PMID- 34621052 OWN - NLM STAT- MEDLINE DCOM- 20211112 LR - 20230207 IS - 1546-170X (Electronic) IS - 1078-8956 (Linking) VI - 27 IP - 10 DP - 2021 Oct TI - Aramchol in patients with nonalcoholic steatohepatitis: a randomized, double-blind, placebo-controlled phase 2b trial. PG - 1825-1835 LID - 10.1038/s41591-021-01495-3 [doi] 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. CI - (c) 2021. The Author(s), under exclusive licence to Springer Nature America, Inc. FAU - Ratziu, V AU - Ratziu V AUID- ORCID: 0000-0002-6865-3791 AD - Sorbonne Universite, Institute for Cardiometabolism and Nutrition and Hopital Pitie- Salpetriere, INSERM UMRS 1138 CRC, Paris, France. vlad.ratziu@inserm.fr. FAU - de Guevara, L AU - de Guevara L AD - Hospital Angeles Clinica Londres, Mexico City, Mexico. FAU - Safadi, R AU - Safadi R AD - Hadassah Medical Organization, Hadassah Hebrew University Medical Center, Jerusalem. The Holy Family Hospital, Nazareth, Israel. FAU - Poordad, F AU - Poordad F AD - Texas Liver Institute/UT Health San Antonio San Antonio, San Antonio, TX, USA. FAU - Fuster, F AU - Fuster F AD - Centro de Investigaciones Clinicas Vina del Mar, Vina del Mar, Chile. FAU - Flores-Figueroa, J AU - Flores-Figueroa J AD - JM Research, Cuernavaca, Mexico. FAU - Arrese, M AU - Arrese M AD - Departamento de Gastroenterologia Facultad de Medicina Pontificia Universidad Catolica de Chile Santiago Chile and Centro de Envejecimiento y Regeneracion, Facultad de Ciencias Biologicas, Pontificia Universidad Catolica de Chile, Santiago, Chile. FAU - Fracanzani, Anna L AU - Fracanzani AL AD - Department of Internal Medicine, Ca' Granda IRCCS Foundation, Policlinico Maggiore Hospital, University of Milan, Milan, Italy. FAU - Ben Bashat, D AU - Ben Bashat D AD - Sagol Brain Institute, Tel Aviv Sourasky Medical Center, Sackler Faculty of Medicine & Sagol School of Neuroscience, Tel Aviv University, Tel Aviv, Israel. FAU - Lackner, K AU - Lackner K AD - Institute of Pathology, Medical University of Graz, Graz, Austria. FAU - Gorfine, T AU - Gorfine T AUID- ORCID: 0000-0003-1790-5124 AD - Galmed Pharmaceuticals Ltd, Tel-Aviv, Israel. FAU - Kadosh, S AU - Kadosh S AD - Statexcellence Ltd, Tel-Aviv, Israel. FAU - Oren, R AU - Oren R AD - Galmed Pharmaceuticals Ltd, Tel-Aviv, Israel. FAU - Halperin, M AU - Halperin M AD - Galmed Pharmaceuticals Ltd, Tel-Aviv, Israel. FAU - Hayardeny, L AU - Hayardeny L AD - Galmed Pharmaceuticals Ltd, Tel-Aviv, Israel. FAU - Loomba, R AU - Loomba R AUID- ORCID: 0000-0002-4845-9991 AD - NAFLD Research Center, University of California at San Diego, La Jolla, CA, USA. FAU - Friedman, S AU - Friedman S AUID- ORCID: 0000-0003-1178-6195 AD - Division of Liver Diseases, Icahn School of Medicine at Mount Sinai, New York, NY, USA. CN - ARREST investigator study group FAU - Sanyal, Arun J AU - Sanyal AJ AUID- ORCID: 0000-0001-8682-5748 AD - Department of Gastroenterology, Virginia Commonwealth University, Richmond, VA, USA. LA - eng SI - ClinicalTrials.gov/NCT02279524 PT - Clinical Trial, Phase II PT - Journal Article PT - Randomized Controlled Trial PT - Research Support, Non-U.S. Gov't DEP - 20211007 PL - United States TA - Nat Med JT - Nature medicine JID - 9502015 RN - 0 (Cholic Acids) RN - 0 (Triglycerides) RN - EC 1.14.19.1 (SCD1 protein, human) RN - EC 1.14.19.1 (Stearoyl-CoA Desaturase) RN - EC 2.6.1.2 (Alanine Transaminase) RN - QE1Q24M65Y (aramchol) SB - IM MH - Alanine Transaminase MH - Biopsy MH - Cholic Acids/*administration & dosage/adverse effects MH - Double-Blind Method MH - Female MH - Humans MH - Liver/*drug effects/metabolism/pathology MH - Magnetic Resonance Spectroscopy MH - Male MH - Middle Aged MH - Non-alcoholic Fatty Liver Disease/*drug therapy/genetics/pathology MH - Stearoyl-CoA Desaturase/*genetics MH - Triglycerides/metabolism FIR - Abdelmalek, M IR - Abdelmalek M FIR - Angelico, F IR - Angelico F FIR - Angelico, M IR - Angelico M FIR - Arancibia, J P IR - Arancibia JP FIR - Bardou-Jacquet, E IR - Bardou-Jacquet E FIR - Barrera, F IR - Barrera F FIR - Barish, C F IR - Barish CF FIR - Baruch, Y IR - Baruch Y FIR - Ben-Ari, Z IR - Ben-Ari Z FIR - Berg, T IR - Berg T FIR - Bourliere, M IR - Bourliere M FIR - Boursier, J IR - Boursier J FIR - Broide, E IR - Broide E FIR - Carmiel, M IR - Carmiel M FIR - Denham, D S IR - Denham DS FIR - Di Cesare, L IR - Di Cesare L FIR - Dumitrascu, D L IR - Dumitrascu DL FIR - Francis, A IR - Francis A FIR - Gawrieh, S IR - Gawrieh S FIR - Gonzalez-Huezo, M S IR - Gonzalez-Huezo MS FIR - Hillon, P IR - Hillon P FIR - Iracheta, A IR - Iracheta A FIR - Kayali, Z IR - Kayali Z FIR - Kupcinskas, L IR - Kupcinskas L FIR - Lau, G IR - Lau G FIR - Serfaty, L IR - Serfaty L FIR - Le Cleach, A IR - Le Cleach A FIR - Loguercio, C IR - Loguercio C FIR - Manns, M IR - Manns M FIR - Martinez Saldivar, B I IR - Martinez Saldivar BI FIR - Mena, E A IR - Mena EA FIR - Morales Garza, L A IR - Morales Garza LA FIR - Neutel, J M IR - Neutel JM FIR - Nikoleishvili, L IR - Nikoleishvili L FIR - Noureddin, M IR - Noureddin M FIR - Pais, R IR - Pais R FIR - Paredes, A H IR - Paredes AH FIR - Paredes, M IR - Paredes M FIR - Peters Watkins, R IR - Peters Watkins R FIR - Picardi, A IR - Picardi A FIR - Pirisi, M IR - Pirisi M FIR - Jofre, G P IR - Jofre GP FIR - Preotescu, L IR - Preotescu L FIR - Saadi, T IR - Saadi T FIR - Samuel, D IR - Samuel D FIR - Sanchez Avila, J F IR - Sanchez Avila JF FIR - Schiefke, I IR - Schiefke I FIR - Shibolet, O IR - Shibolet O FIR - Siddiqui, M S IR - Siddiqui MS FIR - Torres-Mendoza, G IR - Torres-Mendoza G FIR - Trotter, J F IR - Trotter JF FIR - Tsai, E IR - Tsai E FIR - Verna, E C IR - Verna EC FIR - Zuckerman, E IR - Zuckerman E FIR - Zur, D IR - Zur D EDAT- 2021/10/09 06:00 MHDA- 2021/11/16 06:00 CRDT- 2021/10/08 07:02 PHST- 2020/09/01 00:00 [received] PHST- 2021/08/09 00:00 [accepted] PHST- 2021/10/09 06:00 [pubmed] PHST- 2021/11/16 06:00 [medline] PHST- 2021/10/08 07:02 [entrez] AID - 10.1038/s41591-021-01495-3 [pii] AID - 10.1038/s41591-021-01495-3 [doi] PST - ppublish SO - Nat Med. 2021 Oct;27(10):1825-1835. doi: 10.1038/s41591-021-01495-3. Epub 2021 Oct 7.