Clinical RFP Webinar, August 30, 2022 - PowerPoint Presentation

1. Clinical RFP Webinar, August 30, 2022Accelerating Medicines Partnership®Bespoke Gene Therapy Consortium (BGTC)1Clinical Subteam co-chairsSusana Serrate-Sztein, MD (NIAMS/NIH)Ed Neilan, MD, PhD (NORD)Program ManagementCourtney Silverthorn, PhD (FNIH)Brad Garrison, MBA (FNIH)

2. HousekeepingPhones mutedAsk questions in chat or raise hand to speakStructure of the agenda (3 segments with Q and A following each)2

3. AgendaAMP BGTC overview (Ed Nielan)BGTC Clinical Program (Susana Sztein)RFP requirements, expectations for proposal submissions (Susana Sztein)RFP Administration (Susana Sztein/Brad Garrison)3

4. AMP BGTC VisionApproximately 25–30 million people in the United States live with the devastating effects of rare diseases. There are over 5,000 rare diseases that are caused by genetic defects.For the estimate 80 percent of rare genetic diseases caused by a single defective gene, one promising treatment to emerge is adeno-associated virus (AAV) gene therapy—a process that replaces the defective gene with a functional one.The BGTC, a public-private collaboration among the NIH, the FDA, the pharmaceutical industry, and patient organizations – and coordinated by the FNIH – aims to make gene therapy more accessible by creating a platform approach to deliver novel therapies for many different genetic disorders.)4Addressing an unmet need

5. AMP BGTC VisionMake adeno-associated virus technology more accessible to a broader range of diseasesOptimized AAV vector production protocolsImprovements in AAV target gene expressionStreamline preclinical and product testingHarmonized and validated sets of manufacturing and preclinical testing requirements5BGTC goalsFacilitate scientific and regulatory advances that will ultimately benefit the entire fieldStandardized regulatory submission package templatesBring gene therapies to all affected populations soonerClinical development manual to help advance all future AAV gene therapies for rare diseases

6. Pre-clinical testingClinical ability to treat patientsRare disease gene therapy targets62 initial submissions14 most clinical trial readyTherapies for patientsCreate & Build CapacityHarmonize best practicesStreamline Regulatory PathsManufacture of therapeuticAMP® Bespoke Gene Therapy Consortium ComponentsEnhancing AAV Basic Biology and Translational ImplicationsEnhancing therapeutic gene expressionEnhancing Vector GenerationAdvancing Access to AAV Technologies and Vectors for Bespoke Clinical Applications12Goal: Optimized vector generation and gene expression for AAV gene therapyGoal: A streamlined regulatory process that supports cost-efficient and high-quality vector production6CQAsGLP/ToxClinical trials2 rounds RFPTargeting 11 funded proposals

7. 54FirstPatientDosed20212022202320242025AAV Biology RFPsVector Generation / Expression DevelopmentHTS Assay Testing & AnalyticsHTS Assay Testing & AnalyticsDisease NominationsVector Manufacturing,CMC/Pre-Clinical TestingClinical Trials(5-6 disease indications)2026Develop CMC/Pre-Clin consensus proposalsDevelop streamlinedregulatory processesCommunications and Patient Education, continuous updates to website & portal1LaunchDraft RegFrameworkFinalDiseaseSelectionKey MilestonesFinal Framework& ManualClinical Trial RFP720272EstablishCoordinating Center36Primary StudyOutcomes7Follow-up as required by FDAAMP BGTC Timeline

8. Subteams and Working Groups carry out BGTC efforts8

9. BGTC coordinating center9

10. Q and A10

11. BGTC Clinical ProgramGoals:Support the generation of a standard operational playbook for developing gene therapies of rare diseasesPilot use of streamlined templates, master regulatory files, and uniform manufacturing processes Generate critical data on safety and efficacy11

12. BGTC Clinical TrialsClinical trials will be conducted in a highly collaborative and interdependent environmentExpect substantial input from and involvement of other components of BGTC, including the BGTC Steering CommitteeCTs will have a substantial planning phase, length will vary according to vector manufacturing and regulatory requirements and timelinesCTs will be supported by a CC that will be established by BGTC/NIH.The CC hub will facilitate interactions between the scientific and regulatory components of BGTC12

13. 3Primary Study Outcomes2First Patient DosedClinical Program Timeline 13202120222023202420252026Key Milestones2027Q4Q1 Q2 Q3 Q4Q1 Q2 Q3 Q4Q1 Q2 Q3 Q4Q1 Q2 Q3 Q4Q1 Q2 Q3 Q4Q1 Q2 Q3 Q41BGTC LaunchDisease NominationStandup CoordinatingCenterClinical Trials - Primary Safety MeasuresClinical TrialsRFPContractNegotiationsVector Mfg,CMC/Tox TestingVector Mfg,CMC/Tox TestingVector Mfg,CMC/Tox TestingIndications 1-2Indications 3-4Indications 5-6Clinical Trials - Primary Safety MeasuresFollow-up as required by FDAFollow-up as required by FDAClinical Trials - Primary Safety MeasuresFollow-upPlanning

14. BGTC Clinical Program Candidate Rare DiseasesDisease Name (pseudonym)Affected GeneBGTC ClassificationCongenital Hereditary Endothelial Dystrophy (CHED)SLC4A11Eye / CorneaMPS VI corneal diseaseARSBEye / CorneaLeber Congenital Amaurosis 16 (LCA16)KCNJ13Eye / RetinaRetinitis pigmentosa (RP) - CNGB1CNGB1Eye / RetinaNPHP5-RDNPHP5Eye / RetinaCharcot Marie Tooth disease type 4J (CMT4J)FIG4NeurologicalMultiple Sulfatase DeficiencySUMF1NeurologicalSpastic Paraplegia, type 47 (SPG47)AP4B1NeurologicalSpastic paraplegia 50 (SPG50)AP4M1NeurologicalBarth SyndromeTAZCardiacPGM1-Congentital Disorder of Glycosylation (CDG) (PGM1 deficiency)PGM1Inborn error of metabolismPropionic AcidemiaPCCBInborn error of metabolismFibrodysplasia Ossificans Progressiva (FOP)ACVR1OrthopedicMucopolysaccharidosis IVA (MPS IVA, Morquio A Syndrome)GALNSOrthopedicClinical Trial Proposals due October 31st

15. RFP requirements, expectations for proposal submissions15

16. RFP objectives and expectationsCollaboration highly encouraged (include PAGs, avoid competing PIs)Team science approach – expect revisions based on input from BGTC scientistsBGTC will separately arrange for manufacturing, CMC testing, GLP/tox studiesNIH will establish coordinating centerNIH to be sponsor for first-in-human Phase 1/2 trials, IND holderResponses limited to the panel of 14 selected diseasesIntend to issue 5-6 clinical trial awardsMust address diversityFNIH contracts, not NIH grants. CIRM for CA PIs or sites16

17. Important to address in CT ProposalsRationale for the CT: why the CT is needed and feasible within the timeframe of the BGTCProposed design and approach to the CTDemonstrate understanding of natural hx of dx and outcomesDemonstrate capacity to screen, enroll and follow-up patients Capacity to assess, ensure patient safety and confidentialityWillingness to work with other components of the BGTCPrevious performanceBudgetUnderstanding of roles and responsibilities of BGTC structural components.17

18. Roles and responsibilities (included in RFP)18ActivityResponsible PartyVector manufacturingBGTC / CMOVector analytical testingBGTC / CMOProduct packaging, distributionBGTC / CMOPre-Clinical study designBGTC / CMO with CT PI input (see study protocol)Pre-Clinical study executionBGTC / CMOCMO oversightNIH / FNIHClinical study design CT PI Clinical study sponsor / IND holderNIHClinical study execution (years 1-5)CT PIActivityResponsible PartyPatient follow-up after year 5 (optional)CT PIMedical safety monitoringNIH Coordinating Center, in consultation with Applicant Data entry/Study Coordinator/Study NurseCT PIClinical Trial insuranceCT PI OrganizationCentral IRBNIH Coordinating CenterData Safety Monitoring BoardNIH Coordinating CenterData analyses for DSMB meetingsNIH Coordinating CenterData Management and AnalysisNIH Coordinating Center

19. Roles and responsibilities19ActivityResponsible PartyStudy Personnel Training and Certifications NIH Coordinating Center in consultation with ApplicantDesign and Implementation of a Quality Assurance ProgramNIH Coordinating CenterDevelop Standard Operating Procedures (SOPs) addressing all aspects of data management and statistical analysisNIH Coordinating CenterActivityResponsible PartyTransfer data to statistician and others for interim analysis as needed, and at the end of follow-up, cleaning and closing-out the database and submit study results for data sharing.NIH Coordinating CenterTracking of Regulatory documentsNIH Coordinating CenterClinicaltrials.gov submission, updates and reporting of study result CT PIPublication and Presentation of Clinical Trial ResultsCT PI + BGTC representatives

20. RFP components / checklistAppendix 1, proposal submission formAppendix 2, protocol template***COMPLETE SECTIONS 1 – 5, 6.1, 6.5, 8.1, 8.2, 8.3.8, AND 9.2 ONLY***Appendix 3, Budget worksheetAppendix 4, informed consentRace and Ethnicity Diversity Plan Clinical trial insurance policy / certificateBiosketches of Key Personnel20

21. Review criteria – technical evaluation21CRITERION 1: TECHNICAL PLAN/APPROACHAppropriateness, feasibility, and adequacy of the proposed technical plan/approach for accomplishing the tasks outlined in the proposal and the overall objectives of the BGTC including capacity and capability for a broad range of services necessary to support and conduct clinical trials and bioanalysis and when needed, conduct domestic or international natural history, or observational studies. Adequacy of proposed plan to address relevant biological variables, including sex for studies in human subjects as applicable.CRITERIA WEIGHT……………………………………………………………………………………… 100CRITERION 2: SCIENTIFIC AND TECHNICAL PERSONNELAppropriateness and adequacy of the education, training, experience, expertise, and proposed levels of effort of the Principal Investigator and scientific and technical staff including subcontractors/consultants for accomplishing the tasks outlined in the proposal and the overall objectives of the BGTC clinical trials component.CRITERIA WEIGHT………………………………………………………………………...………………40CRITERION 3: PROJECT MANAGEMENTAppropriateness and adequacy of the plans for Project Management in terms of staffing, organizational structure and lines of authority, management of subcontracts/consultants, tracking of project activities,monitoring progress and timelines, and communication with stakeholders.CRITERIA WEIGHT…………………………………………………………………..…….………………40CRITERION 4: FACILITIES, EQUIPMENT, AND OTHER RESOURCESAppropriateness and adequacy of facilities, equipment, space and other resources including those of subcontractors/consultants for accomplishing the tasks outlined in the Statement of Work and the overall objectives of the solicitation.CRITERIA WEIGHT…………………………………………………………………..……………………20

22. Review criteria – other evaluation factors22HUMAN SUBJECT EVALUATIONProtection of Human Subjects from Research Risks, Data and Safety MonitoringRACE AND Ethnicity Diversity PLAN EVALUATION OF DATA SHARING PLANCOST FACTORPAST PERFORMANCE/EXPERIENCE FACTOR

23. Selection23Following Technical Review, and subsequent technical discussions if appropriate, the BGTC Clinical Subteam will rank the proposals and make recommendations to the BGC Steering CommitteeThe BGTC SC is responsible for final trial/offeror selection.FNIH will communicate decisions to the OfferorsFNIH will negotiate budgets with Offerors.

24. RFP timeline24Application Due Date: October 31, 2022, 11:59 PM ET Review Period: November 1, 2022 – January 31, 2023The AMP BGTC Clinical Subteam reserves the right to contact the applicant(s), through the FNIH Project Management team, if additional information is needed from the applicant(s). Potential Oral Presentations from Finalists (If Needed):Applicants will be informed after initial review of proposals whether they will need to provide an oral presentation with the option for Q&A to the AMP BGTC Steering Committee or Clinical Subteam.  Expected Award Announcement: February 2023*Applicants will be notified by email of the outcome of the RFP competition. *FNIH reserves the right to modify the target deadline Expected Award Start Date: April 2023***Time will be of the essence to complete contract negotiations***

25. Q and A25