CRT: Can PHOENIX raise cangrelor from the ashes?

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WASHINGTON, D.C.—Based on the current clinical data that has emerged on cangrelor (The Medicines Company)—which Steven R. Steinhubl, MD, defined as “relatively non-compelling” during a presentation Feb. 5 at the Cardiovascular Research Technologies (CRT) meeting—the PHOENIX trial results may be the agent’s only hope for approval.

“As an intravenous agent, cangrelor overcomes many problems involved with administering oral agents, and it has a very high level of inhibition, so it can overcome the variability and slow onset with clopidogrel,” said Steinhubl, director of cardiovascular wellness at Geisinger Health System in Danville, Pa.

The drug has a relatively rapid decrease in inhibition, and about an hour after the drug is stopped, it’s completely gone, according to Steinhubl. “Compared with any other antiplatelet drug, it has the fastest onset and almost immediate offset. There is a clinical need for a potent parenteral P2Y12 antagonist with cangrelor’s pharmacodynamics profile,” he said.

The BRIDGE trial, referenced by Steinhubl as an example, was a prospective, randomized double-blind, placebo-controlled, multicenter trial that enrolled 210 patients with acute coronary syndromes (ACS) or treated with a stent on a thienopyridine awaiting CABG to receive either cangrelor or placebo. After thienopyridine discontinuation (less than 72 hours), 210 patients were administered cangrelor or placebo for at least 48 hours and up to seven days, which was discontinued one to six hours prior to CABG. In the trial, a greater proportion of patients treated with cangrelor had low levels of platelet reactivity throughout the treatment period, compared with placebo. Plus, there were no additional bleeds with cangrelor.

“With in vivo and ex vivo, it looks pretty promising, and there is a need for it clinically,” said Steinhubl. “Ex vivo platelet inhibition does not consistently translate into clinical efficacy.”

For example, in the CHAMPION PCI and CHAMPION PLATFORM trials, cangrelor was not superior over clopidogrel (Plavix, Sanofi-Aventis, Bristol-Myers Squibb) in reducing the composite of death, MI or ischemic revascularization 48 hours after PCI, nor did the investigative drug prove superior over placebo for combined endpoint of MI, all-cause mortality and revascularization.

Steinhubl pointed out that a secondary analysis of the trials showed that a significant reduction of stent thrombosis and even mortality—however, it was only about 20 patients. “We would prefer to prevent stent thrombosis and death, even these prove to be real findings,” he added.

There are several potential reasons why cangrelor hasn’t proven its efficacy in clinical trials, according to Steinhubl, including:
  1. The design of the CHAMPION trials may have prevented the identification of PCI-associated infarcts;
  2. Earlier studies showed that cangrelor will prevent the clopidogrel and prasugrel’s active metabolite from binding to the P2Y12, so there is a potential for a vulnerable window; and
  3. Cangrelor is metabolized by the CD39 system, which may compete locally with ATP and ADP, and therefore, higher levels of ADP may be generated at the site of the thrombus.
In hopes of answering these questions, the phase III CHAMPION PHOENIX trial has begun enrollment to see if “cangrelor can arise from the ashes.” The trial is comparing cangrelor to clopidogrel standard of care therapy in approximately 10,000 subjects who require PCI.

As part of his disclosures, Steinhubl noted that he had previously been employed by The Medicines Company, and involved with the development of cangrelor.