149: Milvexian Does Not Prolong the QTc Interval: A Thorough QT Study in Healthy Subjects

Statement of Purpose, Innovation or Hypothesis: Vascular and thromboembolic diseases remain leading causes of death and disability worldwide. Anticoagulants are an important class of medications that have demonstrated clinical benefits in the prevention and treatment of thrombosis and associated health disorders. Milvexian is an oral, small molecule, active-site inhibitor of activated clotting Factor XI being evaluated in patients at risk for thrombotic events due to atrial fibrillation, ischemic stroke, or acute coronary syndrome. Results from in vitro studies indicated that milvexian inhibited cardiac potassium (hERG/IKr) channel currents with weak to moderate potency at concentrations that greatly exceed unbound concentrations in the plasma of subjects treated with clinically relevant dose regimens of milvexian. The present study, which was conducted after the in vitro study results became available, evaluated the effect of milvexian on cardiac repolarization in healthy subjects, an important aspect of cardiovascular safety.

Description of Methods & Materials: This randomized, double-blind, double-dummy, placebo- and positive-controlled, multiple-dose, 4-treatment, 4-period, crossover study evaluated the effects of milvexian on cardiac repolarization and was conducted in accordance with relevant regulatory guidelines. Healthy subjects were randomly assigned to one of four possible intervention sequence groups and received each of the study treatments listed below for 4 days (one treatment per period) at which steady-state conditions were achieved. A washout period of ≥5 days separated the last dose of the previous treatment and the first dose of the next treatment.

Treatments Administered Orally Twice Daily	Rationale
100 mg milvexian capsule & placebo solution	Highest clinically relevant dose
200 mg milvexian solution & placebo capsule	To achieve supratherapeutic concentrations; milvexian oral bioavailability is greater as a solution vs a capsule
Capsule and solution placebos	Placebo control
Capsule and solution placebos; 400 mg moxifloxacin (capsule) on 4th day	Positive control

During each period, continuous 12-lead Holter electrocardiograms (ECG) were obtained from predose on Day 1 (i.e., baseline) to 24 hours postdose on Day 4. Time-matched triplicate ECGs and pharmacokinetic samples were collected on Day 1 and Day 4. Corrected (QTc) intervals were derived using Fridericia (QTcF, primary), Bazett, and study-specific power methods. Safety and tolerability were also assessed.

Data & Results: Forty-five subjects completed the study. For each QT correction method, the upper limit of the 2-sided 90% confidence interval of the least-squares mean placebo-corrected change from baseline in QTc (ΔΔQTc) was ˂10 msec at all time points on Day 1 and Day 4 (Figure 1). Based on a prespecified linear mixed-effects model, a relationship between ΔΔQTcF and plasma milvexian concentrations was not apparent. Assay sensitivity was demonstrated by moxifloxacin. Both milvexian regimens were generally safe and well tolerated.

Interpretation, Conclusion or Significance: Milvexian does not prolong the QTc interval at concentrations in plasma achieved after a single dose of 100 mg (capsule formulation) or 200 mg (solution) or after twice daily administration of these doses until steady state was achieved. Based on the study results, ongoing Phase 3 studies have implemented standard-of-care ECG assessments that improved study feasibility by significantly reducing burden for study participants and decreasing resource utilization associated with intense ECG monitoring.

Disclosures: PZ, JP, ST, AP, JJPR, and NG are employees of Janssen Research & Development, LLC, a Johnson & Johnson Company; AD is an employee and shareholder of Janssen Research & Development, LLC, a Johnson & Johnson Company; AM is an employee and shareholder of Kura Oncology Inc; AAH is an employee and shareholder of Bristol Myers Squibb; SM is an employee of Bristol Myers Squibb.

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