Serious Adverse Events Associated with use of the

Anti-TNF alpha Drugs

William B. Tauber, M.D. Division of Therapeutic Biologic Internal

Medicine ProductsCenter 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.