FDA
16th January 2014

FDA Panel Supports Approval of Merck’s ZONTIVITY (vorapaxar sulfate)

Yesterday, the FDA’s Cardiovascular and Renal Drugs Advisory Committee (CRDAC) voted 10-1 in favor of approval for Merck’s vorapaxar sulfate (vorapaxar, proposed name, “Zontivity”) for the reduction of atherothrombotic events in patients with a history of myocardial infarction (MI) but no history of stroke or transient ischemic attack (TIA) (i.e. ‘mini-strokes’).

FDA Panel Supports Approval of Merck’s ZONTIVITY (vorapaxar sulfate)

Yesterday, the FDA’s Cardiovascular and Renal Drugs Advisory Committee (CRDAC) voted 10-1 in favor of approval for Merck’s vorapaxar sulfate (vorapaxar, proposed name, “Zontivity”) for the reduction of atherothrombotic events in patients with a history of myocardial infarction (MI) but no history of stroke or transient ischemic attack (TIA) (i.e. ‘mini-strokes’). Merck is seeking approval with an indication that explicitly excludes patients with a history of stroke.

Vorapaxar is an orally-active protease-activated receptor 1 (PAR-1) inhibitor that targets thrombin-induced platelet activation. It works by preventing blood cells, or platelets, from clumping together and forming clots in the arteries, which can lead to heart attacks. 

Other anti-platelets include aspirin and Plavix (Bristol-Myers Squibb), but they do not specifically inhibit PAR-1 as vorapaxar does.

Vorapaxar was found by panelists to have greater benefit than risk as it would reduce the chance of further heart problems in people who have suffered a recent heart attack. However, they agreed with the company that the drug should not be used in patients with a history of stroke, since there was an increased risk of bleeding in the brain in this group of patients.

Each year about 190,000 Americans have a second heart-related event, according to Merck. Standard therapy to prevent a second episode often includes treatment with aspirin and Plavix. Vorapaxar would be given in addition to standard treatment.

Reviewers were asked to assess the tradeoff between the drug’s efficacy and risk. They weighed evidence from two large, randomized trials, TRA-2P and TRACER. TRA-2P enrolled 26,499 patients with either a prior MI, prior ischemic stroke or established peripheral artery disease. TRACER included almost 13,000 patients with acute coronary syndrome without segment elevation myocardial infarction (STEMI) within 24 hours of presenting at the hospital.

Both trials experienced some setbacks. TRACER was terminated early because of major bleeding in the vorapaxar group. In TRA-2P, patients with a history of stroke were terminated early while the other groups continued.

Nonetheless, panelists noted that TRA-2P results were “robust.” They showed vorapaxar reduced the risk of cardiovascular death, MI or stroke compared to placebo, but had a higher rate of bleeding (1 percent vs. 0.5 percent).

“I think this drug addresses a real unmet medical need,” said Dr. Philip Sager, consulting professor of medicine at Stanford University School of Medicine.

The vote followed a positive analysis by reviewers for the FDA, whose report, published on Monday, also recommended the drug be approved.

Still, Dr. Sanjay Kaul, a cardiologist and professor at UCLA School of Medicine who voted in favor of approval, urged the FDA to “do its due diligence” around the bleeding risk.

Merck has proposed that the drug’s label urge caution when prescribing the drug for patients who weigh less than 60 kilograms (132 lbs) since the risk of bleeding in these patients appears to be higher than in heavier patients. Panelists could not reach a consensus recommendation on how lower-weight patients should be treated. Representatives from the FDA said they will continue to discuss the matter before making their final ruling.

Dr. Daniel Bloomfield, who leads Merck’s cardiovascular research, stated that “We look forward to working with the FDA as it completes its review.”

The FDA is not bound by the CRDAC’s decision but normally follows its recommendation.

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