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

Nature Medicine volume 27, pages 1825–1835 (2021)Cite this article

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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.

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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.

Author information

Authors and Affiliations

  1. Sorbonne Université, Institute for Cardiometabolism and Nutrition and Hôpital Pitié- Salpêtrière, INSERM UMRS 1138 CRC, Paris, France

    V. Ratziu

  2. Hospital Ángeles Clínica Londres, Mexico City, Mexico

    L. de Guevara

  3. Hadassah Medical Organization, Hadassah Hebrew University Medical Center, Jerusalem. The Holy Family Hospital, Nazareth, Israel

    R. Safadi

  4. Texas Liver Institute/UT Health San Antonio San Antonio, San Antonio, TX, USA

    F. Poordad

  5. Centro de Investigaciones Clinicas Viña del Mar, Viña del Mar, Chile

    F. Fuster

  6. JM Research, Cuernavaca, Mexico

    J. Flores-Figueroa

  7. Departamento de Gastroenterología Facultad de Medicina Pontificia Universidad Católica de Chile Santiago Chile and Centro de Envejecimiento y Regeneración, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile

    M. Arrese

  8. Department of Internal Medicine, Ca’ Granda IRCCS Foundation, Policlinico Maggiore Hospital, University of Milan, Milan, Italy

    Anna L. Fracanzani

  9. Sagol Brain Institute, Tel Aviv Sourasky Medical Center, Sackler Faculty of Medicine & Sagol School of Neuroscience, Tel Aviv University, Tel Aviv, Israel

    D. Ben Bashat

  10. Institute of Pathology, Medical University of Graz, Graz, Austria

    K. Lackner

  11. Galmed Pharmaceuticals Ltd, Tel-Aviv, Israel

    T. Gorfine, R. Oren, M. Halperin & L. Hayardeny

  12. Statexcellence Ltd, Tel-Aviv, Israel

    S. Kadosh

  13. NAFLD Research Center, University of California at San Diego, La Jolla, CA, USA

    R. Loomba

  14. Division of Liver Diseases, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    S. Friedman

  15. Department of Gastroenterology, Virginia Commonwealth University, Richmond, VA, USA

    M. S. Siddiqui & Arun J. Sanyal

  16. Duke University Medical Center, Durham, NC, USA

    M. Abdelmalek

  17. Policlinico Umberto I, I Clinica Medica, Day Service di Medicina Interna e Malattie Metaboliche, Rome, Italy

    F. Angelico

  18. Policlinico di Tor Vergata-Epatologia, Rome, Italy

    M. Angelico

  19. Hospital Clínico Universidad de Chile, Santiago, Chile

    J. P. Arancibia

  20. Centre Hospitalier Universitaire de Rennes, Rennes, France

    E. Bardou-Jacquet

  21. Centro de Investigación Clínica Pontificia Universidad Catolica De Chile, Santiago, Chile

    F. Barrera

  22. Wake Research Associates, Raleigh, NC, USA

    C. F. Barish

  23. Rambam MC, Haifa, Israel

    Y. Baruch & T. Saadi

  24. Sheba MC, Ramat-Gan, Israel

    Z. Ben-Ari

  25. University of Leipzig, Leipzig, Germany

    T. Berg

  26. Hôpital Saint Joseph, Marseille, France

    M. Bourliere

  27. Centre Hospitalier Universitaire d’Angers, Angers, France

    J. Boursier

  28. Assaf Harofe MC, Tzrifin, Israel

    E. Broide

  29. Naharia (Galilee) MC, Naharia, Israel

    M. Carmiel & D. Zur

  30. Clinical Trials of Texas, San Antonio, TX, USA

    D. S. Denham

  31. Unità Operativa Complessa Medicina Generale Dipartimento Gastroeneterologia ed Epatologia ‘Ospedale Cristo Re’ dell’Istituto Figlie di N.S. al Monte Calvario, Rome, Italy

    L. Di Cesare & D. L. Dumitrascu

  32. Clinical County Emergency Hospital, Cluj-Napoca, Romania

    L. Di Cesare & D. L. Dumitrascu

  33. Holy Family MC, Nazareth, Israel

    A. Francis

  34. Indiana University, Indianapolis, IN, USA

    S. Gawrieh

  35. Consultorio Médico de la Dra. María Saraí González Huezo, Barrio Santa Cruz, Mexico

    M. S. González- Huezo & G. Torres-Mendoza

  36. CHU Dijon Bourgogne, Dijon, France

    P. Hillon

  37. Biomédica Research Group, Santiago, Chile

    A. Iracheta

  38. Inland Empire Liver Foundation, Rialto, CA, USA

    Z. Kayali

  39. Hospital of Lithuanian University of Health Sciences Kauno klinikos, Kaunas, Lithuania

    L. Kupcinskas

  40. Humanity & Health Medical Group, Central, Hong Kong

    G. Lau

  41. Hôpital Saint-Antoine Assistance Publique-Hôpitaux de Paris, Paris, France

    L. Serfaty & A. Le Cleach

  42. Azienda Ospedaliera Universitaria, Università degli Studi della Campania Luigi Vanvitelli Unità di Epato-Gatroenterologia, Naples, Italy

    C. Loguercio

  43. Medizinische Hochschule Hannover, Hannover, Germany

    M. Manns

  44. Consultorio Médico de la Dra. Laura Ladrón de Guevara Cetina, Mexico City, Mexico

    B. I. Martinez Saldivar

  45. California Liver Research Institute, Pasadena, CA, USA

    E. A. Mena

  46. Accelerium S.de RL de CV, Monterrey Nuevo Leon, Mexico

    L. A. Morales Garza

  47. Orange County Research Center, Charlottesville, CA, USA

    J. M. Neutel

  48. LTD Diacor, Tbilisi, Georgia

    L. Nikoleishvili

  49. Cedars-Sinai Medical Center, Comprehensive Transp, Los Angeles, CA, USA

    M. Noureddin

  50. Hôpital Pitié-Salpêtrière, Paris, France

    R. Pais

  51. Brooke Army Medical Center, San Antonio, TX, USA

    A. H. Paredes

  52. JM Research, Morelos, Mexico

    M. Paredes

  53. Profil Institute for Clinical Research, Inc., The CRU division of ProSciento, Inc., Chula Vista, CA, USA

    R. Peters Watkins

  54. Policlinico Universitario Campus Biomedico, Rome, Italy

    A. Picardi

  55. Medicina Interna I Azienda Ospedialiera Universitaria Maggiore della Carità, Novara, Italy

    M. Pirisi

  56. Centro de Investigación Clinica, Santiago, Chile

    G. P. Jofre

  57. National Institute of Infectious Diseases, Bucharest, Romania

    L. Preotescu

  58. Hôpital Paul Brousse, Villejuif, France

    D. Samuel

  59. Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico

    J. F. Sánchez Avila

  60. Gastroenterologische Schwerpunktpraxis, Leipzig, Germany

    I. Schiefke

  61. Tel Aviv Sourasky MC, Tel-Aviv, Israel

    O. Shibolet

  62. TDDC Research, Dallas, TX, USA

    J. F. Trotter

  63. American Research Corporation at The Texas Liver Institute, San Antonio, TX, USA

    E. Tsai

  64. Columbia University Medical Center, New York, NY, USA

    E. C. Verna

  65. Carmel MC, Haifa, Israel

    E. Zuckerman

Authors
  1. V. Ratziu
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  2. L. de Guevara
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  3. R. Safadi
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  4. F. Poordad
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  5. F. Fuster
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  6. J. Flores-Figueroa
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  7. M. Arrese
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  8. Anna L. Fracanzani
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  9. D. Ben Bashat
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  10. K. Lackner
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  11. T. Gorfine
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  12. S. Kadosh
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  13. R. Oren
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  14. M. Halperin
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  15. L. Hayardeny
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  16. R. Loomba
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  18. Arun J. Sanyal
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Consortia

the ARREST investigator study group

  • 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

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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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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