Positive results from the HOKUSAI-VTE trial for Daiichi-Sankyo's Factor Xa (FXa) inhibitor edoxaban (Lixiana) were announced at the recently completed European Society of Cardiology (ESC)'s Annual Congress. By and large, these results met prior expectations. Edoxaban (60 mg once daily) proved non-inferior for the primary efficacy outcome of recurrent VTE to the benchmark therapy of a low-molecular weight heparin (LMWH) plus warfarin. More significantly, edoxaban demonstrated superiority to LMWH + warfarin therapy for the primary safety outcome of major or clinically relevant nonmajor bleeding.

But that wasn't the only good news to emerge from the HOKUSAI-VTE trial. Among patients with pulmonary embolism (PE) and evidence of right ventricular dysfunction, edoxaban reduced recurrence of VTE by 48 percent compared to warfarin. Furthermore, use of a reduced dose of edoxaban (30 mg) in patients with low body mass (< 60 kg) or impaired renal function (creatinine clearance 30 to 50 ml/min), demonstrated non-significantly lower rates of VTE recurrence and clinically relevant bleeding. The ability to successfully tailor the dose of edoxaban in these patient groups (approximately 18 percent of the overall patient population) goes someway to addressing physician concerns regarding bleeding risk due to excess anticoagulant levels in these patients.

Despite these positive findings, edoxaban is not expected to make a significant impact in the VTE treatment and secondary prophylaxis market (for more information on this market, consult our Pharmacor report on Venous Thromboembolism). These positive findings were largely expected as edoxaban's trial data has been released at a time when the other NOACs have all previously reported similarly positive data (this is a situation that is largely expected to repeat itself in November when Daiichi Sankyo announce results from edoxaban's ENGAGE-AF TIMI 48 trial for stroke prevention in atrial fibrillation [SPAF]).

Dabigatran etexilate (Boehringer Ingelheim's direct thrombin inhibitor Pradaxa) was the first to publish data from the RE-COVER trial in 2009. However, edoxaban can claim an advantage over dabigatran's trial data. Despite both agents also being preceded by prior administration of a LMWH for 5 days, dabigatran did not offer any significant improvements in efficacy or safety, and a twice daily dose administration compared to edoxaban's once daily administration is also likely to benefit edoxaban.

However, the difficulties arise when compared to the other FXa inhibitors, apixaban and rivaroxaban. Both of these agents were investigated for the treatment and secondary prophylaxis of VTE without the use of a preceding LMWH. In the AMPLIFY trial, apixaban was non-inferior to warfarin on efficacy, but like edoxaban, demonstrated superiority over LMWH + warfarin for bleeding. The big disadvantage for edoxaban is that apixaban demonstrated better safety without the LMWH lead-in. Indeed, post-presentation of the data at ESC, it was argued that edoxaban's superior bleeding data compared to warfarin from HOKUSAI-VTE may have been a consequence of the overlap of LMWH and warfarin in the initial therapy period. This overlap of therapies was stated as being necessary in order to allow the patient to achieve the appropriate level of anticoagulation cover using warfarin. It was further argued that it also allowed for edoxaban use to be assessed in more severe PE patients. Unfortunately for edoxaban, in the EINSTEIN-PE trial, rivaroxaban already demonstrated non-inferiority to warfarin for efficacy and safety in these more severe PE patients, and again without the LMWH lead-in to oral anticoagulation.

So while these findings using edoxaban are generally positive, despite all claims to the contrary it would appear that edoxaban will be hamstrung in the VTE market by the requirement for a LMWH lead-in; particularly given the expensive nature of these LMWH drugs in an increasingly cost-driven treatment environment. This is a scenario Daiichi Sankyo appears to have realized for themselves. How else would you explain Daiichi Sankyo initiating a Phase II trial investigating edoxaban without the use of a preceding LMWH Combined with the fact that dabigatran etexilate, rivaroxaban, and apixaban will reach the market ahead of edoxaban; and that physicians in the United States and Europe have gained familiarity with these agents in SPAF, it appears that edoxaban will be reliant on its ability for dose adjustment in underweight and renally impaired patients to make a notable impact within the VTE market. Only time will tell if SPAF offers greater opportunities for edoxaban.

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

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