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A phase I/II study of ARO-HSD, an RNA interference
therapeutic, for the treatment of non-alcoholic steatohepatitis
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Download the PDF here
Dec 2022
Conclusion
This clinical trial was the first to investigate therapeutic modulation of HSD17B13, a genetically validated target for the potential treatment of NASH. ARO-HSD was well tolerated at doses up to 200 mg given once (NHVs) or twice (Days 1 and 29 in patients with confirmed or clinically suspected NASH) with no significant safety or tolerability concerns noted. Reductions in liver HSD17β13 mRNA and protein were observed and corresponded with ALT and AST reductions, which may be a clinically meaningful signal of reduced liver injury. The results of this study provide a rationale for further development of ARO-HSD in a larger phase 2 study with a longer treatment duration and histologic efficacy endpoints.
The HSD17β13 LOF variant gene has been shown to be associated with reduced risk of liver disease, even in individuals carrying the I148M PNPLA3 variant.
Therefore, HSD17β13 knockdown could potentially mitigate the severity of liver disease in patients with genetic polymorphisms of PNPLA3. In our current study, inhibition of HSD17β13 was induced by ARO-HSD in a dose-dependent manner, and the inhibition was consistent across subjects with the PNPLA3 rs738409 CG or GG genotypes that are classically associated with increased risk of NASH, cirrhosis, and hepatocellular carcinoma.
Highlights
• HSD17B13 loss-of-function mutations are protective against alcoholic and non-alcoholic liver disease including NASH.
• ARO-HSD is a hepatocyte targeted siRNA therapeutic designed to silence HSD17B13 expression.
• ARO-HSD demonstrated a favorable safety profile in healthy volunteers and suspected NASH patients.
• Mean change from baseline at Day 71 in hepatic HSD17β13 mRNA was -93.4% (ARO-HSD 200 mg).
• Mean change in alanine aminotransferase from baseline at Day 71 was -42.3% (ARO-HSD 200 mg).
Abstract
Background
Loss-of-function HSD17β13 mutations are protective against development of chronic liver disease. HSD17β13 inhibition represents a potential approach to treat liver disease such as non-alcoholic steatohepatitis (NASH). ARO-HSD is an RNA interference (RNAi) therapeutic designed to selectively reduce expression of HSD17β13 messenger RNA (mRNA) in hepatocytes. The study evaluated the effects of ARO-HSD in normal healthy volunteers (NHVs) and patients with confirmed or clinically suspected NASH.
Methods
This dose-escalating study evaluated the safety, tolerability, and pharmacodynamics of ARO-HSD 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 in patients predose and 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 short in duration. Mean changes from baseline at Day 71 in hepatic HSD17β13 mRNA were -56.9% (25 mg), -85.5% (100 mg), and -93.4% (200 mg). The overall pooled subject HSD17β13 mRNA reduction was 78.6% (p<0.0001). Hepatic HSD17β13 protein levels were similarly reduced across doses. In patients, mean changes in alanine aminotransferase (ALT) from baseline at 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, which is accompanied by reductions in ALT.
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