What is the current understanding of adanexet alpha's safety and efficacy in clinical trials?

Andexanet Alfa: Summary of the Four ANNEXA Studies

ANNEXA-A and ANNEXA-R: Phase 3 Randomized Controlled Trials in Healthy Volunteers

These foundational trials established andexanet alfa's pharmacologic reversal capacity by demonstrating >90% reduction in anti-factor Xa activity within minutes of administration. 1

Study Design and Population

• Both were randomized, placebo-controlled trials conducted in healthy volunteers dosed to steady-state with either apixaban (ANNEXA-A) or rivaroxaban (ANNEXA-R) 1
• Participants received andexanet alfa as an intravenous bolus followed by a 2-hour infusion versus placebo 1

Key Efficacy Findings

• Apixaban reversal (ANNEXA-A): Andexanet reduced anti-factor Xa activity by 94% compared to 21% with placebo, with effects sustained up to 4 hours 1
• Rivaroxaban reversal (ANNEXA-R): Andexanet reduced anti-factor Xa activity by 92% compared to 18% with placebo 1
• Thrombin generation increased for up to 12 hours after andexanet administration in both studies 1
• These pharmacodynamic results formed the basis for FDA approval in 2018 and EMA approval in 2019 1

Clinical Significance

• The rapid onset (within 2 minutes of bolus administration) and magnitude of reversal established andexanet's mechanism as a decoy molecule that binds factor Xa inhibitors with high affinity 1, 2
• However, these studies in healthy volunteers could not assess clinical hemostatic efficacy or safety in actual bleeding scenarios 1

ANNEXA-4: Phase 3b/4 Prospective Observational Study in Major Bleeding

ANNEXA-4 demonstrated that 82% of patients with acute major bleeding achieved excellent or good hemostatic efficacy at 12 hours, though thrombotic events occurred in 10% within 30 days. 1, 3

Study Design and Patient Population

• Open-label, single-cohort prospective study enrolling 479 patients (mean age 78 years, 46% female) with acute major bleeding within 18 hours of factor Xa inhibitor administration 1, 3
• Most patients were taking apixaban (51%) or rivaroxaban (37%) for atrial fibrillation (81%) 1
• Bleeding sites were predominantly intracranial (69%) or gastrointestinal (23%) 1, 3
• Patients with ICH and Glasgow Coma Score <7 or hematoma volume >60 mL were excluded 1

Dosing Protocol

• Low-dose regimen: 400 mg bolus over 15 minutes followed by 480 mg infusion over 2 hours 1
• High-dose regimen: 800 mg bolus over 30 minutes followed by 960 mg infusion over 2 hours 1
• Dose selection based on specific factor Xa inhibitor, dose, and timing since last intake 1, 2

Primary Efficacy Outcomes

• Anti-factor Xa reduction: Median anti-factor Xa activity decreased by 93% in the efficacy population (n=342 with baseline levels ≥75 ng/mL for apixaban/rivaroxaban or ≥40 ng/mL for edoxaban) 1, 3
• For apixaban: median decreased from 149.7 ng/mL to 11.1 ng/mL (92% reduction; 95% CI 91-93%) 3
• For rivaroxaban: median decreased from 211.8 ng/mL to 14.2 ng/mL (92% reduction; 95% CI 88-94%) 3
• Hemostatic efficacy: 204 of 249 evaluable patients (82%) achieved excellent or good hemostasis at 12 hours using prespecified adjudication criteria 1, 3
• For intracranial hemorrhage specifically, 79% achieved hemostatic success defined as <35% hematoma expansion 1, 4

Safety Outcomes and Critical Limitations

• Thrombotic events: Occurred in 34 patients (10%) within 30 days, with 16 events occurring despite parenteral thromboprophylaxis 1, 4
• Mortality: 49 patients (14%) died within 30 days 3
• None of the patients who experienced thrombotic events had resumed oral anticoagulation at the time of the event 1, 4
• Major limitation: The absence of a control group prevents determination of whether andexanet improved outcomes beyond supportive care and natural drug clearance 1, 5
• Reduction in anti-factor Xa activity was not predictive of hemostatic efficacy overall, though modestly predictive in intracranial hemorrhage patients 3

Edoxaban Subgroup Analysis

• Initial evidence from 36 patients (mean age 82 years, 80.6% with intracranial bleeding) showed andexanet decreased anti-factor Xa activity by 68.9% (95% CI 56.1-77.7%) 1, 6
• Excellent or good hemostasis achieved in 78.6% (95% CI 59.0-91.7%) at 12 hours 6
• Thrombotic events occurred in 11.1% and mortality was 11.1% within 30 days 6
• This use remains off-label and requires further confirmatory data 1, 5

ANNEXA-I: Randomized Controlled Trial in Intracranial Hemorrhage

ANNEXA-I represents the first randomized controlled trial comparing andexanet alfa to usual care in patients with factor Xa inhibitor-associated intracranial hemorrhage. 1

Study Design

• Randomized trial enrolling patients with ICH presenting within 6 hours of symptom onset and 15 hours after last dose of apixaban, edoxaban, or rivaroxaban 1
• Patients randomized to andexanet versus usual care 1
• Primary efficacy endpoint focused on clinical outcomes rather than solely pharmacodynamic measures 1

Current Status and Significance

• The evidence provided does not include complete results from ANNEXA-I, as the text cuts off mid-sentence 1
• This trial is critically important because it addresses the major limitation of ANNEXA-4 by including a control group 1
• Results from this study will provide the first randomized evidence on whether andexanet improves clinical outcomes beyond supportive care 1

Critical Clinical Considerations Across All Studies

Transient Reversal Effect

• The reversal effect is transient, with anti-factor Xa activity returning toward baseline approximately 2 hours after completing the infusion 4, 5
• This emphasizes the need for definitive bleeding control measures concurrent with andexanet administration 4

Thrombotic Risk Management

• Thrombotic events occur in 10-18% of patients within 30 days across studies 2, 4, 5
• Prompt resumption of anticoagulation after bleeding control significantly reduces thrombotic risk 5
• In ANNEXA-4, only 40% of patients restarted anticoagulation, and the thrombotic event rate in this group was 12%, with four events occurring within 3 days of andexanet treatment 7

Laboratory Monitoring Limitations

• Plasma levels of anti-factor Xa agents following andexanet administration cannot be reliably measured with standard anti-Xa assays due to dissociation during dilution 1, 5
• Modified anti-Xa assays with reduced dilution are available in some coagulation laboratories 1
• Viscoelastic tests (ROTEM, ClotPro) can provide additional information about residual anti-factor Xa activity 1

Cost Considerations

• Wholesale acquisition cost: $24,750 for standard dose and $49,500 for high-dose regimen 7
• Medicare provides add-on payment up to $14,063 per qualifying case for IPPS-participating hospitals 7
• Estimated annual drug budget for treating 10-100 patients ranges from $248,000 to $4.95 million 7