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

3. Arthritis Advisory Committee March 4, 2003 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 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

4. Arthritis Advisory Committee March 4, 2003 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 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

5. Arthritis Advisory Committee March 4, 2003 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 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

6. Arthritis Advisory Committee March 4, 2003 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 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

7. Arthritis Advisory Committee March 4, 2003 6 Adalimumab Clinical Responses at 6 mo (% of patients) StudyAdalimumab 40 mg q2wPlacebo Monotherapy (N=544) ACR204620 ACR50228 ACR70122 MTX combination (N=619) ACR206330 ACR503910 ACR70213 Add-on to standard of care (N=636) ACR205335 ACR502911 ACR70153

8. Arthritis Advisory Committee March 4, 2003 7 Indications HUMIRA (Adalimumab) Monotherapy or combination with MTX or other DMARDs for RA –Improving signs and symptoms –Inhibition of progression of structural damage Monotherapy or combination with MTX or other DMARDs for RA –Improving signs and symptoms –Inhibition of progression of structural damage

9. Arthritis Advisory Committee March 4, 2003 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 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

10. Arthritis Advisory Committee March 4, 2003 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 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

11. Arthritis Advisory Committee March 4, 2003 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 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

12. Arthritis Advisory Committee March 4, 2003 Serious Adverse Events Associated With 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 Serious infections –Tuberculosis –Opportunistic infections (e.g. histoplasmosis, listeriosis, coccidiodomycosis, PCP) –Non-opportunistic infections Demyelinating events Autoantibodies & Autoimmune disease

13. Arthritis Advisory Committee March 4, 2003 12 Safety Concerns With TNF Blockers For etanercept and infliximab, o bserved 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 For etanercept and infliximab, o bserved 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

14. Arthritis Advisory Committee March 4, 2003 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 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

15. Arthritis Advisory Committee March 4, 2003 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 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

16. Arthritis Advisory Committee March 4, 2003 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 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

17. Arthritis Advisory Committee March 4, 2003 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 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

18. Arthritis Advisory Committee March 4, 2003 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 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

19. Arthritis Advisory Committee March 4, 2003 18 AgendaAgenda 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 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

20. Arthritis Advisory Committee March 4, 2003 19 OVERVIEWOVERVIEW