A Thorough QT Study to Assess the Effects of Milvexian on Cardiac Repolarization in Healthy Participants

TL;DR

This study evaluated the heart safety of milvexian, finding no significant QT interval prolongation in healthy participants.

Contribution

Demonstrated that milvexian does not prolong QTc intervals at clinically relevant concentrations.

Findings

The upper limit of the 90% confidence interval for ΔΔQTcF was less than 10 ms for all milvexian regimens.

Milvexian had weak-to-moderate potency on ion channels at concentrations higher than those observed in participants.

Milvexian was safe and well tolerated in all treatment periods.

Abstract

Milvexian is an oral factor XIa inhibitor in development for prevention of major thromboembolic conditions. This randomized, double‐blind, placebo‐ and positive‐controlled, multiple‐dose, four‐period crossover study assessed the cardic safety of milvexian (including effects on the QT interval of the electrocardiogram), with a supporting in vitro component. Sixty‐six participants were enrolled. In each treatment period, participants received milvexian (100 or 200 mg) or placebo every 12 h for 4 days. A single‐dose moxifloxacin (400 mg) served as a positive control. Electrocardiographs and time‐matched pharmacokinetic samples were collected during each period. In mixed‐effects models, the upper limit of the two‐sided 90% confidence interval for the least squares means for change from baseline QTc (Fridericia [QTcF], as the primary correction method) for milvexian versus placebo (ΔΔQTc) was ˂10 ms at all time points after each milvexian regimen. In addition, there was no apparent relationship between ΔΔQTcF and plasma milvexian concentrations. Moxifloxacin response confirmed assay sensitivity. Milvexian inhibited human ether‐a‐go‐go‐related gene potassium, sodium, and L‐type calcium ion channel currents with weak‐to‐moderate potency at concentrations exceeding the highest mean unbound maximum plasma concentrations of TQT study participants. Milvexian regimens were safe and well tolerated. These data indicate that milvexian does not prolong the QTc interval at clinically relevant concentrations.

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