Pharmacokinetics and Safety of Pelacarsen, a GalNAc3-Conjugated Antisense Oligonucleotide Targeting Apo(a), in Participants With Mild Hepatic Impairment

Pelacarsen, an antisense oligonucleotide, directly inhibits plasma lipoprotein(a) production; however, it remains unknown whether hepatic impairment (HI) impacts its safety and pharmacokinetics. This single-dose, open-label, parallel-group, phase I study (NCT05026996) assessed the effect of mild HI on the pharmacokinetics, safety, and tolerability of pelacarsen. Participants (aged 18–75 years) with mild HI (n = 8; Child-Pugh Class A) or healthy controls (n = 9; matched for sex, age, and body weight) received a single subcutaneous injection of 80 mg pelacarsen. Pharmacokinetic parameters were determined using non-compartmental methods. Log-transformed pharmacokinetic parameters were analyzed using a statistical model with group and matching covariates as fixed effects. Least-squares geometric means for each group and geometric mean ratios between participants with mild HI and healthy controls were extracted. The geometric mean ratios for pelacarsen maximum observed concentration (C_max), area under the concentration-time curve from time 0 to time of last quantifiable concentration (AUC_last), and AUC from time 0 to infinity (AUC_inf) were, on average, 7%, 37%, and 50% higher, respectively, in participants with mild HI versus matched controls. The corresponding between-participant variability estimates ranged from 43.0% to 55.2%. The mean elimination half-life (T_1/2) was comparable between the two groups (mild HI, 533 h; healthy matched controls, 518 h). No safety concerns were identified in participants with mild HI or in matched controls. Overall, pelacarsen was well tolerated, and mild HI had no significant effect on C_max. The increase in AUC, likely due to slower early-phase disposition, was within the exposure range tested in the first-in-human study and considered safe.