And then there were four.
Late Thursday the FDA announced that it had approved edoxaban, the new oral anticoagulant manufactured by Daiichi Sankyo. The drug will be marketed under the brand name of Savaysa and joins three other new drugs in the large and important new oral anticoagulant marketplace: dabigatran (Pradaxa) from Boehringer Ingelheim, rivaroxaban (Xarelto) from Johnson & Johnson, and apixaban (Eliquis) from Pfizer and Bristol-Myers Squibb. All four drugs were designed to overcome the limitations of warfarin, which has long been available as an inexpensive generic drug but which requires extensive monitoring and dose adjustment and has numerous interactions with other drugs and foods.
The FDA approved two indications for edoxaban: for reducing the risk of stroke in patients who have non-valvular atrial fibrillation and for treating deep vein thrombosis and pulmonary embolism in patients who have already been receiving an anticoagulant by injection or by infusion for 5 to 10 days.
Last October the FDA's Cardiovascular and Renal Drugs Advisory Committee voted 9-1 in favor of approval for the AF indication. But the positive vote did not fully reflect the panel's concerns about the drug, which centered on a troubling subgroup analysis in the otherwise positive Engage AF-TIMI 48 trial. This analysis suggested that the benefit associated with edoxaban occurred exclusively in the large group of patients with impaired renal function (and, therefore, presumably, higher circulating levels of the drug). There was a trend suggesting that edoxaban was harmful in the subgroup of patients with normal renal function. Although subgroup analysis is often tricky, both the FDA reviewers and panel members felt that this was a biologically plausible phenomenon that could have important clinical implications.
As a result of this finding edoxaban will contain a boxed warning that the drug is less effective in AF patients with a creatinine clearance greater than 95 ml/min. Physicians should measure creatine clearance before initiating treatment with edoxaban. People with creatine clearance levels over 95 ml/min should receive a different anticoagulant.
Bleeding is the most serious side effect of edoxaban, as with all anticoagulants. Currently there is no treatment that has been shown to reverse the anticoagulant effect of the drug. Premature discontinuation of edoxaban increases the risk of stroke.
The commercial prospects for the drug appear to be limited. Sanjay Kaul, who was a member of the advisory panel, provided the following comment on the FDA approval:
"It appears that the restriction of use in patients with creatinine clearance <95 ml/min applies only for NVAF indication. The creatinine clearance cut off used for impaired renal function during the FDA panel meeting was <80 ml/min; based on this criterion, nearly one-third had normal renal function representing a large subgroup in whom treatment with edoxaban would yield unfavorable results compared with warfarin. The final FDA approval appears to have relaxed this criterion to CrCl <95 ml/min, thereby expanding the pool of patients eligible for edoxaban. Regardless, there is no unique advantage this drug offers relative to existing therapies. As such, clinical acceptability and marketability will pose a major challenge for this drug."
