Daiichi Sankyo released the results from one of the most eagerly awaited clinical trials ENGAGE AF-TIMI 48 at this year's American Heart Association's (AHA) Scientific Sessions in Dallas, Texas last week. Assessing edoxaban's utility as a stroke prevention agent for atrial fibrillation (AF) patients, as the name suggests, the results certainly succeeded in engaging my attention.

The trial was notable for a number of reasons; firstly it was the largest trial of the novel oral anticoagulants, with over 21,100 patients enrolling. Secondly, the trial was assessing two different doses of edoxaban (30 mg and 60 mg) versus warfarin. ENGAGE AF also was stronger for witnessing the weaknesses of the trials for the other novel oral anticoagulants, with warfarin-treated patients having a time in therapeutic range (TTR) of 68.4 percent, notably higher than the 55.1 percent TTR achieved in the ROCKET-AF trial for rivaroxaban (Bayer/Janssen's Xarelto). Patient follow up was considerable (median follow up was 2.8 years), while the average stroke risk of patients was greater than those seen in the RE-LY and ARISTOTLE trials of dabigatran etexilate (Boehringer Ingelheim's Pradaxa) and apixaban (Bristol-Myers Squibb/Pfizer's Eliquis) respectively.

The results demonstrated edoxaban will be a viable alternative to warfarin for stroke prevention in AF patients. Edoxaban proved non-inferior for stroke and systemic embolism, with the higher dose (60 mg) tending towards superiority over warfarin (P=0.08). Both the 30 mg and 60 mg dose of edoxaban significantly reduced the incidence of hemorrhagic stroke compared to warfarin (P < 0.001 for both doses), especially important given the devastating consequences that hemorrhagic stroke can incur.

With regards to safety, edoxaban proved superior to warfarin at both 30 mg and 60 mg doses, with edoxaban significantly reducing major bleeding compared to warfarin. The 60 mg dose did result in significantly greater incidence of gastrointestinal (GI) bleeding compared to warfarin (P = 0.03), although the 30 mg significantly reduced GI bleeding versus warfarin, suggesting that will be a viable alternative to the 60 mg dose in patients at risk of GI bleeds.
Of minor concern will be the significant increase in ischemic bleeds evident in patients treated with 30 mg of edoxaban (Hazard ratio = 1.41, P < 0.001). While the 30 mg dose was non-inferior for overall stroke rates relative to warfarin, the results with ischemic stroke may prove significant in terms of the approval of both doses. History provides a blunt reminder of the difficulty in getting two doses approved in the United States, with the FDA only approving the high dose (150 mg) of dabigatran etexilate, and not approving the 110 mg dose. Daiichi Sankyo will hope that history does not repeat itself; as will physicians, who highlight the ability to adjust the dose of edoxaban as a major attraction to the drug, while also lamenting the absence of the 110 mg dose of dabigatran etexilate.

So how will edoxaban be received following its anticipated launch in late 2014? The results, while positive, have not generated the same level of excitement that the release of data from the Phase III trials for the other agents generated. In effect, the novelty of the novel oral anticoagulants is wearing off. The major factor behind the general antipathy for the results from ENGAGE AF is that, despite the improvements in trial design compared to the other novel agents, edoxaban didn?t demonstrate efficacy or safety data versus warfarin that hasn?t been seen before with the other novel oral agents. But the prospects for edoxaban remain positive. Like rivaroxaban, edoxaban is dosed once daily; whereas apixaban and dabigatran etexilate are both twice daily agents. And should the FDA approve the 30 mg dose, it will become the first of the novel oral anticoagulants to be readily available in two different doses. On the downside, it will be another year before edoxaban hits the market, in which time its competitors will continue to try to increase patient share and broaden their indication labels. The most obvious method for Daiichi Sankyo to establish edoxaban is by discounting its price relative to the other agents. However, Daiichi Sankyo will be loath to discount edoxaban too heavily as they attempt to recoup the costs of a 21,000+ patient trial (not to mention the cost of the HOKUSAI-VTE trial for edoxaban). What we can expect in the meantime is for the intricacies of each drug to be widely marketed in an attempt for differentiation as these agents continue to compete for increasing patient share.

For insight into how we expect the novel oral anticoagulants, and the atrial fibrillation market as a whole, to develop, please consult Decision Resources? update to the Pharmacor report: Atrial Fibrillation (publishing in December 2013). 

Eamonn O'Connor is a business insights analyst with the Cardiovascular, Metabolic and Renal Disorders team at Decision Resources Group.

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