, we may incur substantial costs in order to comply with current or future environmental, health and safety laws and regulations. These current or future laws and regulations may impair our research, development, or production efforts. Failure to comply with these laws and regulations also may result in substantial fines, penalties, or other sanctions.

Although we maintain workers’ compensation insurance to cover us for costs and expenses, we may incur due to injuries to our employees resulting from the use of hazardous materials or other work-related injuries, this insurance may not provide adequate coverage against potential liabilities. We do not carry specific biological waste or hazardous waste insurance coverage, workers compensation or property and casualty and general liability insurance policies that include coverage for damages and fines arising from biological or hazardous waste exposure or contamination.

We are subject to U.S. and certain foreign export and import controls, sanctions, embargoes, anti-corruption laws, and anti-money laundering laws and regulations. Compliance with these legal standards could impair our ability to compete in domestic and international markets. We can face criminal liability and other serious consequences for violations, which can harm our business.

We are subject to export control and import laws and regulations, including the U.S. Export Administration Regulations, U.S. Customs regulations, various economic and trade sanctions regulations administered by the U.S. Treasury Department’s Office of Foreign Assets Controls, the U.S. Foreign Corrupt Practices Act of 1977, as amended (FCPA), the U.S. domestic bribery statute contained in 18 U.S.C. § 201, the U.S. Travel Act, the USA PATRIOT Act, and other state and national anti-bribery and anti-money laundering laws in the countries in which we conduct activities. Trade controls may restrict or prohibit altogether the sale or supply of certain products and services to certain governments, persons, entities, countries, and territories, including those that are the target of comprehensive sanctions, unless there are license exceptions that apply or specific licenses are obtained. Anti-corruption laws are interpreted broadly and prohibit companies and their employees, agents, contractors, and other collaborators from authorizing, promising, offering, or providing, directly or indirectly, improper payments or anything else of value to recipients in the public or private sector. We may engage third parties for clinical trials outside of the United States, to sell our products abroad once we enter a commercialization phase, and/or to obtain necessary permits, licenses, patent registrations, and other regulatory approvals. We may also have direct or indirect interactions with officials and employees of government agencies or government-affiliated hospitals, universities, and other organizations. We can be held liable for the corrupt or other illegal activities of our employees, agents, contractors, and other collaborators, even if we do not explicitly authorize or have actual knowledge of such activities. Any violations of the laws and regulations described above may result in substantial civil and criminal fines and penalties, imprisonment, the loss of export or import privileges, debarment, tax reassessments, breach of contract and fraud litigation, reputational harm, and other consequences.

89


 

Risks Related to Our Dependence on Third Parties

We rely, and expect to continue to rely, on third parties, including independent clinical investigators, contracted laboratories and CROs, to conduct our preclinical studies and clinical trials. If these third parties do not successfully carry out their contractual duties or meet expected deadlines, we may not be able to obtain regulatory approval for or commercialize our product candidates and our business could be substantially harmed.

We have relied upon and plan to continue to rely upon third parties, including independent clinical investigators, contracted laboratories and third-party CROs, to conduct our preclinical studies and clinical trials in accordance with applicable regulatory requirements and to monitor and manage data for our ongoing preclinical and clinical programs. We rely on these parties for execution of our preclinical studies and clinical trials, and control only certain aspects of their activities. Nevertheless, we are responsible for ensuring that each of our studies and trials is conducted in accordance with the applicable protocol, legal and regulatory requirements and scientific standards, and our reliance on these third parties does not relieve us of our regulatory responsibilities. We and our third party contractors and CROs are required to comply with good laboratory practices (GLPs), as applicable, and GCP requirements, which are regulations and guidelines enforced by the FDA and comparable foreign regulatory authorities for all of our products in clinical development. Regulatory authorities enforce these GLPs and GCPs through periodic inspections of laboratories conducting GLP studies, trial sponsors, principal investigators, and trial sites. If we, our investigators, or any of our CROs or contracted laboratories fail to comply with applicable GLPs and GCPs, the clinical data generated in our clinical trials may be deemed unreliable and the FDA or comparable foreign regulatory authorities may require us to perform additional preclinical studies or clinical trials before approving our marketing applications. We cannot assure you that upon inspection by a given regulatory authority, such regulatory authority will determine that any of our preclinical studies or clinical trials comply with applicable GLP or GCP regulations. In addition, our clinical trials must be conducted with product, including biologic product, produced in compliance with applicable cGMP regulations. Our failure to comply with these regulations may require us to repeat preclinical studies or clinical trials, which would delay the regulatory approval process.

Further, these laboratories, investigators and CROs are not our employees and we will not be able to control, other than by contract, the amount of resources, including time, which they devote to our product candidates and clinical trials. If independent laboratories, investigators or CROs fail to devote sufficient resources to the development of our product candidates, or if their performance is substandard, it may delay or compromise the prospects for approval and commercialization of any product candidates that we develop. In addition, the use of third-party service providers requires us to disclose our proprietary information to these parties, which could increase the risk that this information will be misappropriated.

Our CROs have the right to terminate their agreements with us in the event of an uncured material breach. In addition, some of our CROs have an ability to terminate their respective agreements with us if we make a general assignment for the benefit of our creditors or if we are liquidated.

If any of our relationships with these third-party laboratories, CROs or clinical investigators terminate, we may not be able to enter into arrangements with alternative laboratories, CROs or investigators or to do so in a timely manner or on commercially reasonable terms. If laboratories, CROs or clinical investigators do not successfully carry out their contractual duties or obligations or meet expected deadlines, if they need to be replaced or if the quality or accuracy of the clinical data they obtain is compromised due to the failure to adhere to our preclinical or clinical protocols, regulatory requirements or for other reasons, our preclinical or clinical trials may be extended, delayed or terminated and we may not be able to obtain regulatory approval for or successfully commercialize our product candidates. As a result, our results of operations and the commercial prospects for our product candidates would be harmed, our costs could increase and our ability to generate revenues could be delayed.

Switching or adding additional laboratories or CROs (or investigators) involves additional cost and requires management time and focus. In addition, there is a natural transition period when a new laboratory or CRO commences work. As a result, delays occur, which can materially impact our ability to meet our desired clinical development timelines. Though we carefully manage our relationships with our contracted laboratories and CROs, there can be no assurance that we will not encounter similar challenges or delays in the future or that these delays or challenges will not have a material adverse impact on our business, financial condition, and results of operations.

90


 

In addition, clinical investigators may serve as scientific advisors or consultants to us from time to time and may receive cash or equity compensation in connection with such services. If these relationships and any related compensation result in perceived or actual conflicts of interest, or the FDA concludes that the financial relationship may have affected the interpretation of the preclinical study or clinical trial, the integrity of the data generated at the applicable preclinical study or clinical trial site may be questioned and the utility of the preclinical study or clinical trial itself may be jeopardized, which could result in the delay or rejection by the FDA. Any such delay or rejection could prevent us from commercializing our clinical-stage product candidate or any future product candidates.

We rely on third parties to supply and manufacture our product candidates, and we expect to continue to rely on third parties to manufacture our products, if approved. The development of such product candidates and the commercialization of any products, if approved, could be stopped, delayed, or made less profitable if any such third party fails to provide us with sufficient quantities of product candidates or products or fails to do so at acceptable quality levels or prices or fails to maintain or achieve satisfactory regulatory compliance.

We do not currently have the infrastructure or capability internally to manufacture all our product candidates for use in the conduct of our preclinical studies and clinical trials or for commercial supply, if our products are approved. We rely on, and expect to continue to rely on, contract manufacturing organizations (CMOs). Any replacement of our CMOs could require significant effort and expertise because there may be a limited number of qualified CMOs. This could be particularly problematic where we rely on a single-source supplier. Reliance on third-party providers may expose us to more risk than if we were to manufacture our product candidates ourselves. We are dependent on our CMOs for the production of our product candidates in accordance with relevant regulations, such as cGMP, which includes, among other things, quality control, quality assurance and the maintenance of records and documentation. Moreover, many of the third parties with whom we contract may also have relationships with other commercial entities, including our competitors, for whom they may also be conducting product development activities that could harm our competitive position.

Our third-party manufacturers may be subject to damage or interruption from, among other things, fire, natural or man-made disaster, war, disease outbreaks or public health pandemics, power loss, telecommunications failure, unauthorized entry, computer viruses, denial-of-service attacks, acts of terrorism, human error, vandalism or sabotage, financial insolvency, bankruptcy, and similar events. For example, the COVID-19 pandemic impacted our supply chain, in particular our vendors’ ability to find staff, and may in the future impact our manufacturing activities.

If we were to experience an unexpected loss of supply of or if any supplier were unable to meet our demand for any of our product candidates, we could experience delays in our research or ongoing and planned clinical trials or commercialization. We could be unable to find alternative suppliers of acceptable quality, in the appropriate volumes who could meet our timelines at an acceptable cost. Moreover, our suppliers are often subject to strict manufacturing requirements and rigorous testing requirements, which could limit or delay production. The long transition periods necessary to switch manufacturers and suppliers, if necessary, could significantly delay our preclinical studies, our clinical trials, and the commercialization of our products, if approved, which could materially adversely affect our business, financial condition, and results of operation.

In complying with the applicable manufacturing regulations of the FDA and comparable foreign regulatory authorities, we and our third-party suppliers must spend significant time, money, and effort in the areas of design and development, testing, production, record-keeping, and quality control to assure that the products meet applicable specifications and other regulatory requirements. The failure to comply with these requirements could result in an enforcement action against us, including the seizure of products and shutting down of production. We and any of these third-party suppliers may also be subject to audits by the FDA and comparable foreign regulatory authorities. If any of our third-party suppliers fails to comply with cGMP or other applicable manufacturing regulations, our ability to develop and commercialize the products could suffer significant interruptions. We face risks inherent in relying on CMOs, as any disruption, such as a fire, natural hazards, vandalism, or an outbreak of contagious disease affecting the CMO or any supplier of the CMO could significantly interrupt our manufacturing capability. In case of a disruption, we will have to establish alternative manufacturing sources. This would require substantial capital on our part, which we may not be able to obtain on commercially acceptable terms or at all. Additionally, we would likely experience months of manufacturing delays as the CMO builds or locates replacement facilities and seeks and obtains necessary regulatory approvals. If this occurs, we will be unable to satisfy manufacturing needs on a timely basis, if at all.

91


 

Our current and future collaborations will be important to our business. If we are unable to enter into new collaborations as appropriate, or if these collaborations are not successful, our business could be adversely affected.

A part of our strategy is to strategically evaluate and, as deemed appropriate, enter into partnerships in the future when strategically attractive, including potentially with major biotechnology or pharmaceutical companies. We have limited capabilities for product development and do not yet have any capability for commercialization. Accordingly, we may enter into collaborations with other companies to provide us with important technologies and funding for our programs and technology. If we fail to enter into or maintain collaborations on reasonable terms or at all, our ability to develop our existing or future research programs and product candidates could be delayed, the commercial potential of our product could change, and our costs of development and commercialization could increase. Furthermore, we may find that our programs require the use of intellectual property rights held by third parties, and the growth of our business may depend in part on our ability to acquire or in-license these intellectual property rights.

For example, in June 2022, we entered into a collaboration and license agreement with Roche regarding the development and commercialization of our product candidate camonsertib and other specified ATR inhibitors, for which we received written notice of termination on February 7, 2024. In May 2020, we entered into a collaboration and license agreement with Bristol-Myers Squibb pursuant to which we and Bristol-Myers Squibb have agreed to collaborate in the research and development of potential new product candidates for the treatment of cancer. These and any future collaborations we enter into may pose a number of risks, including, but not limited to, the following:

collaborators have significant discretion in determining the efforts and resources that they will apply;
collaborators may not perform their obligations as expected;
collaborators may not pursue development and commercialization of any product candidates that achieve regulatory approval or may elect not to continue or renew development or commercialization programs or license arrangements based on clinical trial results, changes in the collaborators’ strategic focus or available funding, or external factors, such as a strategic transaction that may divert resources or create competing priorities;
collaborators may delay clinical trials, provide insufficient funding for a clinical trial program, stop a clinical trial or abandon a product candidate, repeat or conduct new clinical trials or require a new formulation of a product candidate for clinical testing;
collaborators could independently develop, or develop with third parties, products that compete directly or indirectly with our products and product candidates if the collaborators believe that the competitive products are more likely to be successfully developed or can be commercialized under terms that are more economically attractive than ours;
product candidates discovered in collaboration with us may be viewed by our collaborators as competitive with their own product candidates or products, which may cause collaborators to cease to devote resources to the commercialization of our product candidates;
collaborators may fail to comply with applicable regulatory requirements regarding the development, manufacture, distribution or marketing of a product candidate or product;
collaborators with marketing and distribution rights to one or more of our product candidates that achieve regulatory approval may not commit sufficient resources to the marketing and distribution of such product or products;
disagreements with collaborators, including disagreements over proprietary rights, contract interpretation or the preferred course of development, might cause delays or terminations of the research, development or commercialization of product candidates, might lead to additional responsibilities for us with respect to product candidates, or might result in litigation or arbitration, any of which would be time-consuming and expensive;
collaborators may not properly maintain or defend our intellectual property rights or may use our proprietary information in such a way as to invite litigation that could jeopardize or invalidate our intellectual property or proprietary information or expose us to potential litigation;

92


 

collaborators may infringe the intellectual property rights of third parties, which may expose us to litigation and potential liability;
a collaborator may choose to deemphasize the development or commercialization of a product candidate licensed to it by us;
if a collaborator of ours is involved in a business combination, the collaborator might deemphasize or terminate the development or commercialization of any product candidate licensed to it by us; and
collaborations may be terminated by the collaborator, and, if terminated, we could be required to raise additional capital to pursue further development or commercialization of the applicable product candidates.

If our collaborations do not result in the successful discovery, development, and commercialization of product candidates or if one of our collaborators terminates its agreement with us, we may not receive any future research funding or milestone or royalty payments under such collaboration. Moreover, we may not receive all of the milestone or royalty payments we are entitled to receive under our current and future collaboration agreements. For example, pursuant to the terms of the Roche Agreement we were entitled to receive up to $1.172 billion in potential development, regulatory, commercial and sales milestones, plus royalties on global net product sales. In February 2024, we received a $40 million milestone payment from Roche earned upon dosing of the first patient with camonsertib in Roche’s TAPISTRY trial. Additionally, pursuant to the terms of our collaboration and license agreement with Bristol-Myers Squibb, we are entitled to receive up to $301.0 million in total milestones per each program subject to the agreement. However, given the overlapping nature of the triggers for these milestone payments, as well as the uncertainty associated with achieving any of such milestones, it is unlikely that we will receive the entire $301.0 million in milestone payments with respect to each program subject to the agreement.

All of the risks relating to product development, regulatory approval and commercialization described in this Annual Report also apply to the activities of our therapeutic collaborators. Additionally, if one of our collaborators terminates its agreement with us, we may find it more difficult to attract new collaborators and our perception in the business and financial communities could be adversely affected.

We face significant competition in seeking appropriate collaborative partners. Our ability to reach a definitive agreement for a partnership will depend, among other things, upon an assessment of the collaborator’s resources and expertise, the terms and conditions of the proposed partnership and the proposed collaborator’s evaluation of a number of factors. These factors may include the design or results of preclinical studies or clinical trials, the likelihood of regulatory approval, the potential market for the subject product candidate, the costs and complexities of manufacturing and delivering such product candidate to patients, the potential of competing products, the existence of any uncertainty with respect to our ownership of technology (which can exist if there is a challenge to such ownership regardless of the merits of the challenge) and industry and market conditions generally. The collaborator may also consider alternative product candidates or technologies for similar indications that may be available to collaborate on and whether such a partnership could be more attractive than the one with us.

We may not be able to negotiate collaborations on a timely basis, on acceptable terms, or at all. If we are unable to do so, we may have to curtail the development of the product candidate for which we are seeking to collaborate, reduce or delay its development program or one or more of our other development programs, delay its potential commercialization, reduce the scope of any sales or marketing activities or increase our expenditures and undertake development or commercialization activities at our own expense. If we elect to increase our expenditures to fund development or commercialization activities on our own, we may need to obtain additional capital, which may not be available to us on acceptable terms or at all. If we do not have sufficient funds, we may not be able to further develop product candidates or bring them to market and generate product revenue.

93


 

Risks Related to Our Intellectual Property

Our success depends in part on our ability to obtain intellectual property rights for our proprietary technologies and product candidates, as well as our ability to protect our intellectual property. It is difficult and costly to protect our proprietary rights and technology, and we may not be able to ensure their protection.

Our commercial success will depend in large part on obtaining and maintaining patent, trademark and trade secret protection of our proprietary technologies and our product candidates, their respective components, formulations, combination therapies, methods used to manufacture them and methods of treatment, as well as successfully defending these patents against third-party challenges. Our ability to stop unauthorized third parties from making, using, selling, offering to sell, or importing our product candidates is dependent upon the extent to which we have rights under valid and enforceable patents that cover these activities. If we are unable to secure and maintain patent protection for any product or technology we develop, or if the scope of the patent protection secured is not sufficiently broad, our competitors could develop and commercialize products and technology similar or identical to ours, and our ability to commercialize any product candidates we may develop may be adversely affected. Moreover, we may not be able to obtain intellectual property protection with respect to the SL pairs that we identify which are the targets of our current and future product candidates. Although we expect that the compounds underlying our product candidates will be protectable through intellectual property rights, our competitors could develop their own inhibitors based on the SL pairs we identify that might not be protected by our intellectual property rights.

The patenting process is expensive and time-consuming, and we may not be able to file and prosecute all necessary or desirable patent applications at a reasonable cost or in a timely manner. In addition, we may not pursue or obtain patent protection in all relevant markets. It is also possible that we will fail to identify patentable aspects of our research and development output before it is too late to obtain patent protection. Moreover, in some circumstances, we may not have the right to control the preparation, filing and prosecution of patent applications, or to maintain the patents, covering technology that we license from or license to third parties and are reliant on our licensors or licensees. Roche controls prosecution of patents related to their in-license on camonsertib; however, such rights will revert to Repare upon the effectiveness of termination of the Roche Agreement.

The strength of patents in the biotechnology and pharmaceutical field involves complex legal and scientific questions and can be uncertain. The patent applications that we own or in-license may fail to result in issued patents with claims that cover our product candidates or uses thereof in the United States or in other foreign countries. Even if the patents do successfully issue, third parties may challenge the validity, enforceability, or scope thereof, which may result in such patents being narrowed, invalidated, or held unenforceable. Furthermore, even if they are unchallenged, our patents and patent applications may not adequately protect our intellectual property or prevent others from designing around our claims. If the breadth or strength of protection provided by the patent applications we hold with respect to our product candidates is threatened, it could dissuade companies from collaborating with us to develop, and threaten our ability to commercialize, our product candidates. Further, if we encounter delays in our clinical trials, the period of time during which we could market our product candidates under patent protection would be reduced.

Since patent applications in the United States and most other countries are confidential for a period of time after filing, we cannot be certain that we were the first to file any patent application related to our product candidates. Furthermore, for United States applications in which all claims are entitled to a priority date before March 16, 2013, an interference proceeding can be provoked by a third-party or instituted by the United States patent office (USPTO) to determine who was the first to invent any of the subject matter covered by the patent claims of our applications.

We cannot be certain that we are the first to invent the inventions covered by pending patent applications and, if we are not, we may be subject to priority disputes. We may be required to disclaim part or all of the term of certain patents or all of the term of certain patent applications. There may be prior art of which we are not aware that may affect the validity or enforceability of a patent claim. There also may be prior art of which we are aware, but which we do not believe affects the validity or enforceability of a claim, which may, nonetheless, ultimately be found to affect the validity or enforceability of a claim. No assurance can be given that if challenged, our patents would be declared by a court to be valid or enforceable or that even if found valid and enforceable, a competitor’s technology or product would be found by a court to infringe our patents. We may analyze patents or patent applications of our competitors that we believe are relevant to our activities and consider that we are free to operate in relation to our product candidates, but our competitors may achieve issued claims, including in patents we consider to be unrelated,

94


 

which block our efforts or may potentially result in our product candidates or our activities infringing such claims. The possibility exists that others will develop products which have the same effect as our products on an independent basis which do not infringe our patents or other intellectual property rights, or will design around the claims of patents that we have had issued that cover our products.