Abstract 4135023: Effect of mild hepatic impairment on the pharmacokinetics of pelacarsen

Introduction: Pelacarsen, a hepatocyte-directed, N-acetyl galactosamine (GalNAc 3 )–conjugated antisense oligonucleotide, reduces plasma lipoprotein(a) levels by inhibiting apolipoprotein(a) translation. Pelacarsen uptake is mediated by GalNAc 3 binding to the hepatocyte-specific asialoglycoprotein receptor. Hypothesis: It is unknown whether hepatic impairment (HI) impacts pelacarsen uptake and systemic exposure. Aim: This single-dose, open-label, parallel-group, Phase 1 study (NCT05026996) assessed the pharmacokinetics (PK), safety, and tolerability of a single 80 mg subcutaneous dose of pelacarsen in participants with mild HI compared to healthy controls (normal hepatic function). Methods: Eight adults with prior liver cirrhosis and mild HI (Child-Pugh Class A) were matched for sex, age, and body weight with nine healthy controls. PK parameters (C max , AUC 0-72, AUC last , and AUC inf ) were determined using non-compartmental methods. Log-transformed PK parameters were analyzed using a statistical model with group and matching covariates as fixed effects. Least-square geometric means for each group and geometric mean ratios between participants with mild HI and healthy controls were extracted. Safety was also assessed. Results: Pelacarsen C max , AUC last, and AUC inf were, on average, 7%, 37%, and 50% higher, respectively, in participants with mild HI versus matched controls. All 90% confidence intervals around the HI versus healthy control geometric mean ratios included 1 ( Table ). The ranges of all PK parameters and estimated half-lives were similar between groups. In participants with mild HI, pelacarsen exposure approached the same level as controls after eight hours post-dose ( Figure ). No serious adverse events occurred. Conclusion(s): In participants with mild HI, pelacarsen was well tolerated. Mild HI had no significant effect on pelacarsen C max . The non-statistically significant transient increase in AUC was within the exposure range tested in the first-in-human study.