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FDA Staff Recommends Approval of Once-Rejected Platelet Inhibitor Cangrelor

Pivotal trial data re-analyzed

A platelet inhibitor developed by The Medicines Co. should be approved by the FDA, according to a report from the agency’s Cardiovascular and Renal Drugs Advisory Committee (CRDC).

The intravenous (IV) injection product cangrelor (Kengreal), which received European approval in March, is designed to prevent blood clots during angioplasty, which often includes the use of stents.

Cangrelor, an analogue of adenosine triphosphate, is a parenteral, short-acting inhibitor of adenosine diphosphate (ADP)-induced platelet aggregation. It directly and competitively inhibits ADP binding to the platelet P2Y12 receptor, one of the pathways that activate the platelet glycoprotein 2b/3a complex.

Cangrelor was originally submitted to the FDA with the proposed indication of reduction of thrombotic cardiovascular events in patients with coronary artery disease (CAD) undergoing percutaneous coronary intervention (PCI) who have not received an oral P2Y12 inhibitor prior to the PCI procedure and in whom oral therapy with P2Y12 inhibitors is not feasible or desirable.

The Medicines Co. had conducted three trials –– CHAMPION PCI, CHAMPION PLATFORM, and CHAMPION PHOENIX –– that were intended to provide evidence of efficacy and safety to support approval of the PCI indication. All three were large, randomized, double-blind superiority trials in which patients who had undergone coronary angiography were randomly assigned, immediately before PCI, to receive either cangrelor administered as a 30-mcg/kg IV bolus followed by a 4-mcg/kg/min infusion for at least 2 hours or until the conclusion of the index procedure (whichever was longer), followed by a 600-mg dose of clopidogrel, or clopidogrel alone.

The first two studies, PCI and PLATFORM, were conducted concurrently and were stopped at the same time prior to completion for futility. Post hoc analyses of these two trials generated two hypotheses: 1) the ascertainment of postprocedure MIs was masked by biomarker elevations related to a preprocedural MI, whiich obscured cangrelor’s efficacy, and 2) cangrelor appeared to be effective in reducing the incidence of stent thrombosis. The third trial, PHOENIX, was designed based on these two hypotheses.

The CRDC discussed the original application on February 12, 2014. At that time, the committee voted 7 to 2 against approval for the PCI indication. The committee members who voted “No” indicated concern about the design of the PHOENIX trial and about the two negative studies (PLATFORM and PCI), and also felt that the increased risk of bleeding with cangrelor was not outweighed by the small clinical benefit. In particular, the committee did not believe that a reduction in the risk of intra-procedural stent thrombosis (IPST) was clinically important and expressed uncertainty about the clinical importance of periprocedural myocardial infarctions  detectable only by increases in serum biomarkers.

Consequently, the FDA rejected the blood thinner in April 2014 and asked the company to re-analyze the data from the pivotal PHOENIX trial.

In its new report, released April 13, the CRDC concluded: “The PHOENIX study as a stand-alone trial was sufficient to warrant approval of cangrelor.”

The report comes 2 days ahead of a meeting of independent experts to decide on whether cangrelor should be approved for its proposed indication.

While the FDA is not obligated to follow the recommendations of its advisory committees, it usually does so.

Sources: Reuters, April 13, 2015; and FDA Briefing Document; February 13, 2015.

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