AstraZeneca’s (AZ) oral antiplatelet drug Brilinta (ticagrelor) and Bayer/J&J‘s non-vitamin K antagonist oral anticoagulant Xarelto (rivaroxaban) were the two front-running emerging therapies in the peripheral artery disease (PAD) market. Patients with PAD have serious circulatory problems in their legs and are at increased risk for all cardiovascular (CV) events. Both therapies were expected to substantially change the PAD market dynamics. Expectations were high that Brilinta and Xarelto would address some of the unmet need in PAD. However, all hopes and speculations regarding Brilinta as a potential therapy in PAD were thrashed with the AZ announcement of top-line results showing the Phase III EUCLID trial failed to meet the primary end point: Brilinta did not demonstrate a clinical benefit over clopidogrel.
Failure of the EUCLID trial will significantly affect AZ’s revenue as the company was enthusiastic about the label expansion of Brilinta in PAD and projected annual sales for the drug of $3.5 billion by 2023. Indeed, AZ had invested a lot in making EUCLID the largest cardiovascular outcomes trial conducted exclusively in symptomatic PAD patients. The trial compared Brilinta against clopidogrel for the prevention of atherothrombotic events in almost 14,000 thousand subjects in 28 countries.
After SOCRATES trial (see our blog here) this represents a second setback for Brilinta in 2016. However, unlike the SOCRATES trial, we assess the failure of the EUCLID trial as a major setback considering the longer treatment duration and the larger targeted drug treatment population. Despite the demand for Brilinta in the ACS and post-ACS populations, the company does not now expect to achieve their forecasted sales for the drug, especially given the EUCLID trial would have added a drug treatment population in excess of 10 million patients across the G7 markets (United States, United Kingdom, Japan, France, Spain, Germany, and Italy). A full analysis of the EUCLID trial results is expected to be presented at the American Heart Association Scientific Sessions in New Orleans, Louisiana in November 2016.
The failure of Brilinta now dampens the hopes for Xarelto in PAD. Xarelto is being evaluated in the Phase III COMPASS and VOYAGER PAD trials. The COMPASS trial will evaluate whether treatment with Xarelto + aspirin or Xarelto alone is better than aspirin alone in the prevention of CV events in patients with coronary artery disease (CAD) or PAD. The trial is being conducted in three arms: Xarelto 2.5 mg BID + Aspirin, Xarelto 5 mg BID + placebo, and Aspirin 100 mg + placebo. Based on the results for the 2.5 mg BID dose in the the ATLAS ACS 2 TIMI 51 trial in ACS patients, there is some hope that Xarelto treatment may improve CV outcomes in PAD patients. However, we believe that the COMPASS trial may not succeed due to the likely increase in the underlying bleeding risk outweighing the efficacy benefit. Developers of antithrombotic agents are continuously seeking to strike a balance between increasing the bleeding risk and improving outcomes. While an acceptable increase in bleeding rates might satisfy some regulatory bodies, convincing prescribers can be difficult.
In contrast to the COMPASS trial, we have higher hopes that Xarelto may succeed in the VOYAGER-PAD trial, where it is being assessed in higher risk patients. The VOYAGER-PAD trial will evaluate the safety and efficacy of Xarelto combined with aspirin against placebo combined with aspirin in reducing the risk of major CV events in subjects with symptomatic PAD undergoing peripheral revascularization procedures of the lower extremities. Studies have shown that aspirin has limited efficacy in the high risk patients. Thus, a cumulative daily dose of 5 mg combined with aspirin may show significant benefits in the high risk patients.
In conclusion, the failure of Brilinta in the EUCLID trial represents a major setback for the PAD market. The drug was expected to launch by early 2018 and was expected to achieve a significant market share. It was also a potential competitor for Xarelto in PAD market. Brilinta’s failure now leaves the way open for Xarelto. However, its success will depend upon the balance it achieves between the efficacy and the rate of major bleeding.