Abstract

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 patients was COVID-19 (14%; 5/36); all occurrences were deemed treatment-unrelated. There was no evidence of drug-induced liver injury in either part of the study. Rapirosiran was associated with a dose-dependent reduction in liver HSD17B13 mRNA in Part B, with a median reduction of 78% at 6 months in the highest-dose (400 mg) group. CONCLUSIONS: Rapirosiran exhibited an encouraging safety and tolerability profile, with a robust reduction in liver HSD17B13 mRNA expression. IMPACT AND IMPLICATIONS: Metabolic dysfunction-associated steatohepatitis (MASH) is a prevalent chronic liver disease associated with a high burden of disease. The hydroxysteroid 17-beta dehydrogenase 13 (HSD17B13) gene is implicated in the pathogenesis of MASH. Rapirosiran offers a novel mechanism to treat MASH by directly reducing hepatic HSD17B13 expression. In this phase I study, rapirosiran demonstrated an encouraging safety and tolerability profile and resulted in a robust reduction in liver HSD17B13 mRNA expression following two subcutaneous doses. The data support further development of rapirosiran as a potential treatment option for patients with MASH, a disease for which there is only one approved pharmacological treatment. CLINICAL TRIAL NUMBER: EUDRA-CT: 2020-000847-29; NCT: 04565717.