Safety

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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
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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

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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

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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
• Crohns Disease
• Active disease (CDAI score gt 220)
• Fistulizing disease

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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

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Adalimumab Clinical Responses at 6 mo ( of
patients)
Study Adalimumab 40 mg q2w Adalimumab 40 mg q2w Placebo
Monotherapy (N544) ACR20 46 20
Monotherapy (N544) ACR50 22 8
Monotherapy (N544) ACR70 12 2
MTX combination (N619) ACR20 63 30
MTX combination (N619) ACR50 39 10
MTX combination (N619) ACR70 21 3
Add-on to standard of care (N636) ACR20 53 35
Add-on to standard of care (N636) ACR50 29 11
Add-on to standard of care (N636) ACR70 15 3
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IndicationsHUMIRA (Adalimumab)

• Monotherapy or combination with MTX or other
  DMARDs for RA
• Improving signs and symptoms
• Inhibition of progression of structural damage

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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

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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

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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

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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

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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

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Agencys 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

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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

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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

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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 (N3280)
• Most US patients otherwise at high risk
• Label Bold warning

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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

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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

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OVERVIEW