Novel Oral Anticoagulant for VTE Prevention Misses Primary Endpoint in APEX

The APEX study, comparing extended prophylaxis the investigational oral anticoagulant betrixaban with standard-of-care enoxaparin for prevention of venous thromboembolism (VTE) in patients hospitalized for acute medical illnesses, has missed its primary efficacy endpoint, according to top-line results reported by Portola Pharmaceuticals on Thursday.

The phase III trial, which enrolled 7,513 patients at more than 450 sites around the world, had an atypical statistical analysis plan that involved evaluation of outcomes in three prespecified patient groups in sequence:

• Cohort 1: Patients with elevated D-dimer levels (62% of study population)
• Cohort 2: Patients with elevated D-dimer levels or age ≥ 75 years (91% of population)
• Overall study population

According to the protocol, only if betrixaban was shown to be superior to enoxaparin in terms of preventing a composite of VTE and VTE-related death in Cohort 1—with a P-value ≤ 0.05—would testing continue in the other groups.

That threshold was not met; the relative risk favored betrixaban (0.806) but the P-value was 0.054. Despite missing the primary endpoint in that cohort, trial investigators performed the analysis for the other two patient groups, finding an advantage for betrixaban in Cohort 2 (RR 0.800; P = .029) and in the overall study population (RR 0.760; P = 0.006).

There were no differences in major or fatal bleeding between trial arms and a positive net clinical benefit of betrixaban was seen, according to Portola.

"While we understand that the interpretation of these statistical and clinical results will be subject to discussions with regulatory agencies, we and the APEX study academic leadership believe that the data in Cohort 1 were sufficiently strong to support a full assessment of Cohort 2 and the overall study population," said Portola CEO Bill Lis in a press release. "We believe the overall robustness of the efficacy and safety results in this high-risk patient population, including the positive net clinical benefit observed, provide ample evidence to support the submission of an NDA [new drug application] later this year."

The full data from the study will be presented at the International Society of Thrombosis and Haemostasis’s Scientific and Standardization Committee meeting in May.

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