Abstract
AIM: Small-molecule activin receptor-like kinase-2 inhibitor zilurgisertib (INCB000928) is under investigation in a pivotal trial for the treatment of fibrodysplasia ossificans progressiva (FOP), an ultrarare genetic condition. This analysis assessed effects of renal and hepatic impairment on zilurgisertib pharmacokinetics. METHODS: Two open-label, parallel-group studies were conducted. Participants with renal or hepatic impairment were matched with healthy controls and received a single 200-mg dose of zilurgisertib; those with end-stage renal disease (ESRD) received doses before and after haemodialysis. Plasma concentrations were quantified via validated assay; pharmacokinetic parameters were derived from non-compartmental analysis. Geometric mean ratios (GMRs) and 90% confidence intervals (CIs) for C(max), AUC(0-t) and AUC(0-∞) were compared by ANOVA. RESULTS: Compared with matched controls, GMRs (90% CIs) for C(max) and AUC(0-∞) were as follows: mild renal impairment, 0.92 (0.64-1.34) and 0.98 (0.77-1.24); moderate, 1.22 (0.92-1.63) and 1.64 (1.28-2.10); severe, 1.00 (0.74-1.35) and 1.70 (1.33-2.16), respectively. Among participants with ESRD, values were the following: before haemodialysis, 1.17 (0.91-1.49) and 1.47 (1.15-1.88); after, 1.32 (1.00-1.75) and 1.68 (1.29-2.19), respectively. Among participants with hepatic impairment, values were as follows: moderate, 1.06 (0.80-1.42) and 1.13 (0.93-1.38); severe: 1.36 (1.05-1.76) and 1.25 (1.06-1.48), respectively. CONCLUSIONS: Zilurgisertib exposure was unchanged with mild renal or moderate hepatic impairment, but increased by 30%-70% with moderate or more severe renal impairment and by 25% with severe hepatic impairment. These findings, alongside the therapeutic index, to be defined by the ongoing pivotal FOP trial (NCT05090891), will guide dosing in these populations.