Drug Criteria & Outcomes: Off-label drug use: Etanercept (Enbrel) for Crohn’s disease?

By Angela Jezewski Lowe, PharmD Candidate
Harrison School of Pharmacy
Auburn (AL) University

Inflammatory bowel disease (IBD) has been clinically described for more than a century. Crohn’s disease, one major type of IBD, has an incidence rate in the United States of approximately seven per 100,000. Advancing biotechnological knowledge regarding this idiopathic disease has led to the development of therapies aimed at specific targets in the disease pathway.

In Crohn’s disease, the inflammatory process is consistent with a T-helper 1 immune response. The T-helper 1 immune response is characterized by an increased expression of interferon γ, interleukin (IL)-2, IL-12, IL-18, and pro-inflammatory mediators IL-1 β, tumor necrosis factor (TNF), and nuclear factor β, as well as a compensatory increase in anti-inflammatory IL-10 and transforming growth factor κB. Of particular interest to clinical researchers is the detection of elevated TNF levels in the serum and stool of Crohn’s disease patients. TNF appears to be a pivotal target in the Crohn’s disease pathway, which could result in the interruption of the inflammatory cascade when inhibited.

Currently, two genetically engineered TNF antagonists are available and approved by the Food and Drug Administration (FDA). Infliximab (Remicade) is a chimeric IgG1 monoclonal antibody for anti-TNF therapy in patients with moderate-to-severe Crohn’s disease. The drug has demonstrated significant improvement of symptoms in patients with severe Crohn’s disease refractory to standard treatment, fistulas, and rheumatoid arthritis. It is thought that infliximab binds and neutralizes soluble and membrane-bound TNF. Infliximab demonstrates unique additional effects such as antibody-dependent cellular toxicity, complement-dependent cytotoxicity, and induction of T-lymphocyte apoptosis.

The other FDA-approved TNF antagonist, etanercept (Enbrel), is a dimeric fusion protein with two identical chains of the recombinant human p75 TNF receptor monomer linked to the Fc portion of human IgG1 for the treatment of rheumatoid arthritis. It has demonstrated significant improvement in disease activity and improves quality of life in rheumatoid arthritis patients. The proposed mechanism of action for etanercept is the antagonism of TNF activity by binding to membrane-bound and soluble forms of TNF.

Because etanercept and infliximab are classified as TNF antagonists and are efficacious in rheumatoid arthritis therapy, etanercept use in Crohn’s disease was investigated. Two clinical trials that examined the use of etanercept for active Crohn’s disease provide conflicting results.

D’Haens et al conducted a single-center pilot trial that enrolled 10 patients with at least six months of active Crohn’s disease. Each patient was treated for 12 weeks with the dose of etanercept recommended for rheumatoid arthritis, 25 mg subcutaneously twice weekly, as well as any additional therapy that the patient was taking prior to the study. The patient’s response to treatment was evaluated using the Crohn’s Disease Activity Index (CDAI). The index was developed in 1976 by Best et al and was used as a monitoring tool in the National Cooperative Crohn’s Disease study. The CDAI consists of an eight-question survey evaluating bowel function, emotional status, and systemic involvement. After 12 weeks of treatment, seven patients demonstrated a clinical response measured by a decrease in the CDAI of 70 or more points, and four patients attained remission, with a total CDAI of less than 150. Three out of the four subjects in remission relapsed within four weeks after discontinuing etanercept. D’Haens et al concluded that etanercept at 25 mg subcutaneously twice weekly might be effective in Crohn’s disease refractory to standard therapy, yet may be insufficient to induce remission. Limitations of this study include a small sample size and lack of a placebo control, blinding, or randomization.

Subsequently, Sandborn et al conducted an eight-week, randomized, double-blind, placebo-controlled trial evaluating etanercept use in 43 active Crohn’s disease patients. The patients were randomized to receive 25 mg of etanercept or placebo subcutaneously twice weekly. At week four of the study, the placebo-treated patients had a higher clinical response of 45%, measured by a decrease in CDAI of 70 or more points or total score of less than 150 points, compared to 39% clinical response among the etanercept-treated patients. Sandborn et al concluded that etanercept at 25 mg subcutaneously twice weekly is ineffective for the treatment of active Crohn’s disease. The authors cite an unpublished placebo-controlled dose-finding study with etanercept that produced a similar negative outcome. One plausible explanation for the results of this study is the possibility that dissimilar binding affinities between etanercept and infliximab resulted in distinct rates of response. However, these differences have not been evident in rheumatoid arthritis patients. It also may be possible that etanercept has poor penetration in the gastrointestinal (GI) tract when administered by injection. Additionally, Sandborn et al postulate that perhaps a higher dose or more frequent dosing may be needed to acquire clinical benefit. Although this study had a small sample size, similar demographics between subject groups, and a randomized, double-blind, placebo-controlled design, it provided more convincing evidence compared to the single-center trial.

Despite questionable efficacy in the treatment of Crohn’s disease, etanercept is considered a safe medication overall. The most common adverse events reported in both of the published trials were local pain at the injection site, headaches, asthenia, mild anemia, and skin reactions. A retrospective study of etanercept use in rheumatoid arthritis patients showed that approximately 20% of the patients receiving subcutaneous etanercept experienced a transient injection site reaction, mostly within the first two months of treatment. Infections are the most frequent systemic adverse effects and are primarily present as upper respiratory tract infections. This possibility exists with TNF antagonists because of the mediation of inflammatory and immune responses. Adverse GI effects occurring with use of etanercept include abdominal pain, dyspepsia, nausea, vomiting, and mouth ulcers. Serious, infrequent adverse effects include cardiovascular complications, cholecystitis, pancreatitis, bursitis, depression, deep vein thrombosis, pulmonary embolism, membranous glomerulonephropathy, polymyositis, or thrombophlebitis. In clinical trials, the incidences of these serious adverse effects with etanercept were similar to placebo.

The manufacturer, Amgen (formerly Immunex), launched the Enbrel enrollment program in November 2000 to assist in controlling a shortage and to ensure a continuous supply to patients already taking etanercept. Patients have to be enrolled in the program prior to obtaining the drug. The shortage of etanercept has now been resolved; however, the Enbrel enrollment program is still in place and is not accepting new patients until a new manufacturing plant is completed.

In conclusion, evidence documenting the efficacy of etanercept for the treatment of Crohn’s disease is lacking. Considering the conflicting results demonstrated in the two published studies, etanercept should not be considered as a primary therapeutic option for active Crohn’s disease. Presently, Crohn’s disease therapy with etanercept might be considered as a last alternative for patients who have demonstrated poor response to all other possible treatments. Because both studies evaluated the use of etanercept in Crohn’s disease using the dose recommended for rheumatoid arthritis, researchers suggest further consideration with larger trials to establish efficacy, optimal dosing, dosing frequency, and appropriate candidates for Crohn’s disease therapy with etanercept. It is hoped that discovering possible differences among TNF antagonists ultimately will result in a better understanding of the molecular mechanisms in order to produce long-term biotechnological agents that are safe and effective for Crohn’s disease therapy.

References

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