Results from IIIb/IV ANNEXA-4 study showed that andexanet alfa rapidly and substantially reversed anti-Factor Xa activity, and these levels were sustained for the duration of administration. Excellent or good haemostasis was observed in 87.5% of patients and in 80% of those with intracranial haemorrhage. In 22 patients (mean age 68.0 years, 54.5% male and 63.6% with venous thromboembolism as primary indication) with acute major bleeding on enoxaparin, median anti-factor Xa activity decreased from 0.48 ([IQR] 0.41, -0.61) IU/mL at baseline to 0.14 (IQR 0.10, 0.17) IU/mL at the end of andexanet bolus administration (median decrease of 75.0%, 95% CI: 66.7-79.2%) in 17 patients. Excellent or good haemostasis at 12 hrs was achieved in 14 of 16 (87.5%, 95% CI: 61.7-98.4%) cases of the efficacy population in whom this could be assessed, and in 8 of 10 (80.0%, 95% CI: 44.4-97.5%) cases with intracranial haemorrhage. Earlier results showed that the median anti-Factor Xa activity decreased by 90% from baseline for patients on rivaroxaban and by 93% for patients on apixaban following the bolous dose, and sustained this reversal when followed by a 120-minute infusion. Additionally, 37 of 47 patients (79%) achieved excellent or good haemostasis over a 12-hour period following infusion. Haemostatic efficacy was similar for patients on apixaban (75%) and rivaroxaban (81%). The efficacy population included only those 47 patients whose bleed severity met the specific inclusion criteria. Updated data from 228 patients (of which 132 were adjudicated for efficacy) showed rapid and significant reversal of anti-Factor Xa activity was observed in andexanet alfa treated patients when administered as a bolus with a sustained reversal observed when followed by a 120-minute infusion. Excellent or good haemostasis achieved in 83 percent of andexanet alfa patients over a 12-hour period. Data from adjudicated efficacy population of 132 patients also demonstrated that andexanet alfa rapidly and substantially reversed anti-Factor Xa activity, and these levels were sustained for the duration of administration. The co-primary efficacy endpoint of the trial, anti-Factor Xa activity decreased by a median of greater than 90 percent for both apixaban and rivaroxaban following the bolus dose, which was sustained at similar levels for the duration of the two-hour infusion. 83% of the adjudicated efficacy patients achieved effective haemostasis. In patients with gastrointestinal bleeding, 86 percent had effective haemostasis, as did 81 percent of patients with intracranial bleeding. Both apixaban and rivaroxaban treated patients showed similar haemostatic efficacy of 82 and 83 percent respectively. The prospective, open-label trial evaluated the haemostatic efficacy of andexanet alfa in patients receiving a factor Xa inhibitor who have acute major bleeding. Updated results from 352 patients (249 of which were evaluable for efficacy) showed that rapid and significantly reversal of anti-Factor Xa activity (a measure of the anticoagulant activity of apixaban, rivaroxaban, edoxaban and enoxaparin, the anticoagulants studied in the trial) when administered as a bolus was observed and the reversal was sustained this reversal when followed by a 120-minute infusion. Excellent or good hemostasis (stoppage of bleeding) was achieved over the 12-hour period following treatment with andexanet alfa, as determined by an independent adjudication committee in 204 of 249 (82%) evaluable patients for efficacy. Among 98 evaluable patients in the subset, the median increase in haematoma volume from baseline to 12 hours, was 0.06 milliliters. Further, 71 patients in the subset experienced a spontaneous, single-compartment, intracerebral hemorrhage, which allows for the most precise measurement of hematoma volume. Of the patients that achieved excellent or good haemostatic efficacy within one hour post andexanet alfa treatment, 55 out of 56 patients (98%) maintained excellent or good hemostatic control for 12 hours, following the treatment. New exploratory analysis data showed that among 352 patients, 90 (26%) acute GI bleeding and 62 (18%) were evaluable for hemostatic efficacy. Bleeding was stopped in 82% (n = 51/62) of patients in the treatment arm over a period of 12 hours following treatment with andexxa alfa, which was consistent with the full study results. In 327 patients, who received apixaban or rivaroxaban, thrombine generation (TG) as measured by the endogenous thrombin potential (ETP) at 8 hr post end of infusion (ETP-8H) was increased post bolus and maintained through out infusion. ETP was decreased post infusion, however it was maintained in reference range for 18 hr. There was no difference in ETP-8H in patients with or without thrombotic complications (p = 0.610) and effective hemostasis (p = 0.544). In this analysis, ETP-8H failed to predict effective hemostasis (p = 0.491) or thrombotic events (p = 0.743). Also, ETP-8H did not predict hematoma growth in patients with ICH (p = 0.349). The prospective, open-label trial evaluated the haemostatic efficacy of andexanet alfa in patients receiving a factor Xa inhibitor who have acute major bleeding ^{[2] [3] [4] [5] [6] [7]} .

Phase IIIb/IV: Results from a phase IIIB/IV trial in non-vitamin K oral anticoagulant (Noac) related bleeding demonstrated that the 30 day mortality was lower in patients receiving andexanet alfa treatment. Updated results showed that Within 30 days, of 22 patients, one patient (4.5%) with acute major bleeding on enoxaparin, who received andexanet experienced a thromboembolic event and two (9.1%) patients died. Previous data from 322 enrolled patients showed 65% and 67%of intracranial haemorrhage (ICH) and a 25% and 29% of gastrointestinal bleeding in the andexanet and PCC cohorts respectively. Results showed that 67 patients who received andexanet alfa showed that the antidote was not associated with any infusion reactions, and no patients developed antibodies to Factor Xa or Factor X or neutralizing antibodies. Thrombotic events occurred in 14 patients with spontaneous intracranial hemorrhage (10.9%) and death occurred in 24 patients (18.8%), during the trial. Among 18 patients, who re-started oral anti-coagulation therapy within 30 days, no thrombotic events were observed. However, the majority of thrombotic events occurred in patients who delayed or did not re-start anti-coagulation therapy, with a Factor Xa inhibitor, during the follow-up period. The interim results from ANNEXA-4 study 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 occurrence of rate of events were in the range of expected in the study population given the severity of the bleeding, the study population advanced age and underlying thrombotic risk, and the percentage who restarted anticoagulant therapy (57%) following their bleeding episode. Infusion reaction was observed in two of the 228 patients. No patient developed antibodies to Factor Xa or Factor X or neutralizing antibodies to andexanet alfa. Final results from 352 patients showed that 227 were treated for intracranial hemorrhage (ICH) and 90 were treated for a gastrointestinal bleed. Thrombotic events (TEs) occurred in 34 patients and death was reported in 49 patients, consistent with previously reported trial results and with the high background thrombotic risk of the enrolled patient population. Before restart of any (full or prophylactic) anticoagulation, 26 (76.4%) patients showed TEs (n=34). The majority of thrombotic events occurred in patients who delayed or did not re-start anticoagulation therapy with a Factor Xa inhibitor during the follow-up period. No thrombotic events were observed among the 100 patients who re-started oral anticoagulation therapy. An infusion reaction was reported in two patients and none of the patient developed antibodies to Factor Xa or Factor X or neutralizing antibodies to the drug. The prospective, open-label trial evaluated the haemostatic efficacy of andexanet alfa in patients receiving a factor Xa inhibitor who have acute major bleeding. New exploratory analysis involving 352 patients showed that, of the 90 patients evaluable for safety study, TEs were reported in six patients (7%) and death occurred in 10 patients (11%). TEs were not reported in 40 patients (44%) who re-started oral anticoagulation therapy. The most common TEs observed were stroke and deep vein thrombosis. Patients with venous TEs were more anticoagulated for venous thromboembolism, in comparison with patients with arterial TEs. Median time to first TE was reported as 10.5 days, however time to event was longer for venous TEs, in comparison with arterial TEs. For most patients, the TEs were nonfatal ^{[2] [8] [9] [4] [5] [7] [6]} .

Low titers of anti- andexanet alfa antibodies were observed in 17% of healthy participants, of which 6% and 14% had low titers on day 30 and through days 44 to 48 respectively. Both healthy volunteers and patients of the ANNEXA-4 trial had a similar pattern of antibody response with 6% of the patients having antibodies against andexanet alfa. None of these anti-andexanet alfa antibodies were neutralizing and they showed no cross-reaction with FX or FXa in either healthy volunteers or in bleeding patients. The results were obtained from a total of 98 patients and 145 healthy volunteers ^[10] .