The novel antiplatelet drug vorapaxar has been approved for reducing the risk of myocardial infarction, stroke, cardiovascular death, and need for coronary revascularization procedures in patients with a previous MI or peripheral arterial disease, the Food and Drug Administration announced on May 8.

Vorapaxar is an antagonist of protease-activated receptor-1 (PAR-1), which inhibits the action of thrombin on the platelet, and is the first drug in this class to be approved. Merck Sharp & Dohme will market the drug as Zontivity.

It comes in a tablet formulation.

At a meeting in January, the FDA’s Cardiovascular and Renal Drugs Advisory Committee voted 10-1 to recommend approval of vorapaxar.

"In patients who have had a heart attack or who have peripheral arterial disease, this drug will lower the risk of heart attack, stroke, and cardiovascular death," Dr. Ellis F. Unger, director of the Office of Drug Evaluation I in the FDA’s Center for Drug Evaluation and Research, reported in the FDA statement.

"In the study that supported the drug’s approval, Zontivity lowered this risk from 9.5% to 7.9% over a 3-year period – about 0.5% per year," he noted.

The FDA’s Cardiovascular and Renal Drugs Advisory Committee recommend approval of the novel antiplatelet drug for reducing atherothrombotic events in patients with a history of MI – the indication proposed by Merck. The recommended dose is one 2.5-mg tablet per day.

Because of the increased risk of bleeding, including life-threatening and fatal bleeding, the drug’s prescribing information includes a boxed warning about this risk and a medication guide informing patients about how to use the drug. A history of stroke, or transient ischemic attack, and a history of intracranial bleeding are contraindications.

The indication also includes the statement that treatment with vorapaxar has been shown to reduce the rate of the combined endpoint of cardiovascular death, MI, stroke, and urgent coronary revascularization.

The company conducted two phase III studies in two different groups of patients. In the TRACER (The Thrombin Receptor Antagonist for Clinical Event Reduction in ACS) study, which compared vorapaxar with placebo, added to standard therapy, as acute therapy (2.5 mg per day after a 40-mg loading dose, or placebo) in almost 13,000 hospitalized patients randomized within 24 hours of presenting with ACS (with non-ST elevation), it reduced the risk of atherothrombotic events (N. Engl. J. Med. 2012;366:20-33).

The study, however, was terminated early after an increased risk of major bleeding, including ICH, was detected and the company stopped the treatment in patients with a history of stroke or new stroke in the other phase III trial, the TRA 2P–TIMI 50 (Thrombin-Receptor Antagonist in Secondary Prevention of Atherothrombotic Events) study. The company dropped plans to pursue the acute ACS indication.

The approved indication is based on the results of the TRA 2P–TIMI 50 study, which randomized 26,449 patients to placebo or 2.5 mg of vorapaxar a day, added to standard therapy (including other antiplatelet agents) in 26,449 outpatients with a previous MI, previous ischemic stroke, or peripheral arterial disease (N. Engl. J. Med. 2012;366:1404-13). (Almost 80% of the patients in the study who met the criteria in the proposed indication were on dual antiplatelet therapy with aspirin and a thienopyridine.)

In the overall cohort, including those who had to stop treatment early, compared with placebo, the risk of the primary composite endpoint of cardiovascular death, MI, stroke, or urgent coronary revascularization was reduced by 12%, and the risk of a secondary efficacy endpoint (CV death, MI, stroke) was reduced by 13% over 3 years among those treated with vorapaxar – effects that were statistically significant, Merck said.

The risk of severe or moderate bleeding was increased by 51% among those on vorapaxar over placebo.

The ICH rate over 3 years was 1% among those on vorapaxar, compared with 0.6% among those on placebo, but the absolute risk was higher in those with a history of stroke, according to Merck.

There is "clearly an unmet need" in this group of patients with a history of MI, "and a lack of therapies that have been shown to really be beneficial long term in this population," said the panel chair, Dr. Philip Sager, chair of the scientific programs committee, Cardiac Safety Research Consortium, San Francisco. "While there certainly is some bleeding risk, the benefits on the primary endpoint and secondary endpoint clearly outweigh those risks, and the benefit-risk relationship is positive," he added.

The panelist who voted against approval, Dr. Mori Krantz, director of the Colorado Prevention Center, Denver Health Medical Center, agreed that the primary efficacy endpoint had been met but was concerned about the size of the benefit and the large number of people needed to treat to benefit one patient.

"Although the intracranial hemorrhages and the major bleeds were potentially manageable, I worry about the amplification of that signal," because triple antiplatelet therapy is "unprecedented," he added.

Other safety concerns cited by panelists included a lack of an antidote and the lack of an effect in people weighing less than 60 kg (132 lb), an unresolved issue.

emechcatie@frontlinemedcom.com

FDA approves vorapaxar, a new oral antiplatelet