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    Tauber Tauber Presentation Transcript

    • Serious Adverse Events Associated with use of the Anti-TNF alpha Drugs William B. Tauber, M.D. Division of Therapeutic Biologic Internal Medicine Products Center for Drug Evaluation and Research Food and Drug Administration
    • Introduction
      • Members of the Anti-TNF alpha Drug Group have demonstrated efficacy in a number of serious medical conditions including Rheumatoid Arthritis, Juvenile Rheumatoid Arthritis, Psoriatic Arthritis, Ankylosing Spondylitis, Crohn’s Disease
      • They are IMMUNOSUPPRESSIVE
    • Approved TNF alpha Blocking Agents
      • Infliximab-(Remicade®)- chimeric (murine variable- human constant) monoclonal anti-TNF alpha antibody, FDA approved Oct 1998
      • Etanercept-(Enbrel®)-fusion protein-2 TNF-RII (p75) receptors attached to Fc of human IgG1, FDA approved Nov 1998
      • Adalimumab-(Humira™)-human monoclonal anti-TNF-alpha antibody, FDA approved Dec 2002
    • Mechanism of Action Infliximab
      • Each molecule is able to bind to two molecules of TNF-alpha
      • Forms a relatively stable complex
      • Binds to soluble and membrane bound TNF
      • Such cells lyse in vitro complement mediated-in vivo different mechanism
      • No binding TNF-beta (lymphotoxin alpha).
    • Mechanism of Action Etanercept
      • Binds with TNF alpha and beta
      • Binding is reversible
      • Dissociated TNF remains bioactive
    • Mechanism of Action Adalimumab
      • Stable complex with TNF alpha
      • Soluble and membrane bound targeted
      • Lyse cells with membrane bound TNF in vitro in presence of complement
      • No binding of TNF-beta
    • Serious Adverse Events- Associated with TNF blockers
      • Infections
      • Congestive Heart Failure
      • Neurologic Events
      • Malignancies
      • Autoimmunity
      • Hematologic Events
      • Hypersensitivity
      • Others
      • Those in Yellow will be discussed
    • Protean Role of TNF-alpha in Infections
      • Stimulates the production of other pro-inflammatory cytokines including IL1, IL6
      • Influences maturation of inflammatory cells
      • Promotes expression of adhesion molecules
      • Promotes release of proteolytic enzymes
      • Essential role in granuloma formation through induction of apoptosis of infected cells and maintenance of granuloma formation
      • Role in killing of intracellular organisms such as Listeria, Salmonella.
    • Serious Infections associated with anti-TNF-alpha Agents
      • Serious Infections have been seen in both the pre approval and post approval database for all three of these products.
      • In study of patients with Septic Shock, the use of etanercept appeared to be associated with increased mortality.
    • Tuberculosis and Infliximab-I
      • Cases of Tuberculosis have been seen in Infliximab clinical trials.
      • Post-Approval, 295 cases of Infliximab associated tuberculosis reported to FDA (8/02) for an estimated rate of 37cases/100,000 US and 150 cases/100,000 EU compared to background rate tuberculosis RA patients 6.2 cases/100,000 US and 20 cases/100,000 EU
    • Tuberculosis and Infliximab-II
      • In subgroup of 70, 56% extrapulmonary, 79% concurrent immunosuppressives (CS alone or with MTX)
      • Median Rx duration12 wks, 91% of cases occurred low incidence countries-both suggest reactivation
      • Black Box Warning Infliximab-recommend screening and prophylaxis
    • Tuberculosis and Etanercept
      • No cases of Tuberculosis in etanercept clinical trials. (N=3280 US and EU)
      • 25 cases tuberculosis associated with etanercept reported to FDA MedWatch program as of 2002
      • 52% were extrapulmonary
      • Median etanercept treatment duration 11.5 months
      • Bold Warning in Package Insert
    • Tuberculosis and Adalimumab
      • 13 cases during 4870 patient years of clinical trials with Adalimumab, 8 occurring phase I and II with higher doses, 5 occurred during Phase III
      • Black Box Warning Adalimumab-recommend screening and prophylaxis
    • Fungal Infections and anti-TNF alpha Agents
      • As of June 2002, Ruderman et. al . report that there were 37 cases of histoplasmosis US associated with Infliximab and 2 associated with Etanercept.
      • 10 cases detailed evaluation- all from histoplasmosis endemic areas, all with other immunosuppressives .
      • Anti-TNF Treatment duration 1 wk to 6 months
      • 6 cases of invasive opportunistic infections caused by histoplasmosis, aspergillus and nocardia reported in the Adalimumab clinical trials
      • 44 cases of PCP with Infliximab, 5 with Etanercept, Onset average 1-2 months, 6 deaths
    • Role of TNF-alpha in Heart Failure
      • TNF alpha over-expressed in myocardial tissue in heart failure and hypothesized to contribute to progression by direct toxicity. Increasing levels correlate with worsening New York Heart Association Functional Class.
      • Etanercept and Infliximab evaluated as potential CHF treatment
      • Trials for both were stopped early, Etanercept has a Precaution and Infliximab has a Contraindication regarding use in patients with heart failure
    • Results of anti-TNF alpha Heart Failure Trials
      • Etanercept-RENAISSANCE -925pt, (US) Trend towards higher mortality in 25mg TIW not BIW. RECOVER-1123pt, (Non-US) 25 mg QW and BIW, no increase mortality
      • Infliximab-ATTACH 150 patients- strong trend toward clinical worsening with higher doses (recommended for RA, Crohn’s) due to increase in deaths, hospitalizations for Heart Failure at weeks 14/28.
      • 47 cases of new and or worsening CHF reported through AERS-MedWatch (38 new and 9 exacerbations). Of the 38 new, 19 had no identifiable risk factors, 10 patients <50 years, after discontinuing treatment, 3 complete resolution, 6 improved one died
    • Serious Neurologic Adverse Events
      • Demyelination- human studies of anti-TNF alpha treatment (lenercept-P55 TNF receptor-immunoglobulin G fusion protein) demonstrated more frequent and severe exacerbations of MS compared to placebo
      • 19 cases suggestive CNS demyelination reported to AERS, 17 with Etanercept, 2 with Infliximab; discontinuation led to partial or complete resolution, one patient exhibited an apparent positive rechallenge. Cases of demyelination reported with Adalimumab
    • Lymphomas Associated with Anti-TNF alpha Agents
      • Solid Tumors such as Breast, colon, cervix, prostate, melanoma, gall bladder, squamous and basal-cell carcinoma have been reported with use of anti-TNF Agents but these have not exceeded rates in the general population.
      • Patients with RA, especially with severe, active disease have an increased risk of lymphoma, especially non-Hodgkin’s Lymphoma, which complicates interpretation of data.
    • Lymphomas and Infliximab
      • In the clinical trials for both Crohn’s disease and RA population treated with Infliximab (2421 patients with 4148 patient years follow-up) 6 lymphomas were reported for a Standardized Incidence Ratio (SIR) of 6.98. In the placebo arm, (489 patients with 691 patient years follow-up) no Lymphomas were seen.
      • As of 12/2002, 95 Lymphomas associated with Infliximab were reported to AERS. Median onset 8 weeks of Infliximab. In one case, the lymphoma regressed with discontinuation of Infliximab without cytotoxics.
      • Recently completed clinical trial Infliximab in methotrexate naïve early RA (743 patients with 702.6 years follow-up) with 0.78 years follow-up did not reveal any Lymphomas.
    • Lymphomas and Etanercept
      • 9 lymphomas were reported in clinical trials of Etanercept (3389 patients followed for 7364 patient-years) leading to a SIR of 3.47
      • 63 lymphomas were reported to AERS as of December 2002 predominantly diffuse large B cell non-Hodgkin’s.
      • As with Infliximab, one Lymphoma regressed with cessation of Etanercept in the absence of any specific anti-cytotoxic treatment
    • Lymphomas and Adalimumab
      • 10 Lymphomas were observed in 2468 study drug receiving subjects in the Adalimumab registration clinical trials giving a SIR of 5.4.
      • There is an apparent safety signal although this rate is in range reported for patients with highly active Rheumatoid Arthritis
      • Data collection by the Sponsor is ongoing
    • Autoimmunity and Anti-TNF alpha Agents
      • Animal Data implies that TNF alpha may suppress some autoimmunity
      • Anti-double stranded DNA developed in 17% of 1507 Infliximab recipients versus 0% of placebo in clinical trials, 6 patients developed lupus-like syndrome which improved with Infliximab cessation.
      • 22 case reports of lupus-like syndrome reported with etanercept both case reports and AERS.
      • Adalimumab noted to have 12% positive ANA versus 7% placebo, one patient developed lupus-like syndrome which improved with stopping drug
    • Conclusions
      • As a class, anti-TNF alpha drugs have demonstrated both efficacy and a number of serious adverse events including infections, congestive heart failure, neurologic events including demyelination, lymphomas and autoimmunity including lupus like syndromes.
      • The decision to use these drugs as with all other immunosuppressives should consider both their efficacy and potential side effects.