Portal de Periódicos da CAPES

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

2021; Nature Portfolio; Volume: 27; Issue: 10 Linguagem: Inglês

10.1038/s41591-021-01495-3

1546-170X

Vlad Ratziu, Ladrón de Guevara, Rifaat Safadi, Fred Poordad, Felipe Fuster, Jose Flores‐Figueroa, Marco Arrese, Anna Ludovica Fracanzani, Dafna Ben Bashat, K. Lackner, Tali Gorfine, Shaul Kadosh, R. Oren, Michael Halperin, Liat Hayardeny, Rohit Loomba, Scott L. Friedman, Manal F. Abdelmalek, Francesco Angelico, M. Angélico, Juan Pablo Arancibia, Edouard Bardou‐Jacquet, Francisco Barrera, Charles F. Barish, Yaacov Baruch, Ziv Ben‐Ari, Thomas Berg, Marc Bourlière, Jérôme Boursier, Efrat Broide, Michal Carmiel, Douglas Denham, L. Di Cesare, Dan L. Dumitrașcu, Adi Francis, Samer Gawrieh, María Saraí González Huezo, Patrick Hillon, A De Molina Iracheta, Zeid Kayali, Limas Kupčinskas, George Lau, Lawrence Serfaty, Aline Le Cleach, C. Loguercio, M.P. Manns, Brittany Saldivar, Edward Mena, Luis Alonso Morales-Garza, J NEUTEL, L R Nikoleishvili, Mazen Noureddin, R. Pais, Alfonso Paredes, Marcelo Paredes, Runa Watkins, Antonio Picardi, Mario Pirisi, Gonzalo Pizarro Jofré, Liliana Preoțescu, Tarek Saadi, Didier Samuel, J.F. Sánchez-Ávila, Ingolf Schiefke, Oren Shibolet, M. Shadab Siddiqui, G. Torres-Mendoza, J.F. Trotter, Eugenia Tsai, Elizabeth C. Verna, E. Zuckerman, Dinah Zur, Arun J. Sanyal,

Liver physiology and pathology

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. In a phase 2b study, inhibition of hepatic stearoyl-CoA desaturase in patients with nonalcoholic steatohepatitis was safe and tolerated; although reductions in liver fat were not significant, changes in liver enzymes and histology were observed.