On July 24 2013, more than a year on from TRA 2P-TIMI 50 trial data release, Merck announced that the NDA for its novel antiplatelet agent vorapaxar was accepted for standard review by the FDA. The indication sought is for the secondary prevention of cardiovascular events in patients with a history of myocardial infarction (MI) and no history of stroke or transient ischemic attack (TIA). But the question is: will the FDA approve it? And if so, will physicians prescribe it?

Merck's vorapaxar is a first-in-class oral thrombin receptor antagonist purported to have potential as an adjunct to oral antiplatelet therapy without increasing the risk of bleeding. However, this has not been borne out in clinical trials. Results from the Phase III TRA 2P-TIMI 50 study assessing vorapaxar's effects in secondary prevention of atherothrombotic ischemic events in 26,449 patients with prior stroke, MI or existing PAD were reported at the ACC annual meeting in March 2012. In this trial, an increase in intracranial hemorrhage (ICH) in patients with a history of stroke led to the early discontinuation of treatment in this patient group (approximately 25 percent of the patient cohort), and to the termination of the Phase III TRACER study in ACS patients. Results from TRA 2P-TIMI 50 showed that vorapaxar was associated with a reduction in the composite end point of CV death, MI, or stroke; and those who did best were the post-MI patients with no history of stroke/TIA who weighed more than 60 kg. However, vorapaxar was also associated with increased rates of moderate and severe bleeding, including ICH.

So, first question: will it get approved. All in all, it appears that vorapaxar's results from TRA 2P-TIMI 50 were similar to those seen in Xarelto's (Bayer/Janssen) ATLAS ACS-2-TMI 51 trial in ACS patients, but vorapaxar lacks the mortality benefit seen with the lower dose of Xarelto. So while approval may go smoothly in Europe, vorapaxar's path to market in the United States could prove difficult, as evidenced by Janssen having received a second complete response letter from the FDA in May while simultaneously achieving first time European approval for ACS (see blog: First Time European Approval for Xarelto in ACS). Despite this, we expect approval based on strong efficacy in reducing MI in the post-MI population, with label contraindications similar to those for Effient (Eli Lilly/Daiichi Sankyo): a contraindication in patients with a history of stroke/TIA and additional restrictions for patients older than 75 years, at high risk of bleeding and/or weighing less than 60 kg.

But even if vorapaxar is approved, will physicians prescribe it? Overall, we expect the negative perceptions regarding setbacks in both Phase III trials for vorapaxar to narrow its market opportunity. Added to this are the bleeding concerns, the label restrictions, and potential reimbursement challenges, given the availability of generic Plavix (clopidogrel), in addition to the still branded drugs Xarelto, Effient and Brilinta (AstraZeneca). We anticipate that all of these factors will conspire to restrict vorapaxar to second-line use alongside aspirin in patients at high risk for a repeat MI and at low risk for bleeding.

Nevertheless, we predict that the future of vorapaxar is not so bleak. BMS/Sanofi's Plavix reached peak-year sales of $9.8b in 2009; and we estimate around 40 percent of these sales come from the post-MI market. Thus, by putting the sales potential of agents entering the antiplatelet market into perspective, we can see that a modest market opportunity remains for vorapaxar it's just a pity about the bleeding.

Conor Walsh is a Senior Director on the Cardiovascular, Metabolic and Renal Disorders team at Decision Resources Group.

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