FDA prolongs ticagrelor decision again

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The FDA issued a complete response letter for the new drug application for the antiplatelet drug ticagrelor (Brilinta, AstraZeneca), requesting additional analyses of the PLATO clinical trial data.

However, the agency did not request additional studies, including clinical studies, be conducted as a prerequisite for approval of the ticagrelor NDA. This marks another postponement, as the FDA also extended its decision in September.

The PLATO (PLATelet inhibition and patient Outcomes) study, evaluating 18,624 patients, found that ticagrelor decreased incidences of cardiovascular death, MI and stroke when compared with clopidogrel (Plavix, Bristol-Myers Squibb/Sanofi-Aventis).

The London-based AstraZeneca said it is evaluating the contents of the complete response letter, and will respond to the agency’s request for additional analyses of the PLATO data as soon as possible. “The company remains confident in the NDA submission for ticagrelor and in its ability to respond to the agency’s questions,” AstraZeneca said.

Ticagrelor, an investigational oral antiplatelet treatment for acute coronary syndromes (ACS), is a direct-acting P2Y12 receptor antagonist in a chemical class called cyclo-pentyl-triazolo-pyrimidines. Ticagrelor is a reversibly-binding oral ADP receptor antagonist.

“The drug offers the hope of reducing mortality in ACS patients, whereas no previous antiplatelet therapy on the market has shown a reduction in mortality,” Paul A. Gurbel, MD, from the Center for Thrombosis Research at Sinai Hospital in Baltimore, told Cardiovascular Business News.

“We know the drug has a superior pharmacodynamic effect, as compared with high-loading dose clopidogrel. If you just look at its effect on platelet function, it’s a superior agent. Also, the antiplatelet effect of ticagrelor is effective irrespective of the genotype of the patient.”

In an analysis of the ONSET/OFFSET and RESPOND trials presented at AHA10, Gurbel et al found that genotype variations and metabolizer status do not affect platelet inhibition for patients taking ticagrelor, which has become a concern with clopidogrel non-responders.

“The only reason that I could foresee an FDA rejection is due to the North American discrepancy in the data,” said Gurbel. “In North American patients, there was no benefit seen with ticagrelor over clopidogrel, and there is no uniform agreement of the reason for this occurrence. Beyond this, I can't foresee any other reason why they wouldn't approve ticagrelor.”

Earlier this month, the European Commission approved ticagrelor (marketed as Brilique in the U.K.) for the prevention of atherothrombotic events in ACS patients.

The drug is also undergoing other ongoing research. In October, the TIMI group, based at Brigham and Women’s Hospital in Boston, launched the PEGASUS-TIMI 54 clinical trial, which will assess the safety and long-term efficacy of ticagrelor to reduce cardiovascular events compared to aspirin treatment in ACS patients. The patients will take a once-daily 75 mg to 150 mg dose of aspirin during the trial, and the researchers will use the time-to-first-occurrence of any cardiovascular event, including cardiac death, non-fatal MI or non-fatal stroke as the trial’s primary endpoint.