CardioExchange Archive

Early next year an FDA panel will review a new drug from Merck and a new indication for Xarelto (rivaroxaban), Johnson & Johnson’s highly successful new oral anticoagulant. Both drugs have had a rocky road getting to this stage and their success is by no means assured, but the announcement of the meeting of the FDA’s Cardiovascular and Renal Drugs Advisory Committee suggests that the companies have made progress resolving earlier problems.

Merck’s new drug application (NDA) for vorapaxar (Zontivity is the proposed trade name) will be discussed on January 15 for the proposed indication of reduction of atherothrombotic events in patients with a history of myocardial infarction (MI). (Here’s the notice in the Federal Register.) Merck will also try to demonstrate that the drug reduces the rate of a combined endpoint of cardiovascular death, MI, stroke, and urgent coronary revascularization.

The background story of vorapaxar is quite interesting. The once highly-promising novel antiplatelet drug, 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 last year based on new data from a prespecified analysis of the TRA 2P-TIMI 50 trial published in the Lancet. The new proposed indication is considerably narrower than the company had originally hoped.

In the full trial, which randomized 26,449 patients with a history of MI, ischemic stroke, or peripheral arterial disease to either vorapaxar or placebo in addition to standard therapy, the rate of CV death, MI, or stroke was significantly reduced by vorapaxar, but there was also a doubling of the very serious complication of intracranial bleeding. But the substudy published in the Lancet focused on the subgroup of 17,779  patients with a history of MI. After 2.5 years of followup, the rate of CV death, MI, or stroke was significantly reduced in the vorapaxar group compared to the placebo group, though vorapaxar was also associated with an increased risk of bleeding, though not, importantly, intracranial bleeding.

In general, a substudy does not provide sufficient evidence to support an NDA for a novel drug. But, the study authors pointed out, the substudy was larger than is usually found in the entire population of most clinical trials. It seems likely that the FDA reviewers and the advisory committee members will spend some time considering this issue.

On January 16 the panel will discuss the supplemental NDA for Johnson & Johnson’s Xarelto (rivaroxaban) to reduce the risk of thrombotic cardiovascular events in patients in the first 90 days after suffering acute coronary syndrome (ACS). Earlier this year the FDA turned this supplemental NDA down for the second time.

The ACS indication has proved tantalizingly elusive, the one major blank space in a large trophy case of successful indications garnered by the drug. The proposed indication is based on the ATLAS ACS 2-TIMI 51 trial, which was widely praised when results were first unveiled in 2011. The FDA then granted priority review for the indication. But momentum ground to a halt when FDA reviewers raised questions about the ATLAS trial, largely centering on significant amounts of missing data from the trial. The FDA advisory panel, highlighted by vocal criticisms from Steve Nissen and Sanjay Kaul, resulted in a vote against the ACS indication, leading to the first complete response letter.

Johnson & Johnson has revealed neither the contents of the most recent complete response letter nor the substance of its answer to the FDA.