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  1. 1. 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
  2. 2. Introduction <ul><li>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 </li></ul><ul><li>They are IMMUNOSUPPRESSIVE </li></ul>
  3. 3. Approved TNF alpha Blocking Agents <ul><li>Infliximab-(Remicade®)- chimeric (murine variable- human constant) monoclonal anti-TNF alpha antibody, FDA approved Oct 1998 </li></ul><ul><li>Etanercept-(Enbrel®)-fusion protein-2 TNF-RII (p75) receptors attached to Fc of human IgG1, FDA approved Nov 1998 </li></ul><ul><li>Adalimumab-(Humira™)-human monoclonal anti-TNF-alpha antibody, FDA approved Dec 2002 </li></ul>
  4. 4. Mechanism of Action Infliximab <ul><li>Each molecule is able to bind to two molecules of TNF-alpha </li></ul><ul><li>Forms a relatively stable complex </li></ul><ul><li>Binds to soluble and membrane bound TNF </li></ul><ul><li>Such cells lyse in vitro complement mediated-in vivo different mechanism </li></ul><ul><li>No binding TNF-beta (lymphotoxin alpha). </li></ul>
  5. 5. Mechanism of Action Etanercept <ul><li>Binds with TNF alpha and beta </li></ul><ul><li>Binding is reversible </li></ul><ul><li>Dissociated TNF remains bioactive </li></ul>
  6. 6. Mechanism of Action Adalimumab <ul><li>Stable complex with TNF alpha </li></ul><ul><li>Soluble and membrane bound targeted </li></ul><ul><li>Lyse cells with membrane bound TNF in vitro in presence of complement </li></ul><ul><li>No binding of TNF-beta </li></ul>
  7. 7. Serious Adverse Events- Associated with TNF blockers <ul><li>Infections </li></ul><ul><li>Congestive Heart Failure </li></ul><ul><li>Neurologic Events </li></ul><ul><li>Malignancies </li></ul><ul><li>Autoimmunity </li></ul><ul><li>Hematologic Events </li></ul><ul><li>Hypersensitivity </li></ul><ul><li>Others </li></ul><ul><li>Those in Yellow will be discussed </li></ul>
  8. 8. Protean Role of TNF-alpha in Infections <ul><li>Stimulates the production of other pro-inflammatory cytokines including IL1, IL6 </li></ul><ul><li>Influences maturation of inflammatory cells </li></ul><ul><li>Promotes expression of adhesion molecules </li></ul><ul><li>Promotes release of proteolytic enzymes </li></ul><ul><li>Essential role in granuloma formation through induction of apoptosis of infected cells and maintenance of granuloma formation </li></ul><ul><li>Role in killing of intracellular organisms such as Listeria, Salmonella. </li></ul>
  9. 9. Serious Infections associated with anti-TNF-alpha Agents <ul><li>Serious Infections have been seen in both the pre approval and post approval database for all three of these products. </li></ul><ul><li>In study of patients with Septic Shock, the use of etanercept appeared to be associated with increased mortality. </li></ul>
  10. 10. Tuberculosis and Infliximab-I <ul><li>Cases of Tuberculosis have been seen in Infliximab clinical trials. </li></ul><ul><li>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 </li></ul>
  11. 11. Tuberculosis and Infliximab-II <ul><li>In subgroup of 70, 56% extrapulmonary, 79% concurrent immunosuppressives (CS alone or with MTX) </li></ul><ul><li>Median Rx duration12 wks, 91% of cases occurred low incidence countries-both suggest reactivation </li></ul><ul><li>Black Box Warning Infliximab-recommend screening and prophylaxis </li></ul>
  12. 12. Tuberculosis and Etanercept <ul><li>No cases of Tuberculosis in etanercept clinical trials. (N=3280 US and EU) </li></ul><ul><li>25 cases tuberculosis associated with etanercept reported to FDA MedWatch program as of 2002 </li></ul><ul><li>52% were extrapulmonary </li></ul><ul><li>Median etanercept treatment duration 11.5 months </li></ul><ul><li>Bold Warning in Package Insert </li></ul>
  13. 13. Tuberculosis and Adalimumab <ul><li>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 </li></ul><ul><li>Black Box Warning Adalimumab-recommend screening and prophylaxis </li></ul>
  14. 14. Fungal Infections and anti-TNF alpha Agents <ul><li>As of June 2002, Ruderman et. al . report that there were 37 cases of histoplasmosis US associated with Infliximab and 2 associated with Etanercept. </li></ul><ul><li>10 cases detailed evaluation- all from histoplasmosis endemic areas, all with other immunosuppressives . </li></ul><ul><li>Anti-TNF Treatment duration 1 wk to 6 months </li></ul><ul><li>6 cases of invasive opportunistic infections caused by histoplasmosis, aspergillus and nocardia reported in the Adalimumab clinical trials </li></ul><ul><li>44 cases of PCP with Infliximab, 5 with Etanercept, Onset average 1-2 months, 6 deaths </li></ul>
  15. 15. Role of TNF-alpha in Heart Failure <ul><li>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. </li></ul><ul><li>Etanercept and Infliximab evaluated as potential CHF treatment </li></ul><ul><li>Trials for both were stopped early, Etanercept has a Precaution and Infliximab has a Contraindication regarding use in patients with heart failure </li></ul>
  16. 16. Results of anti-TNF alpha Heart Failure Trials <ul><li>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 </li></ul><ul><li>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. </li></ul><ul><li>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 </li></ul>
  17. 17. Serious Neurologic Adverse Events <ul><li>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 </li></ul><ul><li>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 </li></ul>
  18. 18. Lymphomas Associated with Anti-TNF alpha Agents <ul><li>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. </li></ul><ul><li>Patients with RA, especially with severe, active disease have an increased risk of lymphoma, especially non-Hodgkin’s Lymphoma, which complicates interpretation of data. </li></ul>
  19. 19. Lymphomas and Infliximab <ul><li>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. </li></ul><ul><li>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. </li></ul><ul><li>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. </li></ul>
  20. 20. Lymphomas and Etanercept <ul><li>9 lymphomas were reported in clinical trials of Etanercept (3389 patients followed for 7364 patient-years) leading to a SIR of 3.47 </li></ul><ul><li>63 lymphomas were reported to AERS as of December 2002 predominantly diffuse large B cell non-Hodgkin’s. </li></ul><ul><li>As with Infliximab, one Lymphoma regressed with cessation of Etanercept in the absence of any specific anti-cytotoxic treatment </li></ul>
  21. 21. Lymphomas and Adalimumab <ul><li>10 Lymphomas were observed in 2468 study drug receiving subjects in the Adalimumab registration clinical trials giving a SIR of 5.4. </li></ul><ul><li>There is an apparent safety signal although this rate is in range reported for patients with highly active Rheumatoid Arthritis </li></ul><ul><li>Data collection by the Sponsor is ongoing </li></ul>
  22. 22. Autoimmunity and Anti-TNF alpha Agents <ul><li>Animal Data implies that TNF alpha may suppress some autoimmunity </li></ul><ul><li>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. </li></ul><ul><li>22 case reports of lupus-like syndrome reported with etanercept both case reports and AERS. </li></ul><ul><li>Adalimumab noted to have 12% positive ANA versus 7% placebo, one patient developed lupus-like syndrome which improved with stopping drug </li></ul>
  23. 23. Conclusions <ul><li>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. </li></ul><ul><li>The decision to use these drugs as with all other immunosuppressives should consider both their efficacy and potential side effects. </li></ul>