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
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
Congestive Heart Failure
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
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.