On March 24, Daiichi Sankyo announced that it received approval from the Ministry of Health, Labour and Welfare (MHLW) in Japan for the oral antiplatelet agent prasugrel (Efient; marketed as Effient in the United States) for the treatment of patients with ischemic heart disease undergoing percutaneous coronary intervention (PCI). Prasugrel is an oral antiplatelet agent discovered by Daiichi Sankyo and its Japanese research partner Ube Industries and co-developed and co-marketed with Eli Lilly. This approval in Japan should provide a significant boost to worldwide sales of the drug, which have been slowing over the last year (U.S. sales grew 11 percent from 2012 to 2013, driven primarily by higher prices).

The application in Japan was based on the results of two Phase III trials in Japanese patients undergoing PCI, one in PCI-treated ACS patients (PRASFIT-ACS) and one in stable CHD patients (those with stable angina or evidence of previous myocardial infarction [MI]) undergoing elective PCI (PRASFIT-Elective). Results from both trials demonstrated risk reductions in the composite primary end point of cardiovascular death, nonfatal MI, and nonfatal ischemic stroke versus clopidogrel, with similar bleeding rates. This approval in patients with ischemic heart disease undergoing PCI provides the drug with a broader patient coverage in Japan than it has in Europe and the United States, where the drug is indicated only for PCI-treated ACS patients.

The European and U.S. launches for prasugrel in 2009 were based on the results of the Phase III TRITON-TIMI 38 trial, where prasugrel demonstrated greater efficacy than clopidogrel in preventing ischemic events in PCI-treated ACS patients, albeit at the risk of more bleeding events, which resulted in the FDA issuing a black box warning regarding potentially fatal bleeding complications. However, it should be noted that the prasugrel dose tested in the Japanese studies (20 mg loading dose followed by a 3.75 mg maintenance dose) was significantly lower than that tested in TRITON-TIMI 38 (60 mg loading dose followed by a 10 mg maintenance dose).

Since its launch in the United States and Europe, uptake of prasugrel has been strongest in PCI-treated STEMI patients where results were more robust. Attempts to broaden the label have so far failed:

  • The TRIGGER-PCI study, which was assessing the efficacy of prasugrel versus clopidogrel in elective PCI patients, was halted in 2011 after a preliminary analysis made clear that the trial was not going to see enough primary end point events to deliver any meaningful results.
  • In 2012, it was revealed that the TRILOGY-ACS trial, to evaluate prasugrel's use in more than 9,000 medically managed UA and NSTEMI patients who did not undergo revascularization, failed to significantly reduce the frequency of the primary end point compared with clopidogrel.
  • In late 2012, the ACCOAST trial, designed to test the benefits of prasugrel preloading at the time of diagnosis versus administering it after the coronary angiography was halted following a recommendation from the data monitoring committee to terminate the trial because of excessive bleeding and lack of ischemic benefit.

So, what does the future hold for prasugrel. We believe that prasugrel's overall penetration in ACS in the United States and Europe will be constrained by its failure to expand the label, by ticagrelor's (AstraZeneca's Brilinta/Brilique) growing popularity and by physician familiarity with clopidogrel (which is now available as a generic). However, we expect prasugrel to maintain its niche in STEMI patients.

The backing of a Japanese company that has a particularly strong track recorded in the cardiovascular market, support from robust efficacy and safety trial data in Japanese patients, the lack of competition from generic clopidogrel and the broader label compared to Europe and the United States, should enable prasugrel to gain significant market share in PCI-treated patients in Japan.

Near-term competition will come from ticagrelor (due for launch for PCI-treated ACS patients in Japan in late 2014) and generic clopidogrel (which we expect to launch in 2015). However, we expect prasugrel to maintain a strong presence in this market.  Meanwhile, Daiichi Sankyo expects to complete a Phase III trial in ischemic stroke patients in the Japanese fiscal year 2014; we expect an approval for this indication in 2016. Positive data from this trial and a label extension will significantly boost prasugrel's target population size and support its sales growth in this region.

Senior Analyst Graeme Green and Senior Director Conor Walsh are part of the Cardiovascular, Metabolic and Renal Disorders team at Decision Resources Group.

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