Clinical Trial Safety and Mortality Analyses in Patients Receiving EtanerceptAcross Approved Indications

March 2011 | Volume 10 | Issue 3 | Original Article | 289 | Copyright © 2011

Alice B. Gottlieb MD PhD,a Kenneth Gordon MD,b Edward H. Giannini MSc DrPH,c Philip Mease MD,d Juan Li PhD,e Yun Chon PhD,e Judy Maddox DO,e Haoling H. Weng MD MHS,e Joseph Wajdula PhD,f Shao-Lee Lin MD PhD,e Scott W. Baumgartner MDe

aTufts Medical Center and Tufts University School of Medicine, Boston, MA bNorthShore University HealthSystem, University of Chicago, Pritzker School of Medicine, Skokie, IL cCincinnati Children's Hospital Medical Center, Cincinnati, OH dSeattle Rheumatology Associates, Swedish Medical Center and University of Washington, Seattle, WA eAmgen Inc., Thousand Oaks, CA fPfizer Inc., Collegeville, PA

Abstract

Objectives: Assessment of associations between etanercept treatment and rare adverse events has been limited by the size of clinical trial populations. The authors examined the collective safety of etanercept in clinical trials across approved indications.
Patients and Methods: Forty-nine U.S. and non-U.S. trials of etanercept, involving up to 13,977 patients for approved indications, with final trial reports as of May 2006, were selected from the Amgen Inc. clinical trials database. Exposure-adjusted rates of serious infections, opportunistic infections, malignancies and deaths were reported by trial, indication and dosage.
Results: Rates of serious infections were generally similar between etanercept and controls. Overall rates of opportunistic infections and tuberculosis were low. The standardized incidence ratio (SIR) (95% CI) for malignancy was 1.00 (0.83–1.19) for all etanercept patients across all indications. The SIR for lymphoma for patients with rheumatoid arthritis was 3.45 (1.83-5.89); all other indications reported SIRs similar to those observed in the general population. The SIRs for cutaneous squamous cell carcinoma in patients with psoriasis relative to the general population with high or low sun exposure were 2.09 (1.27-3.22) and 4.96 (3.03-7.66), respectively. SIRs were less than 1.0 for all other indications regardless of sun exposure. Rates of melanoma and basal cell carcinoma were not significantly different from those in the general population. There was no increase in mortality associated with etanercept use relative to control populations.
Conclusion: These data support the overall tolerability of etanercept across approved indications.

J Drugs Dermatol. 2011;10(3):289-300.

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INTRODUCTION

Etanercept (Enbrel,® Immunex-Wyeth, Thousand Oaks, CA) is a recombinant, fully human, soluble, dimeric fusion protein consisting of two copies of the extracellular ligand-binding domain of the human 75 kd tumor necrosis factor alpha (TNF-α) receptor linked to the Fc portion of human immunoglobulin G1.1 The drug competitively binds to TNF, thus preventing its binding to endogenous receptors located on the cell surface.1 Etanercept is approved by the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA) for the treatment of moderate-to-severe rheumatoid arthritis (RA), moderate-to-severe juvenile idiopathic arthritis (JIA), psoriatic arthritis (PsA), ankylosing spondylitis (AS) and moderate-to-severe plaque psoriasis (PsO).1,2

Although etanercept has been extensively studied during the past decade and has a proven tolerability profile,3,4 rare adverse events, such as serious and/or opportunistic infections and malignancy remain of interest. Conclusions regarding associations between treatment and rare events are often limited by the size of the study population required to interpret such findings.5 Notably, Burmester and colleagues recently reported a comprehensive analysis of the safety of adalimumab across multiple clinical trials and indications.6 Therefore, to further characterize the tolerability profile of etanercept, an integrated pooled analysis of adverse event data from 49 etanercept clinical trials across approved indications was conducted.

METHODS

Data Sources and Searches

We searched for and reviewed all finalized clinical study reports for etanercept in the internal Amgen database as of May 2006 across approved indications, including RA, JIA, PsA, AS and PsO. This database is a repository of data from Amgen- and/or Wyeth-sponsored clinical trials.

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