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AstraZeneca’s (LON: AZN) Brilinta (ticagrelor), a potential blockbuster, is expected to get expedited regulatory approval with no major label restrictions, expert clinicians told Pharmawire.
Brilinta has been developed as a new fast-acting oral antiplatelet agent, targeting a slice in a market that is currently worth around USD 9bn and growing.
It is the first antiplatelet drug to demonstrate it can reduce cardiovascular (CV) deaths compared to the current gold standard treatment, Plavix (clopidogrel) in patients with acute coronary syndromes (ACS). Results of the 18600 patient Phase III PLATO trial comparing the two drugs, were revealed at the recent European Society of Cardiology (ESC) Congress in Barcelona.
Lars Wallentin of the Uppsala Clinical Research Center University Hospital, Sweden, and co-chair of the PLATO executive committee, said that the overall mortality improvement – a 1.4% absolute reduction in death – that Brilinta achieved is “larger than people think.”
One independent cardiology professor agreed that this mortality reduction is the most important figure in PLATO, describing it as “big” and “amazing.” Platelet expert Dr Victor Serebruany agreed the mortality data is ”marvelous,” with 107 extra lives saved compared to Plavix. “It has never been seen before and no one expected it,” he said.
Serebruany described the results as a ”home run” for AstraZeneca. ”As an unbiased observer I believe it is the best ever trial on any antithrombotic agent in humans. Most people do not realise even now how good the data is,” he added.
Steve Nissen, chairman of the department of Cardiovascular Medicine at the Cleveland Clinic, Ohio, said that the PLATO results are extremely important. The significant mortality benefit achievement has a very positive impact for Brilinta, as mortality benefit is the “hardest of hard” to demonstrate in a clinical trial, he said.
Serebruany believed that given the results of PLATO are maintained after the regulatory agencies conduct their own analyses, Brilinta will receive an expedited approval (within six months in the US). “Especially given the fact that another oral anticoagulant, Effient (prasugrel), was approved with a black box warning, under a (delayed) priority review umbrella, with much less justification even for applying for such priority,” he said.
Major bleeding comparable to Plavix
There was more overall bleeding with Brilinta, although the rates of major, fatal and life threatening bleeding were comparable to Plavix, clinicians noted, stating that this was important.
Brilinta also resulted in less bleeding in patients having coronary artery bypass graft (CABG) surgery and significantly less fatal non-intracranial bleeding than Plavix, clinicians said. However, one issue they raised is that in non-CABG patients, there was significantly more major bleeding versus Plavix, including more intracranial bleeding and significantly more fatal intracranial bleeding.
Wallentin noted this non-CABG group finding was a “surprise” but said the real concern in terms of bleeding is whether it leads to more myocardial infarction, stroke or something more significant, which overall it did not.
Clinicians agreed there were not bleeding concerns with Brilinta on the scale of those with Effient.
Glitch in North American data
The regulatory agencies have indicated they are very interested in seeing a drug that substantially decreases mortality without increasing the risk of major bleeding, said Wallentin.
He believed that in Europe and many other countries the drug would have “no problem” gaining marketing approval, but conceded that explanations will have to be provided to the US regulator addressing the fact that in a sub-analysis of the small (1800) group of North American patients in the trial, Brilinta actually saw an increase in CV events versus Plavix.
One independent professor agreed that because the results in this sub-population “went the wrong way and it is unclear why,” this will be an issue for the North American regulators to deal with.
However, Nissen stated that if you study enough subgroups, you will often see results that are different from the main outcome. “We generally place very little emphasis on such subgroup analyses, and this should not be an approvability issue,” he said.
Serebruany agreed that there is a danger in doing too much slicing and dicing of the data. ”PLATO has nothing to hide and the FDA will see that the data are honest and good,” he said, insisting that the trial has ”so much leverage” with the significant mortality benefit that will overcome everything else.
Both Serebruany and Nissen noted that the “robust” PLATO trial results are strengthened by the large number and type of ACS patients it tested.
Drug label
Nissen said that the patient population studied in the pivotal trial - ACS patients with and without subsequent percutaneous coronary intervention (PCI) - is likely to represent the drug label granted by the regulators.
Wallentin said the effect of Brilinta was very consistent across the broad patient population studied in the trial. He believed the effects of dyspnea, ventricular pauses and a “slight, stable, and reversible increase” in creatinine in 2% of patients with poor kidney function, were not of concern to regulators.
“I do not expect any major labeling restrictions, since the data are clean, unless some major flaw will be picked up by the regulatory authorities,” agreed Serebruany. The FDA will require “real world” safety studies to follow after approval, he added.
Serebruany noted that there will be large sections in the drug’s package insert addressing potential side effects, but the outcome benefit is so huge, and overcomes the drug’s shortcomings so greatly, that no black boxes are expected.
“This is especially obvious keeping in mind the controversial approval of Effient,” Serebruany said.
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