Portola Pharmaceuticals has announced interim results from the ongoing phase3b/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 when administered as a bolus, and sustained this reversal when followed by a 120-minute infusion.
Additionally, 79% of these patients achieved excellent or good haemostasis over a 12-hour period following infusion. These interim results were presented in a late-breaking science “Hot Line” session at the European Society of Cardiology (ESC) 2016 Congress in Rome. The interim results were published simultaneously online by The New England Journal of Medicine.
“In this preliminary analysis, andexanet alfa was effective in rapidly reversing anti-Factor Xa inhibitor activity and restoring normal blood clotting in real-world patients with Factor Xa inhibitor-related bleeding. Based on these interim results, we believe that ANNEXA-4 is on track to achieve its co-primary efficacy endpoints upon study completion,” says Stuart J Connolly, ANNEXA-4 executive committee chairman and professor in the Department of Medicine of the Faculty of Health Sciences at McMaster University in Hamilton, Canada. “The haemostatic efficacy results are especially important because no US Food and drug Administration (FDA) or European Medicines Agency (EMA)-approved antidote is available for these patients and no existing therapies, including plasma-derived products for warfarin reversal, have demonstrated reversal of Factor Xa inhibitor activity or clinical efficacy and safety.”
The interim results from all 67 patients who received andexanet alfa showed that the antidote was not associated with any infusion reactions. No patients developed antibodies to Factor Xa or Factor X or neutralising antibodies to andexanet alfa. During the 30-day follow-up period, thrombotic events occurred in 12 patients (18%), and death occurred in 10 patients (15%). According to a company release, these events occurred within the range expected in this population given the severity of the bleeding, their underlying thrombotic risk, and the low percentage that restarted anticoagulant therapy following their bleeding episode.
“The ANNEXA-4 interim results are preliminary yet encouraging because the percentage of patients who have achieved excellent or good haemostasis is higher than the co-primary endpoint threshold of above 50% defined in the study protocol,” says John Curnutte, executive vice president, research and development at Portola. “This threshold was determined based on historical benchmarks of haemostatic control achieved with agents in studies of warfarin reversal and on expert opinion. What is also encouraging is that following two reviews that included the patients described in this report, the Data and Safety Monitoring Board recommended that the study proceed as planned.”
ANNEXA-4 is a global, single-arm, open-label clinical 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 multi-centre, prospective cohort study is not randomised 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 the time they received it. Patients are evaluated for 30 days following AndexXa administration. The co-primary efficacy endpoints are the percent change in anti-Factor Xa activity at two hours and assessment of haemostasis over 12 hours following the infusion. Haemostatic efficacy is assessed by an independent endpoint adjudication committee as either excellent, good or poor/none. To date, ANNEXA-4 has enrolled more than 130 patients of the approximately 270 patients targeted for inclusion.
The interim results included 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 (4 patients).
The efficacy population included only those 47 patients whose bleed severity met the specific inclusion criteria, as determined by an independent adjudication committee, and whose baseline anti-Factor Xa activity was substantially elevated. The interim efficacy results showed the following:
- AndexXa rapidly and substantially reversed anti-Factor Xa activity, and these levels were sustained for the duration of administration. Following the bolus dose, median anti-Factor Xa activity decreased by 89% from baseline for patients on rivaroxaban and by 93% for patients on apixaban, and was sustained at similar levels for the duration of the two-hour infusion.
- AndexXa was associated with normalisation of blood clotting and cessation of bleeding. The independent adjudication committee determined that 37 of 47 patients (79%) achieved excellent or good haemostasis. Among patients with gastrointestinal bleeding, 84% had excellent or good haemostasis, as did 80% of patients with intracranial bleeding. Haemostatic efficacy was similar for patients on apixaban (75%) and rivaroxaban (81%).