LIBREXIA Study Overview
The LIBREXIA studies are a series of Phase 3 clinical trials investigating milvexian, an oral Factor XIa inhibitor, for stroke prevention in atrial fibrillation (LIBREXIA AF) and secondary prevention after acute coronary syndrome (LIBREXIA ACS). 1, 2
LIBREXIA AF Trial
Milvexian 100 mg twice daily is being compared to apixaban (5 mg or 2.5 mg per label indication) twice daily for stroke prevention in patients with atrial fibrillation or atrial flutter. 1
Trial Design
- Enrollment target: 15,500 participants from approximately 1,000 sites across 30+ countries 1
- Primary efficacy endpoint: Noninferiority of milvexian versus apixaban for prevention of stroke and systemic embolism 1
- Principal safety endpoint: Superiority of milvexian in reducing ISTH major bleeding events and the composite of major plus clinically relevant nonmajor (CRNM) bleeding 1
- Expected duration: Approximately 4 years until 430 primary efficacy events and 530 principal safety events are observed 1
Rationale for Factor XIa Inhibition
- People with Factor XI deficiency have lower rates of ischemic stroke than the general population with infrequent spontaneous bleeding, suggesting Factor XI plays a more important role in thrombosis than hemostasis. 3
- Direct oral anticoagulants remain the standard of care for stroke prevention in atrial fibrillation, but bleeding concerns limit their use. 1
- Milvexian may offer similar anticoagulant efficacy with reduced bleeding risk compared to traditional anticoagulants. 1
LIBREXIA ACS Trial
Milvexian 25 mg twice daily is being tested in addition to conventional antiplatelet therapy after recent acute coronary syndrome. 2
Trial Design
- Enrollment target: Approximately 16,000 patients 2
- Eligibility criteria: Symptoms of spontaneous ischemia, ACS diagnosis with cardiac biomarker elevation within 7 days before randomization, plus at least 2 risk-enhancing factors 2
- Primary efficacy endpoint: Time to first occurrence of cardiovascular death, myocardial infarction, or ischemic stroke (target 875 events) 2
- First major secondary endpoint: Time to cardiovascular death, MI, ischemic stroke, major adverse limb events, and symptomatic venous thromboembolism 2
- Principal safety endpoint: Bleeding Academic Research Consortium 3c or 5 bleeding 2
Clinical Context
- Despite current antiplatelet therapy, patients remain at risk of recurrent ischemic events after ACS, which may reflect persistently elevated thrombin generation. 2
- Factor XIa inhibition reduces thrombin generation and may improve clinical outcomes with minimal bleeding risk. 2
- This will be the first trial testing whether Factor XIa inhibition added to standard antiplatelet therapy reduces major adverse cardiovascular events without increased significant bleeding. 2
Phase 2 Data (AXIOMATIC-SSP)
In the Phase 2 AXIOMATIC-SSP trial for secondary stroke prevention, milvexian added to dual antiplatelet therapy did not substantially reduce symptomatic ischemic stroke or covert brain infarction, and did not meaningfully increase major bleeding risk. 3
Key Findings
- No significant dose-response was observed among five milvexian doses (25 mg once daily, 25 mg twice daily, 50 mg twice daily, 100 mg twice daily, 200 mg twice daily) for the primary composite efficacy outcome. 3
- Major bleeding rates were low across all groups (1-2%) with no apparent dose-response relationship. 3
- These findings informed the design of the Phase 3 LIBREXIA trials. 3
Important Distinction
The LIBREXIA studies should not be confused with the LIBRA trial, which is investigating short versus long-term levetiracetam use in brain tumor patients with seizures—an entirely unrelated study. 4