FDA advisory panel decisions

FDA advisory panel recommends against approval of cangrelor for two indications

The FDA Cardiovascular and Renal Drugs Advisory Committee today voted against recommending approval for cangrelor, a novel P2Y12 receptor antagonist, for both of the two proposed indications.

The committee voted against approval for cangrelor (The Medicines Company) for the reduction of thrombotic CV events among patients with CAD treated with PCI (2 yes, 7 no), and unanimously against approval for the maintenance of P2Y12 inhibition for patients with ACS or those with stents who are at high risk for thrombotic events and require an interruption to oral P2Y12 treatment due to surgery.

Cangrelor in PCI

The Medicines Company sought approval for the PCI indication based on results from the CHAMPION trial program, which includes the PLATFORM, PCI and PHOENIX trials. Both the PLATFORM and PCI trials were terminated early according to prespecified stopping rules and neither trial met their primary objectives, but informed the design of the multicenter, double blind, double-dummy PHOENIX trial. In that trial, significantly fewer patients assigned cangrelor achieved the primary composite endpoint of all-cause mortality, MI, ischemia-driven revascularization and stent thrombosis, both within 48 hours of PCI (OR=0.79; 95% CI, 0.66-0.93) and at 30-day follow-up (OR=0.85; 95% CI, 0.73-0.99). 

In the briefing documents issued ahead of the advisory committee meeting, medical team leader Thomas A. Marciniak, MD, recommended against approval of the drug for the PCI-related indication, writing that the CHAMPION program did not indicate either superiority or noninferiority for cangrelor compared with clopidogrel or standard of care. He also indicated that the use of a 300-mg loading dose only in the clopidogrel group in the PHOENIX trial compared with a 600-mg dose in the cangrelor group raised potential ethical questions.

Several of the members who voted “no” indicated concerns about study design, though few agreed with the idea that there were ethical issues with the trials. Milton Packer, MD, professor of clinical science at University of Texas Southern Medical School, said that although he voted no, he “really wanted to vote yes. The concept behind this drug was so intuitively appealing. ... The sponsor did a very nice job of reducing my discomfort in several areas, but I remained uncomfortable with so many components of this."

Members also voiced concerns about the benefit-to-risk advantage indicated by the available data.

“Like Milton, I find the drug intuitively very appealing,” said member James DeLemos, MD, cardiology service chief at Parkland Memorial Hospital, Dallas. “... When I look at the data in aggregate, I'm just unconvinced that the risk/benefit is clearly favorable for clinically relevant endpoints.”

Jennifer S. Li, MD, MHS, division chief of pediatric cardiology at Duke Translational Medicine Institute, provided one of the two affirmative votes. She said that, despite issues with the design of the trial, there was evidence of a net clinical benefit from cangrelor, and that an additional, IV treatment option for this population would be beneficial.

Acting chairperson Philip Sager, MD, consulting professor of medicine at Stanford University School of Medicine, provided the other “yes” vote. "There were definitely trial design issues; however, I felt that the different analyses of the data ... reassured me that the trial really did show a reduction in the primary endpoint and that ... there was still overall net benefit,” Sager said.

Cangrelor as bridge treatment

The sponsor had also sought approval for the P2Y12 inhibition indication following results from BRIDGE, a double blind, placebo-controlled, multicenter trial of 210 patients with ACS or a coronary stent, who were scheduled for CABG and receiving oral P2Y12 inhibitor therapy.

In this trial, nearly all cangrelor recipients (98.8%) maintained target platelet inhibition levels at each evaluated time point compared with 19% of placebo recipients (RR=5.2; 95% CI, 3.3-8.1). Pre-surgery platelet function was similar between both groups after cangrelor discontinuation (P=.212), and adverse events occurred at similar rates between the groups.

The primary reason given by committee members for their no votes was a lack of sufficient evidence of the nature of the unmet need, as well as the relationship between the assessed pharmacodynamic endpoint and clinical endpoints.

“I don't have a sense of why I can be confident that, just based on pharmacodynamics, that will translate into adequately reliable evidence that cangrelor will address a meaningful fraction of those to-be-determined unmet need events,” said Thomas Fleming, PhD, professor of biostatistics at the University of Washington.

Several members also expressed concern about benefits vs. risks for this indication.

“I think the drug is likely to be highly effective in the period it’s given, based on what we know about the role of stopping P2Y12 inhibitors and stent thrombosis,” DeLemos said. “But I don't know what the risk/benefit will be until we have a better sense of the unmet need.”

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