Quantitative Model-Informed Dose Selection for a Milvexian Phase III Study in Patients With Atrial Fibrillation

Area of Science:

• Pharmacology and Thrombosis Research
• Clinical Trial Design and Modeling

Background:

• Milvexian is an investigational activated factor XI inhibitor.
• The LIBREXIA phase III program is evaluating milvexian for thrombotic event prevention, including in atrial fibrillation (AF).

Purpose of the Study:

• To determine an optimal phase III dose regimen for milvexian in atrial fibrillation patients.
• To characterize the exposure-response relationship of milvexian for efficacy, safety, and biomarkers.

Main Methods:

• Population pharmacokinetic and exposure-response modeling using Phase I and II data.
• Model-based meta-analysis of comparator anticoagulants in orthopedic surgery patients.
• Simulations to predict efficacy and safety in an AF population.

Main Results:

• The 100 mg twice-daily milvexian regimen showed a simulated venous thromboembolism rate of 9.4%, lower than enoxaparin.
• No correlation between milvexian exposure and bleeding events was observed.
• Simulated systemic embolism odds ratio was 0.84 compared to apixaban in AF patients.

Conclusions:

• The integrated model-informed approach supports 100 mg twice-daily milvexian for the LIBREXIA AF phase III study.
• This dose regimen appears to offer a favorable balance of efficacy and safety for stroke prevention in AF.