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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.

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Fig. 1: Trial patient disposition.
Fig. 2: Histological and biochemical efficacy results.

Data availability

The data supporting the findings of this study are owned by Galmed Research and Development Ltd. (Galmed) and contains potentially identifying or sensitive patient information since it includes, among others, human research participant data. Therefore, data are not publicly available due to patients’ right of privacy and confidentiality as well as ethical and commercial limitations imposed on Galmed. On request, Galmed will consider sharing certain datasets in accordance with applicable local laws as well as patient consent. Data sharing requests should include the type of data requested, the reason the data is requested and the intended use of the data.

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Acknowledgements

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.

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Contributions

V.R. designed the study, was responsible for patient recruitment and treatment, data analysis and interpretation, is a member of the study advisory committee and wrote the manuscript. L.d.G. was a principal investigator responsible for patient recruitment and treatment and is a member of the study advisory committee. R.S., F.P., F.F., A.L.F. and J.F-F. recruited and treated patients. M.A. recruited and treated patients and is a member of the study advisory committee. D.B.B. performed the Central MRI Reading. K.L. performed the Central Pathology Reading. T.G. helped with the data analysis and interpretation and manuscript writing. S.K. helped with the statistical analysis plan, data analysis and interpretation. R.O. helped with study design, data review and interpretation. M.H. helped with study planning and design. L.H. helped with the data analysis and interpretation. R.L. helped with patient recruitment and treatment and is a member of the study advisory committee. S.F. helped with data review and interpretation. A.J.S. was the US lead principal investigator, helped with study design, data analysis and interpretation, supported the setup of the MRS Central Reading and is a member of the study advisory committee. Members of the ARREST investigator study group helped in patient recruitment and treatment.

Corresponding author

Correspondence to V. Ratziu.

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Competing interests

V.R. and R.L. are Galmed consultants and investigators in the Galmed-sponsored study described in the article. S.F. and A.J.S. are Galmed consultants, T.G., M.H., R.O. and L.H. are current or former Galmed employees, D.B.B. was responsible for central lab services for the Galmed-sponsored study described in the article. K.L. was responsible for the histological analysis services for the Galmed-sponsored study described in the article. S.K. is the Galmed statistician. L.d.G., R.S., F.P., F.F., J.F-F., M.A. and A.L.F. were Investigators in the Galmed-sponsored study described in the article. The ARREST investigator study group members were investigators or sub-investigators in the Galmed-sponsored study described in the article.

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Peer review information Nature Medicine thanks Vincent Wong and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Jennifer Sargent was the primary editor on this article and managed its editorial process and peer review in collaboration with the rest of the editorial team.

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Ratziu, V., de Guevara, L., Safadi, R. et al. Aramchol in patients with nonalcoholic steatohepatitis: a randomized, double-blind, placebo-controlled phase 2b trial. Nat Med 27, 1825–1835 (2021). https://doi.org/10.1038/s41591-021-01495-3

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