Contradicting FDA reviews could have The Medicines Co. swinging when its cangrelor steps up to the plate at the Cardiovascular and Renal Drugs Advisory Committee (CRDAC) meeting Wednesday.
One FDA reviewer strongly opposed approval of the intravenous antiplatelet drug for any indication, according to the briefing documents released ahead of the meeting, and two others supported approval for percutaneous coronary intervention (PCI) but not as a bridge to surgery. Cangrelor’s PDUFA date is April 30.
FDA medical team leader Thomas Marciniak gave the harshest review, claiming that cangrelor demonstrated neither superiority nor noninferiority to clopidogrel (Plavix, Bristol-Myers Squibb Co. and Sanofi SA) or standard of care. He also raised concerns about what he considered unethical conduct of the cangrelor trials, a fact that in itself should justify a complete response letter, he said.
Marciniak, who will be presenting the agency’s concerns on the PCI indication to CRDAC, chalked up any statistical superiority for cangrelor to an “inappropriate delay” of administering clopidogrel in the trials and what he perceived as an imbalance in the loading dose that favored the Medicines drug.
While cangrelor and clopidogrel have similar platelet antagonist activities, clopidogrel’s action is more delayed than that of cangrelor. Delaying administration of clopidogrel in a trial could affect outcomes.
Cangrelor’s fast action has been touted as one of its key advantages over clopidogrel. Another advantage is that its inhibitory activity disappears within an hour or so, whereas clopidogrel’s activity lasts for days after the drug is stopped. The fact that cangrelor can be used and stopped quickly gives doctors flexibility until they figure out how to treat a given patient. (See BioWorld Today, March 12, 2013.)
In the CHAMPION PHOENIX trial, subjects undergoing PCI who were given cangrelor had their odds reduced by 22 percent of experiencing the primary endpoint, which was a composite incidence of death, heart attack, stent thrombosis or ischemia-driven revascularization at the 48-hour mark after they were randomized.
Cangrelor also showed a 38 percent drop in the chances of the key secondary endpoint, incidence of stent thrombosis at 48 hours in the 11,145-patient trial, according to data published in The New England Journal of Medicine last year.
In the global trial, the comparator drug was given according to institutional preference at the trial sites, reflecting current treatment practices in various countries. As a result, 74 percent of the subjects receiving clopidogrel were given a 600-mg loading dose, while the others received a 300-mg loading dose. All subjects in the cangrelor arm were given a 600-mg loading dose.
In his review, Marciniak noted that both prasugrel (Effient, Eli Lilly and Co.) and ticagrelor (Brilinta, Astrazeneca plc) have demonstrated superior efficacy to clopidogrel, but cangrelor wasn’t tested against them. “We do not know whether cangrelor affects this superiority so we do not know whether to use cangrelor with or instead of prasugrel and ticagrelor – or prasugrel or ticagrelor instead of cangrelor,” he said.
“Because the superiority involves irreversible harm, i.e., deaths and [heart attacks], we should understand the tradeoffs among these agents,” he added.
Even though the other FDA reviewers disagreed with Marciniak, the agency’s briefing documents came as a bit of a surprise to analysts and investors. Shares of the Parsippany, N.J.-based company (NASDAQ:MDCO) dropped nearly 15 percent Monday morning to $29.15 before making a partial rebound in the heaviest trading the company has seen since last July. Medicines closed the day at $32.42, down $1.80.
Licensed from Astrazeneca plc in 2003, cangrelor has had its share of setbacks. Two phase III trials were halted in 2009 for lack of efficacy after enrolling thousands of subjects. (See BioWorld Today, May 14, 2009.)
With Medicines’ top-selling drug, Angiomax (bivalirudin), facing a patent challenge from Hospira Inc. and patent expiration next year, a cangrelor approval would be welcome, but it’s not critical to the company’s future, J.P. Morgan analyst Cory Kasimov said.
Cangrelor, which may face patent expiration itself in five years, could take advantage of the infrastructure already in place for Angiomax. And Medicines management has been “expressing excitement about the growth prospect of the combination of Angiomax plus cangrelor to potentially treat high-risk PCI patients,” Kasimov noted.
But thanks to recent acquisitions, cangrelor isn’t the only potential player on the Medicines’ bench. If approved, the company could launch oritavancin, a semi-synthetic lipoglycopeptide antibiotic, in the U.S. late this year. And it expects to submit an application in the U.S. and EU for a new indication for Ionsys, a patient-controlled analgesia system, Kasimov said.
A U.S. filing for Fibrocaps, a dry powder topical formulation of fibrinogen and thrombin used to promote blood clotting, is planned for the first half of this year. Also on deck for 2014 is the start of phase III testing for Carbavance, a combination antibiotic, and the potential launch of an improved formulation of antibiotic Minocin I.V. (minocycline for injection). (See BioWorld Today, Dec. 5, 2013.)