A phase I/II study of ARO-HSD, an RNA interference therapeutic, for the treatment of non-alcoholic steatohepatitis
Abstract
Background & aims Loss-of-function HSD17β13 mutations protect against the development of chronic liver disease. HSD17β13 inhibition represents a potential approach to treat liver diseases, such as non-alcoholic steatohepatitis (NASH). ARO-HSD is an RNA interference (RNAi) therapeutic designed to selectively reduce expression of HSD17β13 mRNA in hepatocytes. In this study, we evaluated the effects of ARO-HSD in normal healthy volunteers (NHVs) and patients with confirmed or clinically suspected NASH.Methods The safety, tolerability, and pharmacodynamics of ARO-HSD were evaluated in 32 NHVs and 18 patients with confirmed/clinically suspected NASH. Double-blind NHV cohorts received single escalating doses of ARO-HSD (25, 50, 100, or 200 mg) or placebo subcutaneously on Day 1. Open-label patient cohorts received ARO-HSD (25, 100, or 200 mg) subcutaneously on Days 1 and 29. Liver biopsy was performed pre-dose and on Day 71 to evaluate expression levels of HSD17β13 mRNA and protein.Results ARO-HSD treatment was well tolerated with no treatment-related serious adverse events or drug discontinuations. The most frequently reported treatment-emergent adverse events were mild injection site reactions, which were short in duration. Mean changes in hepatic HSD17β13 mRNA from baseline to Day 71 were: -56.9% (25 mg), -85.5% (100 mg), and -93.4% (200 mg). The mean HSD17β13 mRNA reduction was 78.6% (p <0.0001) across pooled cohorts. Hepatic HSD17β13 protein levels were similarly reduced across doses. In patients, mean changes in alanine aminotransferase from baseline to Day 71 were -7.7% (25 mg), -39.3% (100 mg), and -42.3% (200 mg) (p <0.001 for pooled cohorts).Conclusions ARO-HSD was well tolerated at doses ≤200 mg. This proof-of-concept study demonstrated that short-term treatment with ARO-HSD reduces hepatic HSD17β13 mRNA and protein expression, which is accompanied by reductions in alanine aminotransferase.Clinicaltrials Gov number NCT04202354.Impacts and implications There is an unmet medical need for new therapies to treat alcohol-related and non-alcoholic liver disease. ARO-HSD is a small-interfering RNA designed to silence HSD17β13 expression and hence to phenocopy the protective effect seen in individuals with HSD17β13 loss-of-function. The reductions in HSD17β13 expression and in transaminases seen with ARO-HSD administration represent an initial step towards clinical validation of HSD17β13, a drug target with substantial genetic validation, as an important modulator of human liver disease.
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Genetic variants in PNPLA3 and HSD17B13 can be targeted by RNA interference therapies that are under evaluation in clinical studies on individuals with MASLD carrying at-risk genotypes, but there is not yet any clinical indication for genotyping outside the clinical research setting.
“Genetic variants in PNPLA3 and HSD17B13 can be targeted by RNA interference therapies that are under evaluation in clinical studies on individuals with MASLD carrying at-risk genotypes, but there is not yet any clinical indication for genotyping outside the clinical research setting. 214,215”
From EASL-EASD-EASO Clinical Practice Guidelines on the management of metabolic dysfunction-associated steatotic liver disease (MASLD). (2024) · cites this paper as [214]
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- Authors
- Mak, L.-Y., Gane, E., Schwabe, C., Yoon, K. T., Heo, J., Scott, R., Lee, J.-H., Lee, J. I., Kweon, Y. O., Weltman, M., Harrison, S. A., Neuschwander-Tetri, B. A., Cusi, K., Loomba, R., Given, B. D., Christianson, D. R., Garcia-Medel, E., Yi, M., Hamilton, J., & Yuen, M.-F.
- Affiliations
- Queen Mary Hospital (CN)
- University of Auckland (NZ)
- New Zealand Clinical Research (NZ)
- Pusan National University Yangsan Hospital (KR)
- Pusan National University Hospital (KR)
- Seoul National University (KR)
- Kyungpook National University (KR)
- Nepean Hospital (AU)
- Pinnacle Clinical Research (US)
- University of Florida (US)
- University of California San Diego (US)
- Arrowhead Pharmaceuticals (United States) (US)
- Corresponding author
- Yuen, Man-Fung
- ORCID
- Venue
- Journal of Hepatology
- Publisher
- Elsevier BV
- Published
- 2023-04
- Volume
- 78
- Issue
- 4
- Pages
- 684-692
- ISSN
- 0168-8278 (ISSN-L)
- OpenAlex
- W4310975413
- Cited by
- 98
- References
- 21
- Citations by year
- 2026: 37 · 2025: 28 · 2024: 23 · 2023: 9
- FWCI
- 10.83
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Hepatology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Arrowhead Pharmaceuticals
- Topics
- Health Sciences › Medicine › Epidemiology › Liver Disease Diagnosis and Treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Drug-Induced Hepatotoxicity and Protection
- Keywords
- RNA interference therapy, gene silencing, hepatocytes, drug safety and tolerability, pharmacodynamics, alanine aminotransferase, chronic liver disease, dose escalation, healthy volunteers, liver biopsy, proof of concept
- MeSH terms
- Alanine Transaminase, Double-Blind Method, Humans, Liver, Liver Function Tests, Treatment Outcome, RNA Interference, Non-alcoholic Fatty Liver Disease
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