Andexanet alfa is an agent developed to reverse the activity of factor Xa (fXa) inhibitors. Phase 2 proof-of-concept studies in patients taking rivaroxaban, apixaban, edoxaban, and enoxaparin have been completed and andexanet is now being studied in phase 3 confirmatory trials. In part 2 of the phase 3 ANNEXA-A trial [NCT02207725], subjects were treated with apixaban, dosed to steady state, and randomized 3:1 to receive an andexanet bolus plus an infusion or placebo. Mark Crowther, MD, McMaster University, Hamilton, Ontario, Canada, presented the study results.

Because of the difficulty in conducting trials in actively bleeding patients, the ANNEXA-A study was designed to enroll older subjects (50 to 75 years) who were otherwise healthy and to utilize biomarker end points. The primary end point was the percentage change in anti-fXa activity from baseline to the nadir after infusion. Baseline was defined as the measurement at peak anti-Xa before the start of bolus, and the nadir was the lowest anti-Xa value between 10 minutes prior to and 5 minutes after the end of infusion.

A total of 32 subjects were enrolled, 24 to the andexanet arm and 8 to placebo. Twenty-two patients (68.8%) were male and 29 patients (90.6%) were white with a mean age of approximately 59 years (range, 50 to 73). Subjects who were randomized to active treatment received an andexanet bolus of 400 mg followed by 480 mg for a 2-hour continuous intravenous infusion (4 mg/min).

The safety results were consistent with those observed in earlier studies of andexanet. One subject discontinued during the andexanet infusion after experiencing mild hives; there were no other allergic symptoms or cardiorespiratory effects. Six subjects had mild infusion-related reactions, 4 (16.7%) in the andexanet group and 2 (25.0%) receiving placebo. None experienced severe or serious adverse events. Transient elevation of prothrombin fragment 1 &0x002B; 2 was seen in most subjects who received andexanet but it returned to ≤ 2 times the upper limit of normal by the fourth day after treatment. D-dimer did not increase for more than 1 day. Dr Crowther commented that no thrombotic events were noted in anyone infused with this product across all studies. No clinically important antibodies to factor X or fXa were reported.

Subjects in part 2 of the ANNEXA-A study met its primary study end point. The mean anti-fXa significantly decreased by 92% from baseline, which was also significantly lower than the placebo group (P < .001). In addition, andexanet significantly reduced free apixaban (P = .0002 vs placebo). Thrombin generation was restored to preapixaban levels in all andexanet-treated subjects (P < .0001). A large, multicenter, open-label phase 4 study of andexanet is now being conducted at centers in North America and Europe. This study will enroll subjects with acute bleeding who are taking fXa inhibitors to determine the change in anti-fXa activity as well as the number of patients who can achieve effective hemostasis.