# Presentation: 265056

## 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-(HumiraTM)-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.