A Randomized, Open-Label, Phase I, Single-Dose Study of Antisense Oligonucleotide, Vupanorsen, in Chinese Adults with Elevated Triglycerides

• Published in: Drugs in R&D 2024-06, Vol.24 (2), p.253-262
• Main Authors: Wu, Xiaojie, Yu, Jicheng, Ge, Beikang, Wang, Jeffrey, Han, Xiaoran, Zhang, Chunye, Mao, Xiaomeng, Kalluru, Hindu, Bramson, Candace, Terra, Steven G., Liu, Jing
• Format: Article
• Language: English
• Subjects: Internal Medicine; Medicine; Medicine & Public Health; NCT; NCT04916795; Original; Original Research Article; Pharmacology/Toxicology; Pharmacotherapy
• ISSN: 1174-5886; 1179-6901; 1179-6901
• DOI: 10.1007/s40268-024-00467-5

Background Vupanorsen is a GalNAc 3 -conjugated antisense oligonucleotide targeting angiopoietin-like 3 (ANGPTL3) mRNA shown to reduce atherogenic lipoproteins in individuals with dyslipidemia. Objectives The aim of this study was to satisfy Chinese regulatory requirements and support ethnic sensitivity assessment by evaluating pharmacokinetics (PK), pharmacodynamics (PD), and safety of vupanorsen in healthy Chinese adults with elevated triglycerides (TG). Methods In this phase I, parallel-cohort, open-label study, 18 Chinese adults with elevated fasting TG (≥ 90 mg/dL) were randomized 1:1 to receive a single subcutaneous dose of vupanorsen 80 mg or 160 mg. PK parameters, PD markers (including ANGPTL3, TG, non–high-density lipoprotein cholesterol [non–HDL-C]), and safety were assessed. Results Absorption of vupanorsen was rapid (median time to maximum concentration [ T max ]: 2.0 h for both doses), followed by a multiphasic decline (mean terminal half-life 475.9 [80 mg] and 465.2 h [160 mg]). Exposure (area under curve [AUC] and maximum plasma concentration [ C max ]) generally increased in a greater than dose-proportional manner from 80 mg to 160 mg. Time-dependent reductions in ANGPTL3 and lipid parameters were observed. Mean percentage change from baseline for the 80-mg and 160-mg doses, respectively, were – 59.7% and – 69.5% for ANGPTL3, – 41.9% and – 52.5% for TG, and – 23.2% and – 25.4% for non–HDL-C. No serious or severe adverse events (AEs), deaths, or discontinuations due to AEs were reported. Three participants experienced treatment-related AEs; all were mild and resolved by end of study. Conclusions This study provided the first clinical vupanorsen data in China. In Chinese participants with elevated TG, PK and PD parameters were consistent with those reported previously in non-Chinese participants, including in Japanese individuals. No safety concerns were noted. Trial Registration ClinicalTrials.gov identifier: NCT04916795.