RNAi therapeutic shows promise in protection against NASH
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A novel GaINAc-conjugated RNAi therapeutic meant to replicate the protective nature of a mutation showed promising efficacy in a proof-of-concept study in the first five patients treated with the medication.
“This is really a pivotal point in NASH therapeutics where we are starting to see treatment of NASH related to what we’ve learned from genetic underpinnings related to NASH pathogenesis,” Rohit Loomba, MD, of University of California, San Diego, said during a press conference at the International Liver Congress.
Loomba explained that a known loss-of-function mutation in HASD17B13 confers protection against a variety of liver diseases including alcoholic and non-alcoholic steatohepatitis.
“ARO-HSD (Arrowhead Pharmaceuticals) is an RNA interferon-based therapeutic designed to selectively target HSD17B13 in mRNA in hepatocytes, thereby reducing the expression of the protein and potentially improving downstream liver injury related to steatohepatitis,” he said.
This first-in-human study treated both healthy volunteers and five patients with NASH or suspected NASH.
Healthy participants received subcutaneous injections of ARO-HSD in single-dose escalation, ranging from 25 mg to 200 mg and followed to day 113. The five patients with NASH received 100 mg of ARO-HSD and completed the day 71 biopsy, Loomba said.
The researchers used laboratory measures of liver function to assess safety along with biopsies at baseline and day 71.
The novel therapy was well tolerated by both groups of patients with no treatment-related serious adverse events reported and no discontinuations due to adverse events. There were no grade 3 or 4 laboratory abnormalities.
In the five patients treated with ARO-HSD, Loomba showed that hepatic HSD17B13 decreased by a mean of 84% (62-96) from baseline. Two of the five showed a protein decrease of 92% and 97%, respectively, while the other three showed measurements below the level of quantification after the day 71 biopsy. The mean decrease in ALT was 46% (26-53) from baseline at day 85.
“This is again proof of concept – just the first five patients with NASH,” Loomba said. “ARO HSD was well tolerated with confirmed evidence of gene target silencing based upon the protein and mRNA production and associated with reduction in mean ALT as well. These data support continued development of ARO HSD in patients with non-alcoholic steatohepatitis.”
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Loomba R. LBP-2580. Presented at the International Liver Congress (Virtual); June 23-26, 2021.
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