LTFU PresentationBRMAC Long-Term Follow-up of Subjects in Gene Transfer Studies Philippe Bishop, M.D. FDA/CBER/DCTDA/Oncology

LTFU PresentationBRMAC Presentation Outline Prior BRMAC discussions Areas of clinical concerns Epidemiologic database (Steven Rosenthal, MD)

LTFU PresentationBRMAC Prior BRMAC Discussions

LTFU PresentationBRMAC CURRENT FDA LTFU GUIDANCE LTFU is limited to GT strategies involving retroviral vectors October 18, 2000 Guidance Document

LTFU PresentationBRMAC BRMAC Meeting November 16-17, 2000 Efforts to gather data pertaining to the long-term risks of exposure are necessary for all GT products. Vector characteristics may correlate with long term risks to participants.

LTFU PresentationBRMAC BRMAC Meeting April 5-6, 2001 FDA proposed a three-tier system based on vector characteristics.

LTFU PresentationBRMAC Proposed 3-Tier System TierVector Characteristics 1 Ex vivo gene transfer with non- replicating vector into cells with demonstrated limited survival 2All other gene transfer products that are not in tiers 1 or 3 3 Replicating or potential to replicate, (except poxvirus and adenovirus) High integration potential Altered receptor tropism Latency potential

LTFU PresentationBRMAC BRMAC Discussion “Where we left off…” It was generally felt that identifying and focusing on the most important data would improve compliance.

LTFU PresentationBRMAC FDA Working Group Define clinical concerns related to gene transfer studies. Define the duration of clinical follow-up appropriate to the specific clinical concerns.

LTFU PresentationBRMAC FDA Working Group Considerations Vector characteristics Duration of gene product expression Mode of administration Targeted tissue Patient-specific factors

LTFU PresentationBRMAC FDA Working Group NameArea of Expertise/Role Philippe Bishop, MDOncology Patricia Keegan, MDOncology/Hematology Harvey Luksenburg, MDHematology Anne Pilaro, Ph.D.Toxicology Cindy Rask, MDNeurology Steve Rosenthal, MDVaccines/Epidemiology Stephanie Simek, Ph.D.FDA RAC Liaison Joseph Temenak, Ph.D.Vaccines/Molecular Biol. Mark Thornton, MDImmunology Carolyn Wilson, Ph.D.Virology

LTFU PresentationBRMAC areas of clinical concerns were identified: Malignancy Hematopoeitic dysfunction Autoimmune disease Neurologic disease FDA Working Group

LTFU PresentationBRMAC Malignancy

LTFU PresentationBRMAC Malignancy DNA and RNA viruses are known to cause or to be associated with human cancers: HTLV-I  adult T-cell leukemia HPV  cervical cancer HCV  hepatocellular carcinoma

LTFU PresentationBRMAC Mechanisms of viral oncogenesis have been described: Transformation by trans-gene expression (HTLV-1 tax) Insertional mutagenesis (c-myc) Chronic inflammation (HCV) “Hit and run” hypothesis (Ad5 E1A + E4orf6) Malignancy

LTFU PresentationBRMAC Malignancy GT related mutagenesis has previously been demonstrated in non- human primates (Donahue et al, 1992)

LTFU PresentationBRMAC Malignancy Treatment induced cancer may take years before clinical presentation Hodgkin’s lymphoma Breast Cancer Testicular Cancer

LTFU PresentationBRMAC Hematopoeitic Disorders

LTFU PresentationBRMAC Virus induced hematologic syndromes are well known: Parvovirus B19  anemia HBV  aplastic anemia HIV  isolated or combined cytopenia Hematopoietic Disorders

LTFU PresentationBRMAC Hematopoietic Disorders Hematopoietic progenitor cells (HPC) are self-replicating and give rise to HPC decendents. HPC decendents make up the differentiated cells of blood and BM essential to human life

LTFU PresentationBRMAC GT related hematologic disorders (cytopenias), pre- malignant (MDS) and malignant (Leukemia) conditions may occur months to years following initial exposure. Hematopoietic Disorders

LTFU PresentationBRMAC Neurologic Disorders

LTFU PresentationBRMAC GT vectors and administration strategies may lead to neurologic disorders –Integrating vectors –Long latency –Prolonged transgene expression –Immunogenic reactions Neurologic Disorders

LTFU PresentationBRMAC Neurologic Disorders CNS is a highly specialized organ that has redundancy in functional capacity. Many known neurologic disorders require significant neurologic damage before being clinically evident.

LTFU PresentationBRMAC Neuronal injury may go on for years before being clinically detected. HIV  dementia Prion  CJD Diabetes  neuropathy Neurologic Disorders

LTFU PresentationBRMAC Autoimmune Disorders

LTFU PresentationBRMAC Autoimmune Disorders Environmental and other xenobiotic agents can cause autoimmunity (e.g., viruses and bacteria can induce antibody- mediated autoimmune disease via molecular mimicry): Group A strep  rheumatic fever Infectious mononucleosis  ITP

LTFU PresentationBRMAC Autoimmune Disorders Mechanisms for autoimmune diseases have been described: Unmasking of “AID genes” Molecular mimicry Humoral autoimmunity T-cell mediated autoimmunity

LTFU PresentationBRMAC Autoimmune Disorders Immune responses to GT vectors or transgene product are possible. Risk may relate to vector characteristics, duration of transgene expression, route of administration, and host specific factors.

LTFU PresentationBRMAC Clinical manifestation of autoimmune disorders resulting from environmental insults may take months to years. Minocycline  SLE Autoimmune Disorders

LTFU PresentationBRMAC Summary

LTFU PresentationBRMAC Summary LTFU of GT participants should focus on 4 clinical areas: Malignancies Neurologic disorders Hematologic disorders; Autoimmune disorders. Years to decades Months to years

LTFU PresentationBRMAC FDA has previously proposed a 3-tiered system to assess risks to subjects based on vector characteristics. Summary