AstraZeneca has yet to solve the mystery about why its Brilinta antiplatelet drug failed to help North American patients in a very large clinical trial. But there is a new clue - the bloodthinner may be less effective when patients get a high dose of aspirin.

During an Oct. 29 conference call to discuss third-quarter earnings, the drug maker disclosed that recent analyses of four subgroups of patients - one of which consisted of North Americans - suggested a "possible association" with aspirin.

The 18,624-patient, head-to-head study known as PLATO (the Study of Platelet Inhibition and Patient Outcomes) compared Brilinta plus aspirin with Bristol-Myers Squibb and Sanofi-Aventis' Plavix plus aspirin. Results were released at the European Society of Cardiology congress on Aug. 30.

Initial reaction to the data was that the North American discrepancy could be an issue for regulators (Also see "Brilinta's North America Anomaly Stymies AstraZeneca, Worries Analysts" - Pink Sheet, 7 September, 2009.).

For their part, AstraZeneca executives continue to maintain the outcome may have been due to chance. And in an Oct. 29 statement, they reiterated earlier remarks that the mysterious findings about the North American subgroup may yet be explained by geographic differences between patient populations or "practice patterns" involving aspirin usage.

"We don't have a definitive explanation to date," said Exec VP-Development Anders Ekblom. To give a sense of the scope of the trial, he noted there were 66 subgroups of patients from 43 countries in PLATO.

The aspirin explanation was among those considered by the PLATO investigators, who noted that aspirin doses in the U.S. were higher than the rest of the world, but the trial team did not find it a conclusive explanation.

The company execs are not yet ready to put forth a hypothesis, but they're certainly considering the possibility of an effect of the aspirin doses. Ekblom pointed out increasing aspirin dose would have reduced efficacy, but was clear that "this is part of an ongoing analysis of various hypotheses."

The aspirin doses used in the study ranged from 75 mg to 325 mg, and Ekblom said that the drug maker will review the extent to which Brilinta was effective with different doses. "That's something we're starting to look at," said Jonathan Hunt, the head of investor relations, in response to a question. "No answers yet. We're still investigating. But we did say ... we'll look to publish it and put it into a sort of peer-review setting. We're just not there yet."

The disclosure appears likely to add further uncertainty over Brilinta (ticagrelor) and the extent to which the FDA can be expected to scrutinize the drug, which AstraZeneca hopes to submit to the agency in coming weeks.

Questions about North American patients were first raised after the PLATO trial was released. But for the most part, the findings were well received - Brilinta prevented 16 percent more heart attacks, strokes and deaths than Plavix, and without an increase in major bleeding.

Moreover, Brilinta was also associated with an overall mortality benefit: the rate of death from any cause was reduced by 5.9 percent compared with 4.5 percent among patients given Plavix. The findings had the investment and medical communities buzzing that Brilinta may prove stiff competition for the new entrant to the antiplatelet filed, Eli Lilly/Daiichi Sankyo's Effient (prasugrel), which is associated with a risk of increased bleeding.

Yet the analysis of the North American subgroup - arguably the most relevant population for FDA - not only showed no treatment advantage for Brilinta, but also indicated patients on the bloodthinner actually had a greater chance of having a cardiovascular event than those on Plavix.

The North American subgroup numbered only 1,814 patients, or roughly just 10 percent of the entire study. Nonetheless, the findings suggested that AstraZeneca may find the FDA to be more cautious about approval and the latest disclosure prompted one analyst to say approval may, in fact, be questionable.

"It didn't show a benefit in the U.S. In fact, it was worse than Plavix," said Tim Anderson of Sanford C. Bernstein. "You're talking about a subset out of a large trial, but there's always the potential for trouble with subsequent analyses. They're saying aspirin use in the U.S. is different and may have confounded results. But aspirin use is what it is and this makes me wonder if it's an approvable drug in the U.S. And it wasn't as good as Plavix, and in that type of drug area, you better be good."

- Ed Silverman (e.silverman@elsevier.com)

AstraZeneca: Aspirin May Be To Blame For Poor Results In Some Brilinta Trial Patients

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