Aramchol in patients with nonalcoholic steatohepatitis: a randomized, double-blind, placebo-controlled phase 2b trial.

Abstract

Nonalcoholic steatohepatitis (NASH), a chronic liver disease without an approved therapy, is associated with lipotoxicity and insulin resistance and is a major cause of cirrhosis and hepatocellular carcinoma. Aramchol, a partial inhibitor of hepatic stearoyl-CoA desaturase (SCD1) improved steatohepatitis and fibrosis in rodents and reduced steatosis in an early clinical trial. ARREST, a 52-week, double-blind, placebo-controlled, phase 2b trial randomized 247 patients with NASH (n = 101, n = 98 and n = 48 in the Aramchol 400 mg, 600 mg and placebo arms, respectively; NCT02279524 ). The primary end point was a decrease in hepatic triglycerides by magnetic resonance spectroscopy at 52 weeks with a dose of 600 mg of Aramchol. Key secondary end points included liver histology and alanine aminotransferase (ALT). Aramchol 600 mg produced a placebo-corrected decrease in liver triglycerides without meeting the prespecified significance (-3.1, 95% confidence interval (CI) -6.4 to 0.2, P = 0.066), precluding further formal statistical analysis. NASH resolution without worsening fibrosis was achieved in 16.7% (13 out of 78) of Aramchol 600 mg versus 5% (2 out of 40) of the placebo arm (odds ratio (OR) = 4.74, 95% CI = 0.99 to 22.7) and fibrosis improvement by ≥1 stage without worsening NASH in 29.5% versus 17.5% (OR = 1.88, 95% CI = 0.7 to 5.0), respectively. The placebo-corrected decrease in ALT for 600 mg was -29.1 IU l-1 (95% CI = -41.6 to -16.5). Early termination due to adverse events (AEs) was <5%, and Aramchol 600 and 400 mg were safe, well tolerated and without imbalance in serious or severe AEs between arms. Although the primary end point of a reduction in liver fat did not meet the prespecified significance level with Aramchol 600 mg, the observed safety and changes in liver histology and enzymes provide a rationale for SCD1 modulation as a promising therapy for NASH and fibrosis and are being evaluated in an ongoing phase 3 program.

• Authors: V Ratziu, L de Guevara, R Safadi, F Poordad, F Fuster, J Flores-Figueroa, M Arrese, Anna L Fracanzani, D Ben Bashat, K Lackner, T Gorfine, S Kadosh, R Oren, M Halperin, L Hayardeny, R Loomba, S Friedman, ARREST investigator study group, Arun J Sanyal
• Journal: Nature medicine (Nat Med) Vol. 27 Issue 10 Pg. 1825-1835 (10 2021) ISSN: 1546-170X [Electronic] United States
• PMID: 34621052 (Publication Type: Clinical Trial, Phase II, Journal Article, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)
• Copyright: © 2021. The Author(s), under exclusive licence to Springer Nature America, Inc.

Chemical References

• Cholic Acids
• Triglycerides
• SCD1 protein, human
• Stearoyl-CoA Desaturase
• Alanine Transaminase
• aramchol

Topics

• Alanine Transaminase
• Biopsy
• Cholic Acids (administration & dosage, adverse effects)
• Double-Blind Method
• Female
• Humans
• Liver (drug effects, metabolism, pathology)
• Magnetic Resonance Spectroscopy
• Male
• Middle Aged
• Non-alcoholic Fatty Liver Disease (drug therapy, genetics, pathology)
• Stearoyl-CoA Desaturase (genetics)
• Triglycerides (metabolism)