Evaluation of clinical cardiac safety of zilurgisertib, an activin receptor-like kinase-2 (ALK2) inhibitor, in healthy participants.

The oral, small molecule inhibitor of activin receptor-like kinase-2, zilurgisertib (INCB000928), is under evaluation in fibrodysplasia ossificans progressiva. Cardiac safety was assessed using electrocardiogram (ECG) parameters and a plasma concentration-heart rate-corrected QT (C-QTc) interval analysis of pooled data from single ascending dose (SAD) and multiple ascending dose (MAD) studies of zilurgisertib in healthy adult participants (SAD: 10-500 mg; INCB00928-102: 50-400 mg QD, 300 mg BID). Overall, 91 (SAD) and 79 (MAD) participants provided at least one pair of PK/ECG data. As both studies indicated a dose-dependent effect of zilurgisertib on heart rate, individualized QT correction (QTcI) was used as the primary endpoint for QTc analysis. Estimated population slope of the individualized C-ΔQTc (C-ΔQTcI) relationship was shallow (0.02 ms per µm [90% CI, -0.60, 0.65]) and not statistically significantly different from 0; treatment effect-specific intercept was small and not significant (-0.83 ms [90% CI, -2.26, 0.61]). No significant relationship between zilurgisertib plasma concentration and change in QTcI was identified; zilurgisertib did not have a clinically relevant effect on QTc prolongation. QT effect >10 ms could therefore be excluded within the dose range studied (up to 300 mg BID). No clinically meaningful effects on cardiac conduction (PR and QRS intervals) or any categorical PR or QRS outliers were observed. These data support further clinical development of zilurgisertib.