Phase I randomized double-blind study of an RNA interference therapeutic targeting HSD17B13 for metabolic dysfunction-associated steatohepatitis

作者：Arun J. Sanyal, Jörg Täubel, Prajakta Badri, Sarah Bond, Nune Makarova, Weizhi Zhao, Swati Duggal, Farshad Kajbaf, Benjamin A. Olenchock, John M. Gansner · 发表于：Journal of Hepatology · 年份：2025 · DOI：10.1016/j.jhep.2025.05.031 · 被引用次数：28 · 研究领域：Hormonal Regulation and Hypertension、Liver Disease Diagnosis and Treatment、Estrogen and related hormone effects

BACKGROUND & AIMS: Genome-wide association studies have identified loss-of-function variants in the hydroxysteroid 17-beta dehydrogenase 13 gene (HSD17B13) associated with reduced risk of chronic liver disease. In this phase I study, we evaluated the safety, tolerability, pharmacokinetics, and pharmacodynamics of rapirosiran, an investigational, N-acetylgalactosamine-conjugated small-interfering RNA targeting liver-expressed HSD17B13 mRNA. METHODS: ALN-HSD-001 was a randomized, double-blind, placebo-controlled, multicenter study conducted in two parts. Part A evaluated single ascending subcutaneous doses of rapirosiran or placebo in 58 healthy adults. Part B evaluated two doses, administered 12 weeks apart, in 46 adults with metabolic dysfunction-associated steatohepatitis (MASH). Patients with MASH underwent liver biopsies during screening and once post-randomization for measurement of HSD17B13 mRNA. The primary endpoint was frequency of adverse events (AEs). Rapirosiran plasma and urine pharmacokinetics and change from baseline in liver HSD17B13 mRNA were secondary endpoints. RESULTS: In Part A, the only AE occurring in ≥10% of rapirosiran-treated individuals was injection-site reaction (11%); all occurrences were mild and transient. There were no treatment-related serious AEs. Plasma concentrations of rapirosiran declined rapidly by 24 h post-dose. Across doses, rapirosiran showed 17%-37% excretion in urine. In Part B, the only AE occurring in ≥10% of rapirosiran-treated p...