Regulatory Decision Summary for LIXIANA

LIXIANA (edoxaban) is an oral, once-daily anticoagulant that specifically inhibits factor Xa, which is an important factor in the coagulation system that leads to blood clotting. The global edoxaban clinical trial program included two pivotal phase III studies, ENGAGE AF-TIMI 48 and HOKUSAI-VTE and were filed to support the safety and efficacy of edoxaban for the prevention of stroke in patients with atrial fibrillation (AF) and for the prevention of symptomatic venous thromboembolism (VTE) in patients with deep vein thrombosis (DVT) and/or pulmonary embolism (PE), respectively.

In the pivotal ENGAGE AF-TIMI 48 study (an event-driven, phase 3, multi-centre, randomized, double-blind double-dummy parallel-group study), 21,105 subjects were randomized to receive either edoxaban 30 mg (or 15 mg if dose reduction was required) once daily, edoxaban 60 mg (or 30 mg if dose reduction was required) once daily or warfarin titrated to a target international normalized ratio (INR) of 2.0 to 3.0. Subjects in both edoxaban groups had their dose reduced, if one or more of the following clinical factors, known to increase drug exposure, were present at randomization or during the trial: moderate renal impairment (creatine clearance (CrCL) 30 - 50 mL/min), low body weight (≤ 60 kg) or concomitant use of specific P-gp inhibitors (for example [e.g.], quinidine, dronedarone). Key exclusion criteria were, severe renal insufficiency, conditions associated with high bleeding risk, and patients with prosthetic heart valves, or those with hemodynamically significant rheumatic heart disease.

The primary efficacy endpoint was the composite of stroke and systemic embolic events (SEE) and the median study drug exposure for both the edoxaban 60/30 mg and 30/15 mg regimens was 2.5 years.

In the ENGAGE AF-TIMI 48 study edoxaban 60/30 mg regimen was non-inferior to warfarin for the primary endpoint of stroke and SEE (edoxaban 60/30 mg, 1.18% per year; warfarin 1.5% per year; Hazard Ratio [HR] = 0.79; 97.5% CI, 0.63-0.98; p <0.0001 for non-inferiority). Edoxaban 60/30 mg regimen also significantly reduced the Major Adverse Cardiovascular Event (MACE) (HR 0.89, 95% CI: 0.80-0.97), compared with warfarin. Significant reduction of cardiovascular (CV) mortality (HR 0.86, 95% CI: 0.76-0.97) and fewer all-cause deaths were also observed with edoxaban compared to warfarin. The positive benefit-risk profile of edoxaban was also illustrated by the significant reduction in the important bleeding risks such as the hemorrhagic strokes, major bleeds and fatal bleed compared to warfarin.

The efficacy has been consistently demonstrated across multiple subgroups, including higher risk subjects with renal impairment, low body weight or concomitant P-gp inhibitor use that had a dose reduction to edoxaban 30 mg. An exploratory subgroup analysis in patients with a CrCL > 80 mL/min suggested lower relative efficacy for edoxaban compared to well-managed warfarin (HR = 1.41). As a result of lower rates of major bleeding in patients with higher levels of CrCL, the net clinical outcome (stroke, major bleeding or death) remained favorable for edoxaban compared to warfarin. More prospective data need to be obtained to understand this observation; in fact a post-authorisation study is planned for a new higher dose of edoxaban (75 mg) in relation to stroke in patients with normal kidney function (CrCl over 100 mL/min). The results of this study are expected by end of 2018.

In summary, ENGAGE AF-TIMI 48 provides evidence that edoxaban 60 mg daily dose offers an alternative to warfarin. This was based on numerically improved efficacy, coupled with a clinically meaningful and statistically significant reduction in relevant, major and life threatening bleeding risks. The 60 mg once daily dose (with a reduction to 30 mg in subjects with low body weight, moderate renal impairment, or use of P-gp inhibitors) appears to provide the greatest benefit for the population studied. Edoxaban 15 mg will only be used in special circumstance of transition therapy to another anticoagulant therapy.

The second proposed indication of edoxaban for the treatment of DVT and PE, and the prevention of recurrent DVT and PE was supported by the pivotal HOKUSAI-VTE study. In this study, 8,292 subjects were randomized to receive initial heparin therapy (enoxaparin or unfractionated heparin for 5-10 days) followed by edoxaban 60 mg once daily or the comparator. In the comparator arm, subjects received initial heparin therapy concurrently with warfarin, titrated to a target INR of 2.0 to 3.0, followed by warfarin alone. The treatment duration was from 3 months up to 12 months, determined by the investigator based on the patients clinical features. Patients were excluded if they required thrombectomy, insertion of a cava filter, use of a fibrinolytic agent, had a creatinine clearance < 30 mL/min, significant liver disease, or active bleeding. The primary efficacy endpoint was the recurrence of symptomatic VTE, defined as the composite of recurrent symptomatic DVT, non-fatal symptomatic PE and fatal PE.

The HOKUSAI-VTE study demonstrated that edoxaban 60 mg was non-inferior to warfarin for recurrence of VTE (edoxaban, 3.2%; warfarin, 3.5%; HR = 0.89; 95% CI 0.70-1.13; p <0.0001 for non-inferiority to a pre-specified margin of the ratio of 1.5). Relative efficacy was maintained across a wide spectrum of VTE manifestations ranging from limited proximal DVT to severe PE. HOKUSAI-VTE study also demonstrated that edoxaban was superior to warfarin with regards to clinically relevant bleeding, and especially severe and fatal bleeding complications (such as intracranial) associated with standard warfarin VTE anticoagulant therapy (edoxaban, 8.5%; warfarin, 10.3%; HR = 0.81; 95% CI, 0.71-0.94; p = 0.004 for superiority). Taking together, the data from HOKUSAI-VTE study indicated a favorable benefit versus risk profile for the edoxaban therapeutic regimen when considering the primary efficacy and principal safety outcomes.

Overall, edoxaban has been shown to be non-inferior to warfarin for the prevention of stroke and systemic embolic events in patients with atrial fibrillation, as well as the treatment and prevention of venous thromboembolism, but with a lower overall risk of bleeding. It is unclear at this time what advantages edoxaban has over existing the other novel oral anticoagulants.