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A Placebo-Controlled Trial of Subcutaneous Semaglutide in Nonalcoholic Steatohepatitis

List of authors.
  • Philip N. Newsome, M.B., Ch.B., Ph.D.,
  • Kristine Buchholtz, M.D., Ph.D.,
  • Kenneth Cusi, M.D.,
  • Martin Linder, M.Sc.,
  • Takeshi Okanoue, M.D., Ph.D.,
  • Vlad Ratziu, M.D., Ph.D.,
  • Arun J. Sanyal, M.D.,
  • Anne-Sophie Sejling, M.D., Ph.D.,
  • and Stephen A. Harrison, M.D.
  • for the NN9931-4296 Investigators*

Abstract

Background

Nonalcoholic steatohepatitis (NASH) is a common disease that is associated with increased morbidity and mortality, but treatment options are limited. The efficacy and safety of the glucagon-like peptide-1 receptor agonist semaglutide in patients with NASH is not known.

Methods

We conducted a 72-week, double-blind phase 2 trial involving patients with biopsy-confirmed NASH and liver fibrosis of stage F1, F2, or F3. Patients were randomly assigned, in a 3:3:3:1:1:1 ratio, to receive once-daily subcutaneous semaglutide at a dose of 0.1, 0.2, or 0.4 mg or corresponding placebo. The primary end point was resolution of NASH with no worsening of fibrosis. The confirmatory secondary end point was an improvement of at least one fibrosis stage with no worsening of NASH. The analyses of these end points were performed only in patients with stage F2 or F3 fibrosis; other analyses were performed in all the patients.

Results

In total, 320 patients (of whom 230 had stage F2 or F3 fibrosis) were randomly assigned to receive semaglutide at a dose of 0.1 mg (80 patients), 0.2 mg (78 patients), or 0.4 mg (82 patients) or to receive placebo (80 patients). The percentage of patients in whom NASH resolution was achieved with no worsening of fibrosis was 40% in the 0.1-mg group, 36% in the 0.2-mg group, 59% in the 0.4-mg group, and 17% in the placebo group (P<0.001 for semaglutide 0.4 mg vs. placebo). An improvement in fibrosis stage occurred in 43% of the patients in the 0.4-mg group and in 33% of the patients in the placebo group (P=0.48). The mean percent weight loss was 13% in the 0.4-mg group and 1% in the placebo group. The incidence of nausea, constipation, and vomiting was higher in the 0.4-mg group than in the placebo group (nausea, 42% vs. 11%; constipation, 22% vs. 12%; and vomiting, 15% vs. 2%). Malignant neoplasms were reported in 3 patients who received semaglutide (1%) and in no patients who received placebo. Overall, neoplasms (benign, malignant, or unspecified) were reported in 15% of the patients in the semaglutide groups and in 8% in the placebo group; no pattern of occurrence in specific organs was observed.

Conclusions

This phase 2 trial involving patients with NASH showed that treatment with semaglutide resulted in a significantly higher percentage of patients with NASH resolution than placebo. However, the trial did not show a significant between-group difference in the percentage of patients with an improvement in fibrosis stage. (Funded by Novo Nordisk; ClinicalTrials.gov number, NCT02970942.)

Funding and Disclosures

Supported by Novo Nordisk. Dr. Newsome was supported by the NIHR Birmingham Biomedical Research Centre.

Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.

Dr. Newsome reports receiving grant support from Pharmaxis, consulting fees, paid to the University of Birmingham, and grant support from Boehringer Ingelheim and Novo Nordisk, donated supplies from Echosens, and consulting fees, paid to the University of Birmingham, from Bristol-Myers Squibb, Gilead, Intercept Pharmaceuticals, Pfizer, and Poxel; Dr. Buchholtz, being employed by Novo Nordisk; Dr. Cusi, receiving consulting fees from Allergan, AstraZeneca, Bristol-Myers Squibb, Merck, Janssen, Coherus BioSciences, Pfizer, Genentech, Gilead Sciences, ProSciento, and Eli Lilly, grant support from Cirius Therapeutics, Novartis, Echosens, Poxel, and Zydus, and grant support and consulting fees from Novo Nordisk and Inventiva; Dr. Linder, being employed by Novo Nordisk, and holding pending patents (US15/931093, EP20171536.4, and EP20173341.7) on semaglutide for use in medicine; Dr. Ratziu, receiving consulting fees from Novo Nordisk; Dr. Sanyal, receiving grant support, consulting fees, and donated supplies from Conatus Pharmaceuticals, receiving consulting fees and owning stock in GenFit, HemoShear, and Tiziana, owning stock in Sanyal Bio, Exhalenz, and Akarna Therapeutics, receiving grant support and consulting fees from Gilead, Mallinckrodt, Salix Pharmaceuticals, Novartis, Bristol-Myers Squibb, Merck, and Novo Nordisk, receiving grant support, serving as a consultant, and receiving donated supplies from EchoSensCSandhill Scientific, donated supplies from Intercept Pharmaceuticals, consulting fees from Pfizer, Boehringer Ingelheim, Eli Lilly, Ardelyx, Terns Pharmaceuticals, ENYO Pharma, Bird Rock Bio, Sanofi, Janssen, Poxel, Servier Pharmaceuticals, General Electric, 89bio, Alnylam Pharmaceuticals, Regeneron, Amgen, and Genentech, grant support, consulting fees, and fees for serving on a data and safety monitoring board from Sequana Medical, receiving grant support and serving as a consultant for Fractyl, serving as a consultant and owning stock in Durect and Indalo Therapeutics, receiving grant support and serving as a consultant for Allergan, serving as a consultant for Chemomab, Afimmune, Teva, Albireo Pharma, Takeda, Zydus Pharmaceuticals, AMRA, Owlpharma, ProSciento, and PathAI, serving as a trial investigator for NorthSea Therapeutics, serving as a collaborator for Second Genome, receiving grant support and serving as a trial investigator for Perspectum, and holding a pending patent (15/764,25) on metabolic signature of diagnosis and disease progression in nonalcoholic fatty liver disease; Dr. Sejling, being employed by Novo Nordisk; and Dr. Harrison, receiving consulting fees and advisory board fees from Akero Therapeutics, Altimmune, Axcella Health, Echosens, Foresite Labs, Metacrine, Poxel, Prometic, Ridgeline Therapeutics, and Terns, advisory board fees from Arrowhead Pharmaceuticals, Gelesis, and Medpace, consulting fees from Blade Therapeutics, BVF Partners, Can-Fite BioPharma, Chronic Liver Disease Foundation, Corcept Therapeutics, Fibronostics, Fortress Biotech, HistoIndex, Indalo Therapeutics, Inipharm, Innovate Pharmaceuticals, Merck Sharp and Dohme, Microba Life Sciences, and Perspectum, grant support from Bristol-Myers Squibb, Conatus Pharmaceuticals, Genentech, Immuron, Pfizer, Second Genome, and Tobira TherapeuticsCAllergan, grant support, consulting fees, and advisory board fees from Cirius Therapeutics, CiVi Biopharma, Corcept Therapeutics, CymaBay Therapeutics, Galectin Therapeutics, Galmed Pharmaceuticals, GenFit, Hepion Pharmaceuticals, HighTide Therapeutics, Intercept Pharmaceuticals, Madrigal Pharmaceuticals, NGM Biopharmaceuticals, NorthSea Therapeutics, Novartis Pharmaceuticals, Novo Nordisk, and Sagimet Biosciences, grant support and consulting fees from ENYO Pharma and Viking Therapeutics, and grant support and honoraria from Gilead Sciences. No other potential conflict of interest relevant to this article was reported.

The views expressed are those of the authors and not necessarily those of the National Health Service, the National Institute for Health Research (NIHR), or the Department of Health.

This article was published on November 13, 2020, at NEJM.org.

A data sharing statement provided by the authors is available with the full text of this article at NEJM.org.

We thank the independent pathologists who performed central biopsy evaluations (Cynthia Behling and Oscar W. Cummings); all the participants, investigators, and trial staff who were involved in the conduct of the trial; and Nicola Beadle, Paul Barlass, and Andy Bond of Axis (a division of Spirit Medical Communications Group) for medical writing and editorial assistance (funded by Novo Nordisk) with an earlier version of the manuscript.

Author Affiliations

From the National Institute for Health Research Biomedical Research Centre at University Hospitals Birmingham NHS Foundation Trust and the Centre for Liver and Gastrointestinal Research, Institute of Immunology and Immunotherapy, University of Birmingham, and the Liver Unit, University Hospitals Birmingham NHS Foundation Trust, Birmingham (P.N.N.), and the Radcliffe Department of Medicine, University of Oxford, Oxford (S.A.H.) all in the United Kingdom; Novo Nordisk, S?borg, Denmark (K.B., M.L., A.-S.S.); the Division of Endocrinology, Diabetes, and Metabolism, University of Florida, Gainesville (K.C.); the Department of Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Kyoto, Japan (T.O.); the Institute of Cardiometabolism and Nutrition, Sorbonne Universit, H?pital PitiCSalptrire, Assistance PubliqueCH?pitaux de Paris, INSERM Unit Mixte de Recherche Scientifique 1138 Centre de Recherche des Cordeliers, Paris (V.R.); and the Division of Gastroenterology, Hepatology, and Nutrition, Virginia Commonwealth University School of Medicine, Richmond (A.J.S.).

Address reprint requests to Dr. Newsome at the Centre for Liver and Gastrointestinal Research, 5th Flr., Institute of Biomedical Research, Institute of Immunology and Immunotherapy, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, United Kingdom, or at .

A complete list of the investigators in this trial is provided in the Supplementary Appendix, available at NEJM.org.

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