TY - JOUR
T1 - Aramchol in patients with nonalcoholic steatohepatitis
T2 - a randomized, double-blind, placebo-controlled phase 2b trial
AU - the ARREST investigator study group
AU - Ratziu, V.
AU - de Guevara, L.
AU - Safadi, R.
AU - Poordad, F.
AU - Fuster, F.
AU - Flores-Figueroa, J.
AU - Arrese, M.
AU - Fracanzani, Anna L.
AU - Ben Bashat, D.
AU - Lackner, K.
AU - Gorfine, T.
AU - Kadosh, S.
AU - Oren, R.
AU - Halperin, M.
AU - Hayardeny, L.
AU - Loomba, R.
AU - Friedman, S.
AU - Abdelmalek, M.
AU - Angelico, F.
AU - Angelico, M.
AU - Arancibia, J. P.
AU - Bardou-Jacquet, E.
AU - Barrera, F.
AU - Barish, C. F.
AU - Baruch, Y.
AU - Ben-Ari, Z.
AU - Berg, T.
AU - Bourliere, M.
AU - Boursier, J.
AU - Broide, E.
AU - Carmiel, M.
AU - Denham, D. S.
AU - Di Cesare, L.
AU - Dumitrascu, D. L.
AU - Francis, A.
AU - Gawrieh, S.
AU - González- Huezo, M. S.
AU - Hillon, P.
AU - Iracheta, A.
AU - Kayali, Z.
AU - Kupcinskas, L.
AU - Lau, G.
AU - Serfaty, L.
AU - Le Cleach, A.
AU - Loguercio, C.
AU - Manns, M.
AU - Martinez Saldivar, B. I.
AU - Mena, E. A.
AU - Morales Garza, L. A.
AU - Neutel, J. M.
N1 - Funding Information:
Financial support for medical editorial assistance was provided by Galmed Pharmaceuticals. We thank medical writer S Diskin (Bioforum Group) for editorial assistance with this manuscript. This study was sponsored by Galmed Pharmaceuticals. The protocol was written by a panel of experts and sponsor representatives. Authors participated actively in drafting and reviewing the manuscript. The corresponding author had full access to all data in the study and had final responsibility for the decision to submit for publication.
Publisher Copyright:
© 2021, The Author(s), under exclusive licence to Springer Nature America, Inc.
PY - 2021/10
Y1 - 2021/10
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85116816489&partnerID=8YFLogxK
U2 - 10.1038/s41591-021-01495-3
DO - 10.1038/s41591-021-01495-3
M3 - Article
C2 - 34621052
AN - SCOPUS:85116816489
SN - 1078-8956
VL - 27
SP - 1825
EP - 1835
JO - Nature Medicine
JF - Nature Medicine
IS - 10
ER -