FDA Gives Edoxaban Favorable Review Prior to Advisory Committee Meeting

October 29, 2014

SILVER SPRING, MD — Food and Drug Administration (FDA) officials charged with the task of reviewing edoxaban (Savaysa, Daiichi-Sankyo) in advance of tomorrow's advisory committee meeting are recommending the novel anticoagulant be approved for the treatment of patients with atrial fibrillation (AF)[1].

The recommendation is based on the results of Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation—Thrombolysis in Myocardial Infarction 48 (ENGAGE AF-TIMI 48) trial, a large, event-driven study in 21 105 patients with nonvalvular AF.

On Thursday, the FDA Cardiovascular and Renal Drugs Advisory Committee will review the ENGAGE AF study, as well as other data, and take the reviewers' opinion into consideration as part of their daylong excavation into the safety and efficacy of edoxaban for preventing stroke in patients with AF.

If approved, edoxaban would be the third oral factor Xa inhibitor to make it to the US market—behind rivaroxaban (Xarelto, Bayer) and apixaban (Eliquis, Pfizer/Bristol Myers-Squibb)—and the fourth novel anticoagulant approved for stroke prevention in AF. In addition to the factor Xa inhibitors, dabigatran (Pradaxa, Boehringer Ingelheim), a direct-thrombin inhibitor, is also approved for reducing the risk of stroke in nonvalvular AF patients.

Recommended for Patients With Impaired Renal Function

In ENGAGE AF, which was reported by heartwire and published in the New England Journal of Medicine, once-daily therapy with edoxaban at either of two dosages was noninferior to warfarin for preventing stroke or systemic embolism in nonvalvular AF patients. Both edoxaban daily dosages, 60 mg and 30 mg, were associated with significantly less major bleeding than the vitamin-K antagonist in the trial.

As part of their review, FDA officials Drs Melanie Blank and Tzu-Yun McDowell highlight a subgroup analysis that showed patients with normal renal function did not fare as well compared with patients who had mild renal impairment. The reduced efficacy compared with warfarin in the normal-renal-function subgroup "became the issue of greatest focus" during their review, a finding they do not believe is due to chance.

As a result, the FDA reviewers are recommending the drug be limited to at-risk individuals with abnormal renal function, defined as a creatinine clearance <80 mL/min.

Another issue that will certainly be discussed tomorrow also relates to efficacy. The FDA review states that two other novel anticoagulants (dabigatran, apixaban) have superiority claims compared with warfarin, whereas edoxaban showed only noninferiority in ENGAGE AF. As the reviewers point out, it raises the possibility that edoxaban might displace more effective therapy. Despite this, the FDA review notes that edoxaban "came close to achieving superiority" in ENGAGE, and "it is not reasonable to conclude that edoxaban is inferior to dabigatran or apixaban in the overall nonvalvular AF patient population."

heartwire will cover tomorrow's FDA advisory panel meeting and report on the panel's recommendations.

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