FDA's request for additional analyses from AstraZeneca's pivotal trial for Brilinta (ticagrelor) suggests the agency remains unconvinced about the antiplatelet agent's efficacy in U.S. patients.

In announcing receipt of a "complete response" letter, AstraZeneca said FDA requested additional analyses of data from the PLATO study comparing ticagrelor with Bristol-Myers Squibb/Sanofi-Aventis' Plavix (clopidogrel) in acute coronary syndrome patients. "The agency did not request that additional studies, including clinical studies, be conducted as a prerequisite for approval of the ticagrelor NDA," the company said.

The U.S. data from PLATO have bedeviled AstraZeneca's bid for NDA approval. In the 43-country, 18,624-patient trial, ticagrelor was associated with a significant 16% reduced risk overall in the composite endpoint of cardiovascular death, myocardial infarction or stroke compared to clopidogrel. Significant risk reductions also were seen on the individual components of CV death and MI, but not stroke.

However, no benefit was seen in patients from the U.S., where the results trended in the wrong direction on adjudicated endpoints. On the composite primary endpoint, ticagrelor was associated with a non-significant 27% increased risk among U.S. patients, while non-U.S. results showed a significant 19% risk reduction.

Aspirin-Only Theory Rebuffed

The disparate U.S. efficacy results were the focus of discussion at the Cardiovascular and Renal Drugs Advisory Committee's July 28 meeting. The committee ultimately voted 7-1 in favor of approval for reduction of thrombotic events in patients with non-ST elevation and ST elevation ACS intended to be managed either by percutaneous coronary intervention or medically ("Also see "Brilinta Panel Leaves FDA With The Task Of Crafting Labeling That Describes Poor U.S Efficacy Results" - Pink Sheet, 28 July, 2010.).

Though swayed by the overall efficacy seen in PLATO, committee members did not buy into AstraZeneca's theory that the discordant results were solely due to the predominance of high-dose aspirin in U.S. subjects, compared with low-dose aspirin in the rest of the world.

The sponsor is proposing that Brilinta be labeled for use in combination with low-dose aspirin; such labeling could pose a significant commercial challenge in the U.S., where high-dose aspirin use for ACS is commonplace (Also see "Low-Dose Aspirin Label Could Pose High Commercial Hurdle For Brilinta" - Pink Sheet, 9 August, 2010.).

Rather than hanging its hat on AstraZeneca's low vs high-dose aspirin theory, the cardio-renal panel believed additional factors may have impacted the efficacy results. These included chance and differences in baseline demographics and treatment patterns in the U.S. and overseas.

FDA's cardio-renal team leader for the application, Thomas Marciniak, speculated that the efficacy disconnect may have resulted from ticagrelor's delayed onset of action, which was exacerbated by differences in medical practice in the U.S. and rest of the world (Also see "FDA Will Present Brilinta Panel With Alternative Explanation For Negative U.S. Data" - Pink Sheet, 26 July, 2010.).

Some committee members said AstraZeneca should be required to conduct a smaller, post-marketing study heavily focused on U.S. ACS patients, although this suggestion stoked ethical concerns (Also see "Brilinta Advisory Cmte. Nod Creates Postmarketing Study Quandary For FDA" - Pink Sheet, 2 August, 2010.).

Labeling Negotiations

The panel's recommendation also left FDA with the task of writing a label that incorporates the dissimilar efficacy results seen in U.S. patients (Also see "Toprol-XL Eyed As Precedent For Brilinta Labeling On U.S. Efficacy Data" - Pink Sheet, 9 August, 2010.). In a Dec. 17 note, Sanford Bernstein analyst Tim Anderson questioned whether the "complete response" resulted from AstraZeneca "trying to negotiate as favorable a label as possible, with the sticking point behind what was seen with U.S. patients and how this should be described."

The FDA action came as a surprise given a previous extension of the user fee date, from Sept. 16 to Dec. 16, and the drug's recent approval in Europe, where it will be marketed as Brilique (Also see "AstraZeneca's Brilique Approved In The EU" - Pink Sheet, 6 December, 2010.). However, it stands to reason that the poor U.S. efficacy showing was far less of a worry for European regulators than FDA.

AstraZeneca said it will respond to FDA's request for additional analyses of the PLATO data as soon as possible, and it affirmed its confidence in the NDA and its ability to address FDA's questions.

Leerink Swann analysts believe a minimum 12-month approval delay is likely. As a result, ticagrelor could face a difficult road as its approval would come close to bumping up against the expected availability of generic clopidogrel in May 2012, which assumes a six-month pediatric extension on the compound. The lack of efficacy against clopidogrel seen in U.S. PLATO patients also would complicate ticagrelor's efforts to grab market share from generic forms of Plavix.

Sanford Bernstein's Anderson forecasts Brilinta sales of $900 million in 2015, which he says is about half that of consensus estimates. "We think that between a U.S. label that is not going to look great, the current availability of generic Plavix in Europe, and the May 2012 scheduled availability of generic Plavix in the U.S., Brilinta will ultimately fall short of consensuses estimates."

-Sue Sutter (s.sutter@elsevier.com)

Brilinta "Complete Response" Letter Suggests FDA Unswayed On U.S. Efficacy

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