FDA Reviewer Comes Down Hard Against Approving Cangrelor for PCI

February 10, 2014

BETHESDA, MD – Cangrelor (the Medicines Company, Parsippany, NJ), an intravenously administered antiplatelet agent, should not be approved for the reduction of thrombotic events in patients undergoing PCI, according to one clinical reviewer at the Food and Drug Administration (FDA)[1].

The clinical trials supporting the cangrelor application, including CHAMPION-PHOENIX , an 11 000-patient trial testing cangrelor in patients undergoing PCI for stable angina or for acute coronary syndromes (ACS), including STEMI, are flawed, the reports says, and the drug should not be approved until further studies address the shortcomings of these studies.

The opinions and conclusions of Dr Thomas Marciniak, a medical team leader at the FDA's Center for Drug Evaluation, were published today in advance of the FDA Cardiovascular and Renal Drugs Advisory Committee that will take place on Wednesday, February 12, 2014. Specifically, the Medicines Company is seeking approval for two uses. The first is an indication for cangrelor to reduce thrombotic cardiovascular events, including stent thrombosis, in coronary artery disease (CAD) patients undergoing PCI. In addition, it is seeking an approval for cangrelor as a "bridging" therapy in ACS patients at increased risk for thrombotic events when oral P2Y12 therapy is interrupted due to surgery. Marciniak did not comment on the second proposed indication.

Other FDA reviewers were less critical. Drs Fred Senatore and Nhi Beasley suggested that the benefits of cangrelor in the PCI setting might outweigh the risks, depending on the bleeding end points used.

The major trials investigating cangrelor, all of which were reported by heartwire , include CHAMPION-PCI and CHAMPION-PLATFORM , both of which investigated the new IV drug in ACS patients scheduled for PCI. Both were stopped early in 2009 after interim analyses suggested neither study would show a benefit. The PHOENIX study was sponsored by the Medicines Company to address flaws with those earlier trials. According to the company, these two earlier studies were negative because of problems adjudicating new MIs in patients with elevated biomarkers at baseline.

As reported by heartwire , PHOENIX was a positive study, as was a pooled analysis of all three CHAMPION trials that appeared in the Lancet in 2013.

One FDA Review Burns PHOENIX Down

On the whole, Marciniak is extremely critical of the CHAMPION data. In a detailed review, he argues that the "CHAMPION trials do not show superiority or noninferiority of a cangrelor regimen to clopidogrel or to standard of care."

Marciniak argues that clopidogrel was delayed inappropriately in all three trials. In fact, "the greater the delay in administering clopidogrel, the better cangrelor looked for efficacy," he writes. Moreover, clopidogrel was "never consistently administered early enough, such that we cannot even conclude that cangrelor is noninferior to clopidogrel." Such a delay in clopidogrel administration is "very disturbing," he adds, ultimately calling the PHOENIX trial unethical because it delayed the use of clopidogrel until after coronary angiography or later and because it prohibited the routine use of prasugrel (Effient, Lilly/Daiichi-Sankyo), ticagrelor (Brilinta, AstraZeneca), or GP IIb/IIIa inhibitors.

"The PHOENIX informed-consent documents failed to inform patients regarding the advantages of earlier use of clopidogrel and the use of prasugrel, ticagrelor, and [GP IIb/IIIa inhibitors]," writes Marciniak. This reason alone is enough to refuse to approve the cangrelor new drug application, he says.

In addition, Marciniak questions the clinical superiority of cangrelor in PHOENIX, pointing out that the end point included "chemical" MIs. He notes that patients in the cangrelor arm were treated with a 600-mg loading dose of clopidogrel, whereas those in the clopidogrel arm received only 300 mg. This loading-dose differential might account for some of the superiority of the IV antiplatelet agent.

Furthermore, the real benefit of cangrelor appears to be only in patients with stable angina, and these patients are considerably easier to load with clopidogrel than other patient subgroups, writes Marciniak. For example, CABG can be delayed for days to wash out the effects of clopidogrel. One of the advantages of cangrelor is the drug's short half-life of three to six minutes. Marciniak suggests the CHAMPION data even hint at the possibility of harm in STEMI patients.

"While the trials did not demonstrate convincingly superiority of cangrelor for efficacy, they do demonstrate an increased risk of bleeding with it," he writes. In contrast, newer drugs, such as prasugrel and ticagrelor, have demonstrated superiority efficacy compared with clopidogrel.

For Senatore and Beasley, the overall risk/benefit evaluation showed mixed results. They conclude, however, there was a "marginal" benefit in the PCI setting that was driven by a reduction in periprocedural MIs.

"The benefit outweighed the risk using GUSTO, TIMI, and bad-bleed criteria," they write. "One might consider these bleeds to be of greater clinical import. The risk outweighed the benefit in using all non-CABG bleeding and ACUITY major bleeding. All non-CABG bleeding captured minor bleeds, and a large component of the ACUITY major bleeds included hematomas. Thus, one might consider these bleeds to be of less clinical consequence."

A clinical pharmacology review also concluded that cangrelor could be approved based on the grounds of its assessment. Specifically, the pharmacological review assessed the ability of cangrelor to reduce cardiovascular events, including stent thrombosis, and maintain P2Y12 inhibition in ACS patients or patients with stents at risk for thrombotic events when oral therapy was interrupted due to surgery.

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