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 HSD17613 mutations protect against the development of chronic liver disease. HSD17613 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 HSD17#13 mRNA in hepatocytes. In this study, we evaluated the effects of ARO-HSD in normal healthy volunteers (NHVs) and patients with confirmed or clinically sus-pected 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 HSD17#13 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 HSD17#13 mRNA from baseline to Day 71 were:-56.9% (25 mg),-85.5% (100 mg), and-93.4% (200 mg). The mean HSD17#13 mRNA reduction was 78.6% (p <0.0001) across pooled cohorts. Hepatic HSD17613 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 HSD17#13 mRNA and protein expression, which is accompanied by reductions in alanine aminotransferase.