FDA panel backs approval of cangrelor

The FDA’s Cardiovascular and Renal Drugs Advisory Committee voted 9-2 with one abstention that cangrelor, a novel intravenous P2Y12 receptor antagonist, should be approved for reduction of thrombotic events in patients with CAD undergoing PCI.

In February 2014, the panel voted 2-7 against approval of cangrelor (The Medicines Company) for the PCI indication and 0-9 against approval of the drug to maintain P2Y12 inhibition in patients with ACS or stents who are at increased risk for thrombotic events when oral P2Y12 inhibition is interrupted because of surgery. In May 2014, the FDA issued the sponsor a complete response letter denying approval for both indications.

The panel changed its recommendation on the PCI indication, which is narrower than what was voted on in 2014, based on new analyses provided by The Medicines Company, which is not currently seeking approval for the surgery indication. If approved, cangrelor would be marketed under the brand name Kengreal.

Benefit outweighs risk

In a briefing information document prepared for the panel, FDA staff recommended approval for the PCI indication. According to the document: “The benefit of cangrelor compared to clopidogrel is small, but the risk is smaller. We recommend that cangrelor be approved as an adjunct to PCI for the reduction in risk of periprocedural ischemic complications including [MI] and stent thrombosis in patients in whom treatment with an oral P2Y12 platelet inhibitor prior to PCI is not feasible and when glycoprotein IIb/IIIa receptor antagonists are not anticipated to be used.”

A major reason for the denial in 2014 was concern that two subcomponents of the primary endpoint in the pivotal CHAMPION PHOENIX trial — intraprocedural stent thrombosis and periprocedural MI identified solely by increases in serum biomarkers of myocardial necrosis — were not clinically meaningful.

When the sponsor performed a sensitivity analysis removing those two subcomponents, the primary endpoint remained significant compared with clopidogrel (OR = 0.69; 95% CI, 0.51-0.92), according to the briefing document. “The [CHAMPION] PHOENIX study as a standalone trial was sufficient to warrant approval for cangrelor for the prevention of periprocedural MI and stent thrombosis in patients undergoing PCI,” the FDA staff wrote in the briefing document.

Reservations voiced

During the advisory committee meeting, panel members debated a number of topics, including whether two failed trials that preceded CHAMPION PHOENIX — CHAMPION PLATFORM and CHAMPION PCI — should also be considered, whether bleeding risks associated with cangrelor were acceptable in women and whether the protocol for administration of clopidogrel to controls in CHAMPION PHOENIX was appropriate. Those who voted yes generally did so despite reservations on one or more of those topics.

“The thing that concerns me is the comparator, and I hope that the label will reflect what the comparator was in this trial,” said panel member Barry Davis, MD, PhD, Guy S. Parcel Chair in Public Health, professor of biostatistics and director of the Coordinating Center for Clinical Trials at the University of Texas School of Public Health, Houston, who voted yes. “I do also remain concerned about the small benefit vs. the risk. But I think that adding an additional drug to the armamentarium, especially something like this with fast action, will be helpful.”

Panel member Julia B. Lewis, MD, professor of medicine, department of nephrology, Vanderbilt University School of Medicine, Nashville, Tenn., said she voted no because “I am largely, in the end, uncomfortable with this as a single trial. I have concerns about who was studied and whether they are actually the patients who will be included in the label, I have concerns about [CHAMPION] PLATFORM and [CHAMPION] PCI, and I have concerns about the clopidogrel use. Despite the fact that [CHAMPION PHOENIX] might meet some definition of what is acceptable as a single trial, I’m not comfortable with it.”

The FDA is not required to follow the recommendations of its advisory panels, but it usually does. – by Erik Swain

Reference:

CRDAC Briefing Document. NDA 204958.

Disclosure: The members of the Cardiovascular and Renal Drugs Advisory Committee report no relevant financial disclosures.