Highlight
- Rapirosiran is a novel, N-acetylgalactosamine (GalNAc)-conjugated small interfering RNA (siRNA) targeting the liver-expressed HSD17B13 gene, implicated in chronic liver disease.
- In a randomized, double-blind, placebo-controlled Phase I trial (ALN-HSD-001), rapirosiran showed a favorable safety and tolerability profile in both healthy adults and adults with metabolic dysfunction-associated steatohepatitis (MASH).
- Pharmacodynamic assessment revealed a robust, dose-dependent reduction of up to 78% in liver HSD17B13 mRNA expression after two doses over six months in MASH patients.
- These data support further clinical development of rapirosiran as a potential therapeutic option for MASH, addressing a significant unmet medical need.
Study Background and Disease Burden
Metabolic dysfunction-associated steatohepatitis (MASH), previously termed non-alcoholic steatohepatitis (NASH), represents a progressive form of chronic liver disease characterized by hepatic steatosis, inflammation, and fibrotic changes. MASH is strongly associated with metabolic syndrome components, including obesity, type 2 diabetes mellitus, and dyslipidemia, and is projected to become the leading indication for liver transplantation globally. Despite its high prevalence and substantial morbidity and mortality, there remains only a single approved pharmacological treatment option, underscoring a critical unmet need for effective therapies.
Genome-wide association studies have implicated loss-of-function variants in the hydroxysteroid 17-beta dehydrogenase 13 gene (HSD17B13) as being protective against chronic liver disease, including fibrosis and hepatocellular carcinoma. HSD17B13 encodes a liver-specific lipid droplet-associated enzyme believed to modulate lipid metabolism and inflammatory pathways relevant to MASH pathogenesis. These human genetic findings provide a compelling rationale for the therapeutic targeting of HSD17B13 to ameliorate disease progression.
Rapirosiran is an investigational RNA interference (RNAi) therapeutic designed to selectively degrade HSD17B13 mRNA in hepatocytes. By reducing hepatic expression of this pathogenic gene, rapirosiran aims to mitigate liver injury and fibrosis in affected individuals.
Study Design
The ALN-HSD-001 trial was a two-part, randomized, double-blind, placebo-controlled, multicenter Phase I study.
-part A enrolled 58 healthy adults who received single ascending subcutaneous doses of rapirosiran or placebo to characterize safety, tolerability, and pharmacokinetics (PK).
-part B enrolled 46 adults with biopsy-confirmed MASH who received two subcutaneous doses of rapirosiran or placebo 12 weeks apart. Liver biopsies were performed at screening and after treatment to quantify hepatic HSD17B13 mRNA levels.
The primary endpoint in both parts was the frequency and severity of adverse events (AEs), focusing on safety and tolerability. Secondary endpoints included PK profiling of plasma and urine rapirosiran concentrations and changes from baseline in liver HSD17B13 mRNA expression.
Key Findings
Safety and Tolerability
In Part A (healthy adults), rapirosiran was well tolerated across ascending doses. Injection-site reactions were the only adverse events occurring in ≥10% of rapirosiran-treated participants (11%), were mild, and resolved transiently without intervention. No treatment-related serious adverse events were reported. Plasma concentrations of rapirosiran declined rapidly within 24 hours post-dose, and urinary excretion ranged between 17% and 37% across doses.
In Part B (MASH patients), the most common adverse event occurring in ≥10% of rapirosiran recipients was COVID-19 infection (14%; 5/36 cases), all deemed unrelated to the study drug. Importantly, no cases of drug-induced liver injury were observed in either study part, affirming the hepatic safety profile of rapirosiran.
Pharmacodynamics
Rapirosiran demonstrated a potent, dose-dependent inhibition of HSD17B13 mRNA expression in liver biopsy specimens obtained post-treatment. The highest-dose group (400 mg) showed a median reduction of 78% in liver HSD17B13 mRNA at 6 months compared to baseline, signaling effective target engagement in the MASH patient population.
The magnitude and durability of HSD17B13 suppression align with the mechanism of RNAi therapeutics and have important implications for ameliorating pathogenic processes in MASH.
Expert Commentary
This study validates the translational approach of leveraging human genetics to guide RNAi drug development in chronic liver disease. The favorable safety profile of rapirosiran in both healthy volunteers and patients with MASH is especially promising because many investigational agents in this field have encountered adverse hepatic or systemic effects.
Moreover, the achievement of substantial hepatic target mRNA knockdown with only two doses spaced 12 weeks apart reflects the pharmacological advantages of GalNAc-conjugated siRNAs, which facilitate hepatocyte-specific delivery and prolonged activity.
However, this phase I study is limited by its relatively small sample size and short duration. While robust on-target pharmacodynamic effects were observed, clinical efficacy in terms of histological improvement, fibrosis regression, or biochemical markers was not captured and remains to be demonstrated in future trials.
The absence of drug-induced liver injury is reassuring but longer-term safety monitoring will be essential given the chronic nature of MASH treatment.
Conclusion
Rapirosiran represents an innovative RNAi therapeutic targeting HSD17B13, a gene genetically linked to reduced risk of chronic liver disease. This phase I randomized, double-blind, placebo-controlled trial demonstrates that rapirosiran is safe, well tolerated, and effectively reduces hepatic HSD17B13 mRNA expression in adults with MASH.
These promising results lay the groundwork for subsequent phase II/III studies assessing rapirosiran’s clinical efficacy and long-term safety. Given the limited treatment landscape for MASH, rapirosiran offers a novel mechanism to modify disease pathogenesis and potentially improve patient outcomes.
Ongoing and future investigations will determine whether the potent gene silencing achieved translates into meaningful therapeutic benefits in MASH and related metabolic liver diseases.
References
1. Sanyal AJ, Taubel J, Badri P, et al. Phase I randomized double-blind study of an RNA interference therapeutic targeting HSD17B13 for metabolic dysfunction-associated steatohepatitis. J Hepatol. 2025 Oct;83(4):838-848. doi: 10.1016/j.jhep.2025.05.031 IF: 33.0 Q1 . Epub 2025 Jun 27. PMID: 40581300 IF: 33.0 Q1 .
2. Abul-Husn NS, Cheng X, Li AH, et al. A Protein-Truncating HSD17B13 Variant and Protection from Chronic Liver Disease. N Engl J Med. 2018;378(12):1096-1106. doi:10.1056/NEJMoa1702192 .
3. Younossi ZM, Koenig AB, Abdelatif D, Fazel Y, Henry L, Wymer M. Global Epidemiology of Nonalcoholic Fatty Liver Disease—Meta-Analytic Assessment of Prevalence, Incidence, and Outcomes. Hepatology. 2016;64(1):73-84. doi:10.1002/hep.28431 IF: 15.8 Q1 .