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Safety & Efficacy Update on Approved TNF-Blocking Agents

Safety & Efficacy Update on Approved TNF-Blocking Agents. Jeffrey N. Siegel, M.D. OTRR, CBER / FDA Arthritis Advisory Committee March 4, 2003. Center for Biologics Evaluation and Research. TNF BLOCKING AGENTS. Etanercept (Enbrel) first TNF blocker approved for RA: 1998

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Safety & Efficacy Update on Approved TNF-Blocking Agents

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  1. Safety & Efficacy Update on Approved TNF-Blocking Agents Jeffrey N. Siegel, M.D. OTRR, CBER / FDA Arthritis Advisory Committee March 4, 2003 Center for Biologics Evaluation and Research

  2. TNF BLOCKING AGENTS • Etanercept (Enbrel) first TNF blocker approved for RA: 1998 • Currently three approved • Each has demonstrated high ACR response rates • Each associated with uncommon, but serious adverse events

  3. Indications & Use: Etanercept • Monotherapy or combination with MTX for moderately to severely active RA • Improving signs and symptoms • Inhibition of progression of structural damage • Polyarticular-course JRA • Psoriatic arthritis

  4. Indications & Use: Infliximab • Combination with MTX for moderately to severely active RA • Improving signs & symptoms • Inhibition of progression of structural damage • Improvement in physical function • Crohn’s Disease • Active disease (CDAI score > 220) • Fistulizing disease

  5. Adalimumab (Humira) • Monoclonal antibody to TNF-alpha • Sequence human-derived however studies demonstrate immunogenicity • Pivotal trials assessed safety and efficacy of: • Monotherapy • Combination with methotrexate • Add on to standard of care • Licensed in December, 2002

  6. Adalimumab Clinical Responses at 6 mo (% of patients)

  7. IndicationsHUMIRA (Adalimumab) • Monotherapy or combination with MTX or other DMARDs for RA • Improving signs and symptoms • Inhibition of progression of structural damage

  8. Adalimumab: Dosing Considerations • Recommended dose 40 mg SC q2wk • Optimal dose for MTX combination • With monotherapy, 40 q2wk effective, but higher response rates with 40 mg qwk • Monotherapy associated with higher rates of antibody formation than MTX combination • Immunogenicity associated with lower ACR response rates

  9. Safety Update • Follow-up of August, 2001 AAC presentation • Present in depth discussion of new data on previously recognized serious adverse events and some newly recognized adverse events: • TB experience with adalimumab • Lymphoma, malignancies with all agents • Liver injury with infliximab/etanercept • CHF

  10. Analysis of Safety • Based on data from: • Controlled clinical trials • Open-label extension studies • Postmarketing commitment for each product to assess 1000-2000 subjects x 5 years for malignancies and serious infections • Postmarketing registries • Spontaneous post-marketing reports

  11. Serious Adverse Events AssociatedWith All 3 Approved TNF Blocking Agents Serious infections Tuberculosis Opportunistic infections (e.g. histoplasmosis, listeriosis, coccidiodomycosis, PCP) Non-opportunistic infections Demyelinating events Autoantibodies & Autoimmune disease

  12. Safety Concerns With TNF Blockers • For etanercept and infliximab, observed mostly in postmarketing reports; some controlled trials in other diseases • For adalimumab: • Much larger safety database at time of approval • SAEs observed pre-marketing • Many consistent with known mechanism of action, e.g. infections • Others unanticipated, e.g. CHF, demyelination

  13. Agency’s Communication of Risks • Stated in PI under: • PRECAUTIONS section • WARNINGS section • BOX WARNING • Dear Healthcare Provider Letters • Peer-reviewed scientific publications • Presentations to Advisory Committee • Presentations at Medical Meetings

  14. Considerations for Package Insert • Wording not identical for each product • Language dictated by data • Where data are similar, especially where there is a biologic rationale, class labeling may be warranted

  15. TB: Infliximab • TB seen in clinical trials • Cases of TB, some fatal and with unusual presentation, observed in post-marketing reports • Reporting rate several fold higher than incidence in US population* • TB seen in patients not otherwise at risk • Boxed warning: screening and prophylaxis recommended for all patients

  16. TB: Etanercept • Uncommon cases of TB seen in post-marketing experience: • Reporting rate similar to US incidence* • No cases in RA trials in US or EU (N=3280) • Most US patients otherwise at high risk • Label: Bold warning

  17. Why Would AEs Differ Among Different TNF Blockers? • Potential explanations: • Differing mechanisms of action: soluble receptor, monoclonal antibodies • Differing affinity, avidity of binding • Differing ability to lyse TNF-bearing monocytes • Differing immunogenicity • Differences may contribute to unique efficacy and safety properties

  18. Agenda • Update committee on known AEs and on newly documented AEs with TNF-blocking agents: • TB • malignancies and lymphomas • Liver enzyme elevations/hepatic AEs • CHF • Challenges in interpreting open-label and post-marketing safety data

  19. OVERVIEW

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