Alnylam Pharmaceuticals, Inc. announced preliminary Phase 1 data supporting the clinical advancement of ALN-HSD, an investigational RNAi therapeutic targeting HSD17B13 in development for the treatment of nonalcoholic steatohepatitis (NASH). After single-dose evaluation in healthy adult volunteers (Part A), multiple doses of ALN-HSD are being studied in adult patients with NASH (Part B). Patients in the first two Part B cohorts (200 and 400 mg quarterly) have completed at least 6 months on the study; remaining cohorts are exploring a lower dose or a later biopsy time point.

In the first two Part B cohorts, ALN-HSD was associated with robust target knockdown and numerically lower liver enzymes and biopsy-derived nonalcoholic fatty liver disease (NAFLD) Activity Score (NAS)* over six months in patients receiving ALN-HSD (N=20) relative to placebo (N=4). The study was not powered to achieve statistical significance on these endpoints, and the primary outcome measure is frequency of adverse events. ALN-HSD has exhibited an encouraging safety and tolerability profile to date; the most common treatment-emergent adverse event in healthy subjects treated with ALN-HSD (N=44) was injection site reaction in five patients; all injection site reactions were mild in severity.

No treatment-related serious adverse events have been reported in either healthy volunteers or patients with NASH to date. Based on these results, the companies plan to initiate a Phase 2 study in adult patients with NASH in late 2022. The NAFLD Activity Score (NAS) is a widely accepted scoring system developed by the NASH Clinical Research Network for use in clinical trials.

The score is based on histological assessment of liver biopsies and is comprised of a sum of steatosis, ballooning, and lobular inflammation component scores. The Phase 1 trial is a randomized, double-blind, placebo-controlled, multi-center, single-ascending dose (SAD) and multiple-dose (MD) study designed to evaluate the safety, tolerability, pharmacokinetic (PK) and pharmacodynamic (PD) effects of ALN-HSD in healthy adult subjects and adult patients with NASH. The primary endpoint of the study is the frequency of adverse events.

The study was conducted in two parts. Part A enrolled 58 healthy adult subjects randomized 3:1 to receive a single ascending dose of 25, 100, 200, 400, or 800 mg of ALN-HSD or placebo; Part A of the study is complete. Part B enrolled 45 patients with NASH randomized 4:1 to receive two doses of 25, 200, or 400 mg of ALN-HSD or placebo, quarterly.

Patients in the first two cohorts (200 and 400 mg) have completed at least 6 months on the study; remaining cohorts are exploring a lower dose or a later biopsy time point. Secondary and exploratory endpoints of the study include the characterization of plasma and urine PK of ALN-HSD and the evaluation of the drug PD effect.