RNA therapeutics
Mild hepatic impairment modestly raises pelacarsen exposure but does not compromise its safety, phase 1 study finds (Clin Transl Sci 2025)
Original title: Pharmacokinetics and Safety of Pelacarsen, a GalNAc3-Conjugated Antisense Oligonucleotide Targeting Apo(a), in Participants With Mild Hepatic Impairment
This single-dose, open-label, parallel-group phase 1 study (NCT05026996) tested whether mild hepatic impairment affects the pharmacokinetics and safety of pelacarsen, an antisense oligonucleotide that directly inhibits hepatic Lp(a) production. Eight participants with mild hepatic impairment (Child-Pugh Class A) and nine matched healthy controls each received a single 80 mg subcutaneous dose. Geometric mean ratios for maximum concentration, AUC to last quantifiable concentration, and AUC to infinity were on average 7%, 37% and 50% higher, respectively, in the mild hepatic impairment group versus controls, with between-participant variability of 43.0% to 55.2%; elimination half-life was comparable between groups (533 vs. 518 hours). No safety concerns emerged in either group, and the modest AUC increase, attributed to slower early-phase disposition, fell within the exposure range already tested safely in first-in-human studies, supporting pelacarsen's use without dose adjustment in patients with mild liver impairment.
Original abstract
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 (Cmax), area under the concentration-time curve from time 0 to time of last quantifiable concentration (AUClast), and AUC from time 0 to infinity (AUCinf) 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 (T1/2) 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 Cmax. 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.
Summary written by lp-a.org from the published abstract; figures as published. Page updated 17 August 2026. Methods.