Labeling for AstraZeneca's antiplatelet agent Brilinta could follow in the mold of the company's own beta-blocker Toprol-XL in reflecting dissimilar efficacy reported for U.S. patients compared with those in the rest of the world.

The Cardiovascular and Renal Drugs Advisory Committee's 7-1 vote July 28 in favor of approving Brilinta (ticagrelor) for acute coronary syndromes leaves FDA with the task of writing a label that reflects the discordant efficacy results seen in the 43-country, 18,624-patient PLATO trial.

The panelists were swayed by ticagrelor's overall effect: a significant 16 percent reduced risk in the composite endpoint of cardiovascular death, myocardial infarction and stroke compared with Bristol-Myers Squibb/Sanofi-Aventis' Plavix (clopidogrel). Significant risk reductions were also seen on the individual components of CV death and MI, but not stroke (¹ Also see "Brilinta Advisory Cmte. Nod Creates Postmarketing Study Quandary For FDA" - Pink Sheet, 2 August, 2010.).

However, efficacy on the primary endpoint and its individual components was not demonstrated in U.S. subjects, who accounted for less than 8 percent of the study population but represented the second largest group of patients by country.

The U.S. results trended in the wrong direction on all adjudicated endpoints. On the composite primary endpoint, ticagrelor was associated with a non-significant 27 percent increased risk among U.S. patients, while non-U.S. results showed a significant 19 percent risk reduction.

Although AstraZeneca proffered the theory that differences in aspirin dosing alone accounted for the divergent efficacy results, committee members believed other factors likely played a role as well.

While they believed the robust, overall efficacy results in PLATO justified approval, the majority of committee members nevertheless said the U.S. data should be reflected in labeling, and they questioned how FDA has handled other situations in which clinical data outside the U.S. was positive but was neutral or negative domestically.

FDA Center for Drug Evaluation and Research Deputy Director for Clinical Science and Office of Drug Evaluation I Director Robert Temple said the closest example would be the heart failure claim for Toprol-XL (metoprolol). Labeling describes results of the placebo-controlled MERIT-HF study in 3,991 heart failure patients from 14 countries. U.S. patients represented more than one-quarter of the study population.

The trial, which was terminated early after showing efficacy, demonstrated significant reductions in the risk of all-cause mortality (34 percent), all cause-mortality plus all-cause hospitalization (19 percent), and all-cause mortality plus heart failure hospitalization (31 percent).

Toprol-XL labeling states that the combined endpoints of all-cause mortality plus all-cause hospitalization and all-cause mortality plus heart failure hospitalization showed consistent effects in the overall study population and subgroups, including the U.S. population and women. "However, in the U.S. subgroup (n=1,071) and women (n=898), overall mortality and cardiovascular mortality appeared less affected."

A forest plot reflects the study results for various subgroups, including U.S. and non-U.S., and labeling contains this cautionary statement: "Subgroup analyses can be difficult to interpret and it is not known whether these represent true differences or chance effects."

It seems likely that a similar statement would be included in labeling for Brilinta.

Temple did draw some distinctions between the MERIT-HF results and the PLATO data.

"The Toprol-XL trial in heart failure showed a dramatic reduction in mortality everywhere in the world but in the U.S. where it was, so to speak, dead even, although there was a decrease in hospitalization," Temple said. "We approved that, took note of the fact that there was this different effect. That was relatively easy for us because there was a favorable effect, it wasn't no effect on anything."

In contrast, the PLATO study "goes nominally significantly the wrong way. That's a little unusual and it's a little worse than some of the cases where you just don't see effect."

- Sue Sutter ( ² s.sutter@elsevier.com )

Toprol-XL Eyed As Precedent For Brilinta Labeling On U.S. Efficacy Data

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