EU Declines to Approve Tofacitinib (Xeljanz) for RA

Troy Brown


July 26, 2013

The Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) voted not to recommend marketing authorization for tofacitinib (Xeljanz, Pfizer Ltd) for the treatment of moderately to severely active rheumatoid arthritis, according to an EMA statement made today. The decision follows a re-examination of initial recommendations made on April 25, 2013, after the committee decided the risks of taking the medication did not outweigh the benefits.

Tofacitinib is an immunosuppressant that reduces inflammation and other symptoms by blocking the action of the Janus kinase enzymes. Tofacitinib (5-mg tablet) was intended for use in patients in whom at least one other biological disease-modifying antirheumatic drug (biological DMARD) had failed, either because of intolerable adverse effects or inadequate response, the EMA noted in a question-and-answer sheet.

The decision was based on data from 5 studies of more than 3300 patients with rheumatoid arthritis that compared tofacitinib (5- or 10-mg twice daily) with placebo, either alone or in combination with other background drugs (DMARDs).

The primary effectiveness measures were changes in patient reports of disease signs and symptoms, physical function, joint structural damage, and disease activity, which were determined after 3 or 6 months, depending on the trial.

The CHMP had "significant and unresolved concerns" about the overall safety profile of tofacitinib, including the risk and type of serious infections and serious adverse effects such as some cancers, gastrointestinal perforations, liver damage, and increased blood lipid levels. The committee was uncertain whether clinicians could manage these risks successfully.

In April the CHMP decided that overall, the data showed that tofacitinib improved disease signs and symptoms and physical function, but that there was insufficient evidence that it consistently reduced disease activity and joint structural damage, especially at the 5-mg dose and in patients in whom at least 2 other DMARDs had been unsuccessful.

At the meeting that ended yesterday, the company suggested removing claims regarding structural damage from the indication. After re-examination, the CHMP still believed that the benefits of tofacitinib treatment did not outweigh the continued safety concerns, and the committee confirmed its recommendation for refusal of marketing authorization.

Patients taking tofacitinib in clinical trials can continue to receive it as before, and future requests for compassionate use will be considered by the company on an individual basis according to local regulations, the EMA explained. The agency recommends that patients currently in a clinical trial or compassionate use program should contact their physician.

The US Food and Drug Administration (FDA) approved tofacitinib in November 2012 for the treatment of adults with moderately to severely active rheumatoid arthritis who have not responded adequately to, or are intolerant of, methotrexate. The drug carries a boxed warning regarding safety risks such as serious infections, including opportunistic infections, tuberculosis, lymphoma, and other cancers, the FDA said at the time. The drug is also associated with increases in cholesterol and liver enzyme test results and decreases in blood counts.

The drug was approved by the FDA with a risk evaluation and mitigation strategy, "which consists of a Medication Guide advising patients about important safety information and a communication plan to inform health care providers about the serious risks associated with Xeljanz."

"To study the long-term effects of Xeljanz on heart disease, cancer, and serious infections, the FDA is requiring a postmarketing study that will evaluate two doses of Xeljanz and include a group of patients on another approved treatment to serve as a comparison," the agency said.

"Questions and answers: Refusal of the marketing authorisation for Xeljanz (tofacitinib): Outcome of re-examination." EMA. Published online July 26, 2013. Full text


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