January 13th, 2014
Merck’s Vorapaxar Gets Positive FDA Review
A few years ago a novel antiplatelet agent from Merck seemed all but dead. Vorapaxar, a thrombin receptor antagonist, was widely thought to have no future after unacceptably high serious bleeding rates were found in two large clinical trials studying the drug in a wide variety of acute and chronic cardiovascular patients. But hopes for the drug resurfaced with a new analysis of one of those trials, the TRA2P trial. Now the FDA appears willing to give the drug a renewed lease on life.
On Wednesday the Cardiovascular and Renal Drugs Advisory Committee will discuss the new drug application (NDA) for vorapaxar (proposed trade name, Zontivity) for a considerably narrower indication than initially hoped for by the company. The proposed indication is as an adjunct therapy for the reduction of atherothrombotic events in patients with a history of myocardial infarction (MI). The company also wants to claim the drug leads to a reduction of the combined endpoint of cardiovascular death, MI, stroke, and urgent coronary revascularization.
In the full TRA2P trial, 26,449 patients with a history of MI, ischemic stroke, or peripheral arterial disease were randomized to either vorapaxar or placebo in addition to standard therapy. Vorapaxar was found to be effective in cutting the rate of CV death, MI, or stroke. But it was also associated with a doubling of the very serious complication of intracranial bleeding. This finding, along with the high rate of bleeding complications and intracranial hemorrhage that occurred in the TRACER trial in acute coronary syndrome patients, seemed likely to doom the drug.
But TRA2P was redesigned in midcourse based on Data and Safety Monitoring Board concerns about patients with a history of stroke. Patients with stroke were no longer allowed to enter the trial. In the subgroup analysis of the 17,779 patients with a history of MI and no history of stroke, there was a significant reduction in cardiovascular events with no increase in intracranial bleeding.
In general, a substudy does not provide sufficient evidence to support an NDA for a novel drug. But the TRA2P substudy was larger than is usually found in the entire population of most clinical trials. The FDA reviewers conclude that the “results are sufficient to establish the effectiveness of vorapaxar for its proposed indication in patients with prior MI and support the Applicant’s proposal not to include patients with prior stroke in the target population.”
The FDA will webcast the entire session on Wednesday. (Click here for webcast information.)