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

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, M Abdelmalek, F Angelico, M Angelico, J P Arancibia, E Bardou-Jacquet, F Barrera, C F Barish, Y Baruch, Z Ben-Ari, T Berg, M Bourliere, J Boursier, E Broide, M Carmiel, D S Denham, L Di Cesare, D L Dumitrascu, A Francis, S Gawrieh, M S González-Huezo, P Hillon, A Iracheta, Z Kayali, L Kupcinskas, G Lau, L Serfaty, A Le Cleach, C Loguercio, M Manns, B I Martinez Saldivar, E A Mena, L A Morales Garza, J M Neutel, L Nikoleishvili, M Noureddin, R Pais, A H Paredes, M Paredes, R Peters Watkins, A Picardi, M Pirisi, G P Jofre, L Preotescu, T Saadi, D Samuel, J F Sánchez Avila, I Schiefke, O Shibolet, M S Siddiqui, G Torres-Mendoza, J F Trotter, E Tsai, E C Verna, E Zuckerman, D Zur, 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, M Abdelmalek, F Angelico, M Angelico, J P Arancibia, E Bardou-Jacquet, F Barrera, C F Barish, Y Baruch, Z Ben-Ari, T Berg, M Bourliere, J Boursier, E Broide, M Carmiel, D S Denham, L Di Cesare, D L Dumitrascu, A Francis, S Gawrieh, M S González-Huezo, P Hillon, A Iracheta, Z Kayali, L Kupcinskas, G Lau, L Serfaty, A Le Cleach, C Loguercio, M Manns, B I Martinez Saldivar, E A Mena, L A Morales Garza, J M Neutel, L Nikoleishvili, M Noureddin, R Pais, A H Paredes, M Paredes, R Peters Watkins, A Picardi, M Pirisi, G P Jofre, L Preotescu, T Saadi, D Samuel, J F Sánchez Avila, I Schiefke, O Shibolet, M S Siddiqui, G Torres-Mendoza, J F Trotter, E Tsai, E C Verna, E Zuckerman, D Zur

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.

© 2021. The Author(s), under exclusive licence to Springer Nature America, Inc.

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