Portola Pharmaceuticals has announced interim results from the ongoing phase 3b/4 ANNEXA-4 study of andexanet alfa (AndexXa), a factor Xa inhibitor antidote. In this study of patients with factor Xa inhibitor-associated acute major bleeding, a preliminary analysis of interim data from 67 patients (of whom 47 were evaluated for efficacy) showed that andexanet alfa rapidly and substantially reversed anti-factor Xa activity (the anticoagulant mechanism of these drugs) when administered as a bolus, and sustained this reversal when followed by a 120-minute infusion. In addition, 79% of these patients achieved excellent or good hemostasis over a 12-hour period following infusion.
The results were published online in the New England Journal of Medicine.
Factor Xa inhibitors are associated with a reduced risk of intracranial hemorrhage (ICH) compared with warfarin; however, the consequences of the two treatments are similar and can be fatal. In large randomized trials, the 30-day mortality rate in factor Xa inhibitor patients with ICH exceeded 40%.
ANNEXA-4 is a global, single-arm, open-label trial designed to evaluate andexanet alfa, an FDA-designated breakthrough therapy, in patients who present with an acute major bleed while receiving apixaban, rivaroxaban, edoxaban, or enoxaparin. For ethical reasons, this multicenter, prospective study is not randomized, and all participants receive andexanet alfa given as a bolus dose over 30 minutes followed by a two-hour infusion. Patients receive a low or high dose depending on which factor Xa inhibitor they have received and on the time they received it. Patients are evaluated for 30 days after andexanet alfa administration. The coprimary efficacy endpoints are the percent change in anti-factor Xa activity at two hours and hemostasis over 12 hours after the infusion. Hemostatic efficacy is assessed by an independent adjudication committee (IAC) as excellent, good, or poor/none. To date, the ANNEXA-4 trial has enrolled more than 130 of the approximately 270 patients targeted for inclusion.
The new interim results include safety data from 67 patients who experienced life-threatening gastrointestinal bleeding (49%), intracranial bleeding (42%), or bleeding at another site (9%) within 18 hours of administration of apixaban (31 patients), rivaroxaban (32 patients), or enoxaparin (four patients).
The efficacy population included only the 47 patients whose bleed severity met the specific inclusion criteria, as determined by an IAC, and whose baseline anti-factor Xa activity was substantially elevated. The interim efficacy results showed the following:
On August 17, Portola received a complete response letter (CRL) from the FDA regarding its biologics license application for andexanet alfa. The company plans to meet with the FDA as soon as possible to resolve the outstanding questions in the CRL and to determine appropriate next steps.