072: Pharmacokinetics & Pharmacodynamics of Milvexian After Administration Every 12 Hours in Healthy Subjects

Statement of Purpose, Innovation or Hypothesis: Despite advances in antithrombotic treatment, available anticoagulation therapy is associated with increased bleeding risk and therefore thrombotic risk remains for select patient populations. Preclinical, clinical, and epidemiological evidence indicates FXIa inhibition may reduce the burden of thromboembolic cardiovascular diseases while preserving hemostasis. Milvexian, an oral factor XIa inhibitor, is being evaluated in patients at risk for thrombosis due to atrial fibrillation, stroke, or acute coronary syndrome. This Phase 1 study characterized the pharmacokinetics (PK) and safety of milvexian after administration every 12 hours (q12h) and effects on activated partial thromboplastin time (aPTT) to inform on potential dosing regimens in future trials.

Description of Methods & Materials: Parallel groups of healthy adults were randomly assigned to one of the following treatments (milvexian [n=9] or placebo [n=3]) in a double-blind manner: 25 mg, 50 mg, 100 mg, or 200 mg of milvexian (as 25-mg or 100-mg spray-dried solid dispersion capsules) or placebo administered q12h for 8 days. Subjects fasted overnight before dosing on Days 1 and 8. On Days 2 to 7, breakfast was provided at 1 hour postdose. On Days 1 to 8, relative to the morning dose, subjects received meals at 4 and 8 hours, and the evening dose and a snack at 12 hours. Plasma PK samples were collected on Days 1 and 8 (full profiles) and on Days 3 to 7 (troughs). Milvexian concentrations were measured with a validated assay (liquid chromatography with tandem mass spectrometry). Noncompartmental PK parameters were calculated. aPTT was measured on Days 1 and 8.

Data & Results: Forty-eight participants were enrolled and completed the study-related procedures. Maximum milvexian concentrations (C_max) were achieved at 3 hours (median) on Days 1 and 8 for all doses. At the clinically relevant doses of 25 mg and 100 mg, there were small deviations from dose-proportionality for the geometric mean C_max area under the curve over 12 hours (AUC_12h) after the first dose on Day 1 and after q12h administration on Day 8. At 25 mg and 100 mg q12h, geometric mean C_max and AUC_12h accumulation ratios (Day 8 vs Day 1) ranged from 2.1 to 3.3 and geometric mean trough concentrations were 2.1-fold and 2.9-fold higher, respectively, on Day 8, relative to Day 1. Milvexian reversibly prolonged aPTT, relative to baseline (predose on Day 1), with a time course that was consistent with the plasma concentration-time profile. After a single dose and administration q12h, the percent increase from baseline in aPTT was both dose- and concentration-dependent, whereas there were negligible changes in aPTT for the pooled placebo group. The milvexian regimens were generally safe and well tolerated.

Interpretation, Conclusion or Significance: Milvexian PK properties and aPTT prolongation produced by q12h administration were supportive of further clinical development. The results were a complementary component in design, including milvexian regimen, of subsequent trials.

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

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Additional Information/Authors: None