FDA Review Endorses Vorapaxar Approval in Prior MI Patients

January 13, 2014

SILVER SPRING, MD — Reviewers for the Food and Drug Administration (FDA) are giving vorapaxar (Zontivity, Merck Sharpe & Dohme), a novel protease-activated receptor 1 (PAR-1) inhibitor that targets thrombin-induced platelet activation, their blessing[1].

In documents published two days ahead of the Cardiovascular and Renal Drugs Advisory Committee, a committee that will consider data and vote on the drug's immediate future, the FDA review states that vorapaxar should be approved as an "adjunctive therapy in patients with a history of myocardial infarction to reduce the risk of cardiovascular death, myocardial infarction, stroke, and urgent coronary revascularization."

The FDA review is based on an analysis of clinical-trial data by the agency's scientists and statisticians, and their recommendation will be factored into the advisory committee's decision. Although the advisory committee votes on whether or not a drug should be approved, the ultimate decision remains with the FDA. The FDA typically follows the advice of the advisory committee, although it does not have to.

A Large 26 000 Patient Study Guides Recommendation

The FDA reviewers' recommendation for approval is based on results from the TRA 2°P TIMI-50 clinical trial. Reported by heartwire when it was presented in 2012 at the American College of Cardiology Scientific Sessions , the 26 499-patient study met its primary end point. Patients enrolled in TRA 2°P TIMI-50 had at least one of three atherosclerotic conditions (prior MI, prior stroke, or established peripheral arterial disease), but those with a prior MI made up 70% of the trial population.

The primary end point of the trial was the time to cardiovascular death, MI, stroke, or urgent coronary revascularization. Among those treated with vorapaxar 2.5 mg, there was a 13% reduction in the primary end point. When coronary revascularization was excluded, the secondary end point of cardiovascular death, MI, or stroke was also significantly reduced.

Vorapaxar did increase the risk of bleeding, particularly intracranial hemorrhage (ICH), and this led to changes in the study design. Patients with a prior history of stroke were excluded from the trial after recommendations from the data safety and monitoring board (DSMB) were approved by the clinical investigators.

As a result, any approval for vorapaxar would exclude patients with a prior history of ICH, ischemic stroke, or transient ischemic attack, as well as those with current overt pathological bleeding. The increased bleeding risk with vorapaxar should be included in the medication guide to warn physicians, according to the FDA. The medication guide would also likely include information about a higher risk of bleeding in the elderly, those who weigh less than 60 kg, and those with severe renal impairment.

In the review, the FDA states the "consistent advantage of vorapaxar for fatal and nonfatal serious events across subpopulations in TRA 2°P supports approval for indication in patients with prior MI proposed by the applicant."

In the Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome (TRACER) trial with vorapaxar, adding the PAR-1 inhibitor to standard therapy significantly raised the risk of major bleeding complications, including ICH, over two years. Merck discontinued the study and is not seeking an ACS approval, nor are the FDA reviewers recommending it.

Merck sponsored the TRA 2°P and TRACER trials .


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