A phase I/II study of ARO-HSD, an RNA interference therapeutic, for the treatment of non-alcoholic steatohepatitis.

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.

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.