SUMMARY

Andexxa (coagulation factor Xa [FXa; recombinant], inactivated-zhzo) is a product of AstraZeneca. Please refer to the Andexxa Prescribing Information for complete product information or call AstraZeneca at 1-800-236-9933.

• ANNEXA-I was a phase 4, randomized study that compared the efficacy and safety of andexanet with usual care in adult patients experiencing FXa inhibitor-associated intracranial hemorrhage (ICH).¹
  • Hemostatic efficacy (primary endpoint) occurred in 67.0% of patients in the andexanet group and 53.1% of patients in the usual-care group (adjusted difference, 13.4 percentage points; 95% confidence interval [CI], 4.6-22.2; P=0.003).
  • The median percent change in anti-FXa activity between baseline and the 1-to-2-hour nadir was -94.5% (interquartile range [IQR], -96.6 to -88.9) with andexanet and -26.9% (IQR, -54.2 to -9.5) with usual care (P<0.001).
• ANNEXA-R was a phase 3, two-part, randomized study that evaluated the safety and efficacy of andexanet (Andexxa) to reverse the anticoagulant effects of XARELTO in older healthy subjects.²
  • In part 1 of the study, andexanet administered as a rapid bolus (within 2-5 minutes) vs placebo reduced anti-FXa activity to a greater extent (92%±11% vs 18%±15%; P<0.001).
  • In part 2 of the study, andexanet administered as a bolus plus a 2-hour infusion vs placebo reduced anti-FXa activity to a greater extent (97%±2% vs 45±12%; P<0.001).
• ANNEXA-4 was a multicenter, prospective study that assessed the efficacy and safety of andexanet in patients with acute major bleeding within 18 hours after administration of an FXa inhibitor, including XARELTO.^3,4
  • In the initial analysis including 352 patients (April 2015-May 2018), among those who received XARELTO (n=100), anti-FXa activity was reduced by 92% from baseline to the end of andexanet bolus administration.³
  • In the final analysis including 479 patients (April 2015-August 2022), among those who received XARELTO (n=132), anti-FXa activity was reduced by 93.5% from baseline to the end of andexanet bolus administration.⁴
• A two-cohort comparison study included patients on andexanet alpha from the
  ANNEXA-4 study and a synthetic control arm of patients on 4-factor prothrombin complex concentrate (4F-PCC) admitted within a United States (US) healthcare system from December 2016 to August 2020. The study evaluated the hemostatic effectiveness and 30-day all-cause mortality between andexanet alfa and 4F-PCC in patients who developed an ICH while taking apixaban or XARELTO.⁵
  • Andexanet alfa showed greater odds in achieving hemostatic effectiveness compared to 4F-PCC (85.8% vs 68.1%, respectively; odds ratio, 2.73; 95% CI, 1.16-6.42).
  • Weighted incidence of 30-day all-cause mortality was 7.9% (95% CI, 3.6-13.8) in the andexanet group and 19.6% (95% CI, 12.1-24.0) in the 4F-PCC group.
• ICH: A substudy of ANNEXA-4 (ANNEXA-4 Substudy), from the initial analysis (N=352),³ evaluated the efficacy and safety of andexanet in a subgroup of patients with ICH. The median percent change in anti-FXa levels from baseline to nadir for
  XARELTO-treated patients showed a decrease of 92.6%.⁶
• Japanese subanalysis: A prespecified subanalysis of ANNEXA-4, from the final analysis (N=479),⁴ assessed the efficacy and safety of andexanet among patients in Japan. The median percent change in anti-FXa levels from baseline to nadir was 95.4%, 96.1%, and 82.2%, respectively, among patients receiving apixaban, XARELTO, and edoxaban.⁷
• In a post hoc analysis of a cohort of patients with gastrointestinal (GI) bleeding in ANNEXA-4, the median percent reduction in anti-FXa activity from baseline to the end of infusion was ≥90% for patients receiving apixaban and XARELTO.⁸ 
• In 2 phase 2 dose-ranging clinical studies that characterized the pharmacokinetic/ pharmacodynamic parameters of andexanet alfa in healthy subjects receiving rivaroxaban, the anti-FXa activity decreased significantly within 2 minutes following administration of andexanet as a bolus, with a maximum decrease of ~93% (P<0.05) compared with placebo.⁹
• Another phase 2 study in healthy subjects confirmed a dose-dependent decrease in
  anti-FXa activity and a return of anti-FXa activity to placebo levels approximately
  2 hours after andexanet treatment.¹⁰

BACKGROUND

An agent to reverse the anti-FXa activity of rivaroxaban is available. Due to the high plasma protein binding, rivaroxaban is not dialyzable. Protamine sulfate and vitamin K are not expected to affect the anticoagulant activity of rivaroxaban.¹¹

Clinical data

Andexanet Alfa (PRT064445)

Phase 4 Studies

ANNEXA-I¹ was a phase 4, randomized study that compared the efficacy and safety of andexanet with usual care in adult patients experiencing FXa inhibitor-associated ICH. Patients with ICH were eligible if they were on a FXa inhibitor, with the latest dose taken no more than 15 hours prior to randomization. Patients in the andexanet group received either a high-dose bolus or a low-dose bolus over the course of 15-30 minutes followed by a continuous infusion over the course of 2 hours.

• The primary endpoint was hemostatic efficacy assessed at 12 hours after randomization. Hemostatic efficacy was achieved if all the following criteria were met: a change in hematoma volume of ≤20%, or ≤35% within 12 hours after baseline; an increase of <7 points in the National Institutes of Health Stroke Scale (NIHSS) score at 12 hours; and no administration of rescue therapies, such as andexanet, prothrombin complex concentrate, or surgery to decompress the hematoma, within 3 to 12 hours following randomization.

Results

• A total of 452 patients were randomized to receive either andexanet (n=224; mean age, 78.9 years; 42% were female; 28.6% used XARELTO) or usual care (n=228; mean age, 78.9 years; 49.6% were female; 28.5% used XARELTO).
• Hemostatic efficacy occurred in 67.0% of patients in the andexanet group and 53.1% of patients in the usual-care group (adjusted difference, 13.4 percentage points; 95% CI, 4.6-22.2; P=0.003).
• The median percent change in the anti-FXa activity between baseline and the 1-to-2-hour nadir was -94.5% (IQR, -96.6 to -88.9) with andexanet and -26.9% (IQR, -54.2 to -9.5) with usual care (P<0.001).
• For safety analysis, 530 patients (andexanet, n=263 and usual care, n=267) were included.
  • Thrombotic events were reported in 10.3% of patients in the andexanet group and in 5.6% of patients in the usual-care group (difference, 4.6 percentage points; 95% CI, 0.1-9.2; P=0.048).
  • Ischemic stroke was reported in 6.5% and 1.5% receiving andexanet and usual care, respectively (difference, 5.0 percentage points; 95% CI, 1.5-8.8).
  • Death occurred in 27.8% of patients receiving andexanet and 25.5% of patients receiving usual care (adjusted difference, 2.5 percentage points; 95% CI, -5.0 to 10.0; P=0.51).

Phase 3 Studies

ANNEXA-R² was a phase 3, randomized, double-blind, placebo-controlled study in older healthy subjects to evaluate the safety and efficacy of andexanet to reverse the anticoagulant effects of XARELTO. Subjects were randomized in a 2:1 ratio either to placebo or andexanet. The study was performed in 2 consecutive parts: part 1 evaluated andexanet intravenous (IV) bolus alone and part 2 evaluated an IV bolus followed by a continuous 120minute infusion. In ANNEXA-R, subjects received XARELTO 20 mg orally once daily for 4 days. On day 4, 4 hours after the last dose of XARELTO (at or near maximum plasma concentration [C_max]), andexanet was administered as an 800 mg IV bolus (30 mg/min) (part 1) or as an 800 mg IV bolus followed by an 8 mg/min continuous infusion over 120 minutes (960 mg) (part 2).

• Primary endpoint: The percent change of anti-FXa activity, measured using a validated chromogenic assay of FXa enzymatic activity, from baseline (pre-andexanet/placebo) to nadir (post-andexanet/placebo). Nadir was defined as the smaller value for anti-FXa activity at 2 and 5 minutes following the end of the bolus for part 1, and the smallest value between 10 minutes before and 5 minutes after the end of the continuous infusion for part 2.

Results

• A total of 80 subjects were randomized in ANNEXA-R: 53 to the andexanet arm and 27 to the placebo arm. The mean age was 57.9 years and 39% of the subjects were women. The treatment groups were balanced with respect to baseline characteristics.
• Part 1: A bolus of andexanet rapidly (within 2-5 minutes) reduced anti-FXa activity to a greater extent than placebo in subjects receiving XARELTO (92%±11% vs 18%±15%; P<0.001). After completion of the andexanet bolus, reversal of anti-FXa activity persisted for 2 hours.
• Part 2: When administered as a bolus plus a 2-hour infusion, andexanet reduced
  anti-FXa activity to a greater extent than placebo (97%±2% vs 45±12%; P<0.001). In the placebo group, anti-FXa activity decreased over time at the expected rate for clearance of the anticoagulant. Reversal of anti-FXa activity with andexanet persisted for 1-2 hours after completion of the infusion. All andexanet-treated subjects had at least 80% reversal of anti-FXa activity, with the exception of 1 subject who did not receive the full dose of andexanet due to a malfunction with the IV administration, compared to none of the placebo-treated subjects (P<0.001).
• There were no serious or severe adverse events (AEs), and no thrombotic events reported. The most common side effects were urticaria and administration site conditions. No subjects developed antibodies to factor X or FXa (measured through day 43).
• The publication does not present data on the efficacy and safety of andexanet in patients requiring urgent reversal of FXa inhibitor activity for bleeding or emergency surgery. For additional information on this study, please consult the full publication (http://www.nejm.org/doi/pdf/10.1056/NEJMoa1510991).

Andexanet Dosing in XARELTO-Treated vs Apixaban-Treated Patients

• In a separate study evaluating the use of andexanet to reverse the anticoagulant effects of apixaban (ANNEXA-A), subjects received apixaban 5 mg orally twice daily for 3.5 days. On day 4, three hours after the last dose of apixaban (at or near C_max), andexanet was administered as a 400-mg IV bolus (30 mg/min) (part 1) or as a 400-mg IV bolus followed by a continuous infusion of 4 mg/min for 120 minutes (480 mg).
• Due to both the higher initial C_max and larger volume of distribution of XARELTO, the andexanet dose was higher to reverse the effects of XARELTO 20 mg once daily than apixaban 5 mg twice daily.

ANNEXA-4^3,4 is a multicenter, prospective, open-label, single-group study that assessed the efficacy and safety of andexanet in 479 patients with acute major bleeding within 18 hours after administration of a FXa inhibitor. Additionally, data from a secondary analysis that explored the relationship between anti-FXa activity levels, hemostatic efficacy, and mortality were also reported.

Study Design/Methods³

All patients received a bolus of andexanet, followed by a 2-hour infusion. Dosing:

• Patients that had taken XARELTO or apixaban more than 7 hours before andexanet administration:
  • Bolus dose, andexanet 400 mg over 15 minutes; infusion dose, andexanet 480 mg
• Patients that have taken enoxaparin, edoxaban, or XARELTO 7 hours or less before andexanet administration, or at an unknown time:
  • Bolus dose, andexanet 800 mg over 30 minutes; infusion dose, andexanet 960 mg
• Key inclusion criteria: ≥18 years of age; acute major bleeding; and received within 18 hours one of the following: apixaban, XARELTO, or edoxaban at any dose or enoxaparin ≥ 1 mg/kg per day
  • Acute major bleeding was defined as bleeding having ≥1 of the following features: life-threatening bleeding with signs or symptoms of hemodynamic compromise; bleeding associated with a decrease in the hemoglobin level of at least 2 g/dL (or a hemoglobin level of ≤8 g/dL if no baseline hemoglobin level was available); or bleeding in a critical area or organ.
• Key exclusion criteria: Planned surgery <12 hours after andexanet treatment; ICH in a patient with a score of <7 on the Glasgow Coma Scale or an estimated hematoma volume of >60 mL; expected survival of <1 month; the occurrence of a thrombotic event within 2 weeks before enrollment; or use of any of the following agents within the previous 7 days: vitamin K antagonist, dabigatran, prothrombin complex concentrate, recombinant factor VIIa, whole blood, or plasma
• The efficacy population (n=254) included those who met the criteria for bleeding severity and with baseline anti-FXa activity of ≥75 ng/mL, or ≥0.25 IU/mL for those receiving enoxaparin. The safety population (n=352) included all patients who received andexanet.

Results⁴

• Patients had a mean age of 78 years; 54% of patients were male, 86% were White, and 81% underwent anticoagulation therapy for atrial fibrillation. The median time since the last anticoagulant dose was 11.4 hours. The primary sites of bleeding were central nervous system/intracranial, GI tract, and other sites in 331 (69.1%), 109 (22.8%), and 39 (8.1%) patients, respectively.
• Percent change in the anti-FXa activity at the end of bolus administration in the efficacy population (primary efficacy outcome):
  • XARELTO-treated patients (n=132)
    • The median value for anti-FXa activity was reduced from 214.6 ng/mL at baseline to 12.5 ng/mL, a 93.5% reduction (95% CI, 91.6-94.6). At 4, 8, and 12 hours after andexanet infusion, the median percent reduction from baseline in anti-FXa activity was 43.2%, 48.6%, and 61%, respectively.
  • Apixaban-treated patients (n=172)
    • The median value for anti-FXa activity was reduced from 146.9 ng/mL at baseline to 11.2 ng/mL, a 92.3% reduction (95% CI, 91.3-93). At 4, 8, and 12 hours after andexanet infusion, the median percent reduction from baseline in anti-FXa activity was 35.6%, 34.9%, and 38%, respectively.
  • Edoxaban-treated patients (n=28)
    • The median value for anti-FXa activity decreased from 121.1 ng/mL at baseline to 24 ng/mL, a 68.9% reduction (95% CI, 56.1-77.7). At 4, 8, and 12 hours after andexanet infusion, the median percent reduction from baseline in anti-FXa activity was 34.4%, 48.6%, and 58.5%, respectively.
  • Enoxaparin-treated patients (n=17)
    • The median value for anti-FXa activity decreased from 0.48 IU/mL at baseline to 0.14 IU/mL, a 75% reduction (95% CI, 66.7-79.2). At 4, 8, and 12 hours after andexanet infusion, the median percent reduction from baseline in anti-FXa activity was 46.3%, 56.5%, and 62.5%, respectively.
  • The decreased anti-FXa activity at the end of bolus administration was maintained through the end of infusion as well for all FXa inhibitors. Additionally, no significant differences in the anti-FXa activity were observed across races.
• Hemostatic efficacy 12 hours after the andexanet infusion in the efficacy population (primary efficacy outcome):
  • Of the 342 patients who could be evaluated for hemostatic efficacy, 80% had good or excellent hemostatic efficacy at 12 hours (95% CI, 75-84); no significant variations were observed across the following subgroups: FXa inhibitor, sex, age, type of bleeding, or andexanet alfa dose.
  • For patients on XARELTO, apixaban, edoxaban, and enoxaparin, hemostatic efficacy was 81% (95% CI, 73-87), 79% (95% CI, 72-85), 79% (95% CI, 59-92), and 88% (95% CI, 62-98), respectively.
  • For patients with GI, intracranial, and other types of bleeding, hemostatic efficacy was 82% (95% CI, 72-90), 79% (95%, CI, 74-84), and 82% (95% CI, 60-95), respectively.
• Primary safety outcomes:
  • In the safety population, death occurred in 15.7% (n=75) of patients (cardiovascular related, n=58 [12.1%]; noncardiovascular, n=15 [3.1%]; uncertain cause, n=2 [0.4%]) and a thrombotic event occurred in 10.4% (n=50) of patients during the
    30-day follow-up period.
  • There were 16 deaths and 19 thrombotic events within 6 days after andexanet therapy, 28 deaths and 15 thrombotic events between 6 and 14 days, and 31 deaths and 16 thrombotic events between 15 and 30 days. Six patients died after 30 days (on days 33 [2 deaths], 35, 39, 42, and 44).
  • Mortality after ICH, GI bleeding, and bleeding from other sites was 16.9% (n/N=56/331), 11.9% (n/N=13/109), and 15.4% (n/N=6/39), respectively. Mortality was 19.6% (n/N=65/331) and 6.8% (n/N=10/148) for patients ≥75 years and <75 years of age, respectively.  
  • One severe infusion reaction, including rigors, severe chills, hypertension, oxygen desaturation, fever, agitation, and confusion, occurred 75 minutes after andexanet initiation and resolved 80 minutes later with treatment (diphenhydramine, prednisone, haloperidol, paracetamol, and supplemental oxygen).
  • Of the 323 patients who were reinitiated on any anticoagulant, 34 and 16 had a thrombotic event before and after the reinitiation, respectively. Of the 130 patients who were reinitiated on any oral anticoagulant, 50 had a thrombotic event before the reinitiation and none had a thrombotic event after the reinitiation.
  • There were no developments of neutralizing antibodies to factor X, FXa, or andexanet alfa.

A reduction of anti-FXa activity from baseline to nadir, specific to certain populations, significantly predicted hemostatic efficacy in patients with ICH (excluding enoxaparin patients; area under the receiver operating characteristic curve, 0.62; 95% CI, 0.54-0.70) and correlated with lower mortality in patients <75 years of age (adjusted P=0.022; unadjusted P=0.003). A significant correlation was observed between hemostatic efficacy and lower mortality among all patients (P<0.001). By the end of bolus administration through 24 hours for all FXa inhibitors, the median endogenous thrombin potential was within the normal range.

ANNEXA-4 Substudy - Andexanet Alfa in ICH

A substudy of the ANNEXA-4 study (ANNEXA-4 Substudy), from the initial analysis (N=352),³ evaluated the efficacy and safety of andexanet in a subgroup of patients with ICH, including spontaneous and traumatic ICH.⁶

Results

• The safety and efficacy population consisted of 227 (spontaneous, n=128; traumatic, n=99) and 171 (spontaneous, n=99; traumatic, n=72) patients with ICH, respectively.
• In the overall safety population, mean age was 79.3 years, and patients received apixaban (n=140 [61.7%]), XARELTO (n=69 [30.4%]), enoxaparin (n=11 [4.8%]), or edoxaban (n=7 [3.1%]).
• In the efficacy population, median baseline anti-FXa levels among patients receiving apixaban (n=99), XARELTO (n=59), and enoxaparin (n=11) were 144.2 ng/mL, 198.1 ng/mL, and 0.5 IU/mL, respectively.
  • Median percent change in anti-FXa levels from baseline to nadir for apixaban- and XARELTO-treated patients showed a decrease of 93.8% and 92.6%, respectively.
• Of the 98 efficacy evaluable patients with spontaneous ICH, 78.6% (n=77; 95% CI, 69.1-86.2) had excellent (n=70) or good (n=7) hemostatic efficacy at 12 hours after andexanet treatment.
  • Among patients treated with XARELTO (n=40), apixaban (n=50), and enoxaparin (n=6), excellent or good hemostatic efficacy at 12 hours after andexanet treatment was observed in 78% (95% CI, 62-89), 78% (95% CI, 64-88), and 83% (95% CI, 36-100) of patients, respectively.
• Of the 70 efficacy evaluable patients with traumatic ICH, 83% (n=58; 95% CI, 72-91) of patients had excellent (n=47) or good (n=11) hemostatic efficacy at 12 hours after andexanet treatment.
  • Among patients treated with XARELTO (n=19), apixaban (n=47), and enoxaparin (n=4), excellent or good hemostatic efficacy at 12 hours after andexanet treatment was observed in 79% (95% CI, 54-94), 85% (95% CI, 72-94), and 75% (95% CI, 19-99) of patients, respectively.
• Efficacy analysis is not shown for the 7 patients who received edoxaban.
• In the safety population, a thrombotic event occurred in 21 (9.3%) patients within 30 days of andexanet treatment.
  • Thrombotic events included deep vein thrombosis (n=9), stroke (n=11), myocardial infarction (n=2), and pulmonary embolism (n=1).
  • Median time to first thrombotic event was 11 days and most events (n=14 [66.7%]) occurred >6 days after andexanet treatment.
• In the safety population, death occurred in 34 (15.0%) patients within 30 days of andexanet treatment.
  • The most common cause of death was cardiovascular diseases (n=28 [12.3%]).
  • Median time to death was 12.5 days and most deaths occurred >6 days after andexanet treatment.
  • Mortality rates among patients with a hemostatic efficacy of excellent/good and poor/none were 12.7% and 26.3%, respectively.
  • Mortality rates in patients with spontaneous and traumatic ICH were 18.8% (n=24) and 10.1% (n=10), respectively.
• In the safety population, at a median of 3 days, a total of 141 (62.1%) patients resumed anticoagulation (any dose of IV or oral) therapy after andexanet treatment.
  • Of these, 41 (29.1%) patients restarted oral anticoagulation therapy, after which no thrombotic events occurred.

Prespecified Subanalysis of ANNEXA-4 in Japan

A prespecified subanalysis of the ANNEXA-4 study, from the final analysis (N=479),⁴ assessed the efficacy and safety of andexanet among patients in Japan.⁷

Results

• Of the 479 patients, 19 were enrolled at study sites in Japan; 8 were women and the median age was 78 years.
• Of the 19 patients with ICH, 6, 8, and 5 were receiving apixaban, XARELTO, and edoxaban, respectively; all but 1 fatal patient (treated with edoxaban) completed the 30-day follow-up duration.
  • In the efficacy population (n=16), the median baseline anti-FXa levels among patients receiving apixaban (n=5), XARELTO (n=7), and edoxaban (n=4) were
    215.1 ng/mL, 180.8 ng/mL, and 87.9 ng/mL, respectively.
    • The median percent change in anti-FXa levels from baseline to nadir was 95.4%, 96.1%, and 82.2%, respectively.
• Of the 16 efficacy evaluable patients, 14 had excellent or good hemostatic efficacy at 12 hours after andexanet treatment, all 5 patients taking apixaban, 6 of 7 taking XARELTO, and 3 of 4 taking edoxaban. Excellent or good hemostasis was achieved by all 3 patients receiving high dose andexanet and 11 of 13 receiving low dose andexanet.
• Twelve of 19 patients received ≥1 anticoagulation dose within 30 days after treatment; the median time of anticoagulant resumption was 3.5 (IQR, 2.0-8.5) days.
• Over a follow-up period of 30 days, andexanet was generally safe and well tolerated.
  • Treatment emergent adverse events (TEAEs) occurred in 13 of 19 patients (apixaban, n=4; XARELTO, n=5; edoxaban, n=4), with liver dysfunction (XARELTO, n=2; edoxaban, n=2) reported as the most common. A thrombotic event and TEAEs possibly related to treatment occurred in 2 patients each.
  • Serious AEs occurred in 5 patients (taking low dose andexanet), of whom a 91-year-old female taking edoxaban 30 mg once daily for venous thromboembolism (VTE) prevention died on the 28^th day owing to pneumonia and respiratory failure.
  • One patient developed antibodies against andexanet.

Post Hoc Analysis of ANNEXA-4

A post hoc analysis of the ANNEXA-4 study was conducted to evaluate the efficacy and safety of andexanet alfa on anti-FXa activity and hemostatic efficacy in a cohort of patients with GI bleeding.⁸ 

Results

• Of the 479 patients in ANNEXA-4, 109 (mean age, 75.6 years; ~60% were male) had GI bleeding and were included in this study. Atrial fibrillation was the most common cause of anticoagulation; 47.7% of patients received XARELTO, 39.4% received apixaban, 6.4% received edoxaban, and 6.4% received enoxaparin.
• Patients receiving apixaban and XARELTO showed a median percent reduction of ≥90% in anti-FXa activity from baseline to the end of infusion.
• Hemostatic efficacy at 12 hours was adjudicated as good to excellent in 61 of 74 (82.4%) patients in the efficacy population (95% CI, 71.8%-90.3%).
• Thromboembolic event during the 30-day follow-up was reported in 7.3% of patients; 11.9% of patients died within 30 days of enrollment (causes: cardiovascular, n=6; noncardiovascular, n=6; unknown, n=1).

Phase 2 Studies

Lu et al (2020)⁹ conducted two phase 2, randomized, double-blind, placebo-controlled, single-center safety and dose-ranging clinical studies in healthy subjects receiving rivaroxaban or edoxaban to characterize the pharmacokinetic/pharmacodynamic parameters of andexanet alfa during and after administration of an IV bolus or bolus plus infusion. Additionally, the anticoagulant pharmacokinetic profiles of rivaroxaban and edoxaban following andexanet alfa administration were assessed, as were safety and tolerability. Andexanet alfa demonstrated rapid and effective reversal of rivaroxaban- and
edoxaban-induced anticoagulation. Anti-FXa activity decreased significantly within 2 minutes following bolus, with maximum decreases of ~93% (P<0.05) and ~82% (P<0.05), respectively, compared with placebo. Compared with placebo, sustained normalization of thrombin generation for ~2 hours and sustained decrease in unbound anticoagulant (maximum ~80%) for up to ~4 hours following completion of andexanet alfa administration were observed when andexanet alfa was administered as a bolus or as a bolus followed by continuous infusion. Andexanet alfa was well tolerated, with no serious AEs or thrombotic events.

A phase 2 study in healthy subjects confirmed a dose-dependent decrease in anti-FXa activity and a return of anti-FXa activity to placebo levels approximately 2 hours after treatment. AEs in >10% of patients were infusion-related reaction and postural dizziness. No thrombotic events, serious AEs, or severe AEs were reported.¹⁰

Literature Search

A literature search of MEDLINE^®, EMBASE^®, BIOSIS Previews^®, Derwent^® (and/or other resources, including internal/external databases) was conducted on 25 November 2024.