The FDA has accepted a new drug application (NDA) granting priority review for betrixaban (Portola Pharmaceuticals), an oral, once-daily factor Xa inhibitor anticoagulant, for extended-duration prophylaxis of venous thromboembolism (VTE) in acute medically ill patients with risk factors for VTE. A priority review shortens the FDA review timeline to six months from the standard review period of 10 months. The application for betrixaban, an FDA-designated fast-track investigational drug, was given a Prescription Drug User Fee Act (PDUFA) action date of June 24, 2017.
Acute medically ill patients are those hospitalized for serious common medical conditions, including heart failure, stroke, infections, and pulmonary disease. Because of their underlying disorder or immobilization during hospitalization, they are at increased risk of VTE, a serious and potentially life-threatening thrombus. VTE, which includes deep-vein thrombosis (DVT) and pulmonary embolism, is a major cause of preventable morbidity/mortality and rehospitalization in acute medically ill patients.
Betrixaban directly inhibits the activity of factor Xa, an important target in the blood coagulation pathway, to prevent life-threatening thrombosis. According to the treatment’s developer, betrixaban has properties that may allow it to demonstrate clinical benefit without the significant imbalance in the risk of major bleeding seen with other agents in the class. These properties include a 19- to 25-hour half-life with once-daily dosing; a low peak-to-trough drug-concentration ratio that minimizes anticoagulant variability; low renal clearance; and no significant cytochrome P450-3A4 metabolism, which may reduce the risk of drug–drug interactions.
The NDA was supported by data from the pivotal phase 3 APEX trial, which enrolled 7,513 patients worldwide and assessed the superiority of extended-duration anticoagulation with oral betrixaban compared with standard-duration injectable enoxaparin in preventing VTE in high-risk acute medically ill patients. The results were published in the New England Journal of Medicine in August 2016.
In the study, patients who were hospitalized for acute medical illnesses were randomly assigned to receive subcutaneous enoxaparin (40 mg once daily) for six to 14 days plus oral placebo for 35 to 42 days or subcutaneous placebo for six to 14 days plus oral betrixaban (80 mg once daily) for 35 to 42 days. The patients were divided into three cohorts: those with an elevated d-dimer level (cohort 1); those with an elevated d-dimer level or an age of at least 75 years (cohort 2); and all of the enrolled patients. The study’s primary efficacy endpoint was a composite of asymptomatic proximal DVT and symptomatic VTE.
In cohort 1, the primary efficacy outcome occurred in 6.9% of patients receiving betrixaban and in 8.5% of those receiving enoxaparin (relative risk [RR] in the betrixaban group, 0.81; P = 0.054). The rates were 5.6% and 7.1%, respectively, in cohort 2 (RR, 0.80; P = 0.03) and 5.3% and 7.0% in the overall population (RR, 0.76; P = 0.006). The last two analyses were considered to be exploratory because of the result in cohort 1. In the overall population, major bleeding occurred in 0.7% of the betrixaban group and in 0.6% of the enoxaparin group (RR, 1.19; P = 0.55).
The authors concluded that, among acutely ill medical patients with an elevated d-dimer level, there was no significant difference between extended-duration betrixaban and a standard regimen of enoxaparin in the prespecified primary efficacy outcome. However, prespecified exploratory analyses provided evidence suggesting a benefit for betrixaban in the two larger cohorts.