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FDA reviewers express concerns about safety of Pfizer's RA drug candidate

Monday, May 07 2012 | Comments
Evidence Grade 0 What's This?
Staff members from the Food and Drug Administration said Pfizer Inc.'s tofacitinib, an investigational oral treatment for adults with moderately to severely active rheumatoid arthritis (RA), is associated with "serious safety concerns," according to documents posted on the FDA's website ahead of an advisory panel meeting.

The Arthritis Drugs Advisory Committee will meet on May 9 to review data pertaining to tofacitinib and determine whether to recommend approval of the Janus kinase inhibitor.

In the documents, the staff reviewers said all five Phase III clinical trials of tofacitinib provide consistent evidence of improvement in the signs and symptoms of RA. In each study, a statistically significantly higher proportion of the tofacitinib-treated patients achieved a 20 percent improvement from baseline in American College of Rheumatology criteria (ACR20) as compared with those in the placebo arm. Moreover, in three of the trials, a significantly higher percentage of the tofacitinib-treated patients achieved a 28-joint Disease Activity Score (based on erythrocyte sedimentation rate) of less than 2.6 relative to those who were given placebo.

Four of the studies also demonstrated evidence of improvement in physical function, as measured by the Health Assessment Questionnaire-Disability Index.

However, the reviewers said it was not possible to make definitive conclusions about the treatment effect of tofacitinib on structural damage progress, which they noted is particularly important in determining the drug's overall benefit-risk profile.

The proposed recommended starting dose of tofacitinib is 5 mg twice daily, and some patients might benefit from an increase in dosage to 10 mg twice daily, based on clinical response. The proposed dose escalation, however, is not supported by the design of the Phase III tofacitinib trials, controlled data or predetermined analyses, the FDA staff pointed out.

In terms of safety, the FDA reviewers asked that the advisory committee discuss data for tofacitinib pertaining to the risk of malignancy--overall, and lymphoma in particular--as well as serious infections, abnormal hematologic parameters, lipid parameter changes and the drug's cardiovascular safety profile. 

Pfizer, in separate briefing documents, stated that tofacitinib "has demonstrated, through an extensive clinical program, a manageable safety profile and robust efficacy when dosed orally as 5 mg and 10 mg [twice daily], either as monotherapy or on background disease-modifying antirheumatic drugs [DMARDs]."

The company added that the benefit-risk profile of the drug is "consistent with that of biologic therapies currently used in patients that have had an inadequate response to prior DMARD therapy."

The FDA is scheduled to decide whether to approve tofacitinib in August.

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