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Resmetirom (MGL-3196) for the Treatment of Non-Alcoholic Steatohepatitis: A Multicenter, Randomized, Double-Blind, Placebo-Controlled, Phase 2 Trial

166 Pages Posted: 19 Jul 2019

See all articles by Stephen Harrison

Stephen Harrison

University of Oxford - Radcliffe Department of Medicine

Mustafa R. Bashir

Duke University

Cynthia D. Guy

Duke University - Medical Center

Rong Zhou

Medpace

Cynthia A. Moylan

Duke University - Medical Center

Juan P. Frias

University of California, San Diego (UCSD)

Naim Alkhouri

University of Texas at San Antonio

Meena B. Bansal

Mount Sinai Health System - Icahn School of Medicine

Seth Baum

Florida Atlantic University

Brent A. Neuschwander-Tetri

Saint Louis University

Rebecca Taub

Madrigal Pharmaceuticals

Sam E. Moussa

University of Arizona

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Abstract

Background: Non-alcoholic steatohepatitis (NASH) is characterized by hepatic steatosis, inflammation, hepatocellular injury, and progressive liver fibrosis. Resmetirom (MGL-3196) is a liver-directed, orally active, selective thyroid hormone receptor- agonist designed to improve NASH by increasing hepatic fat metabolism and reducing lipotoxicity. We aimed to assess the safety and efficacy of resmetirom in patients with NASH.

Methods: MGL3196-05 (NCT02912260) was a 36-week multicenter, randomized, double-blind, placebo-controlled study in adults with biopsy confirmed NASH (fibrosis stages 1-3). Patients were randomized 2:1 to receive resmetirom 80 mg daily or placebo. The primary endpoint was relative change in MRI-assessed hepatic fat at week 12 compared with placebo. Secondary and exploratory endpoints included effects on serum lipids, liver enzymes, fibrosis biomarkers, and liver histology.

Findings: 348 patients were screened and 84 were randomized to resmetirom and 41 to placebo at 18 sites in the US. Resmetirom-treated patients had a % relative reduction of liver fat compared with placebo at week 12 (-32.9 resmetirom, -10.4 placebo; -22.5 (-32.9, -12.2), p<0.0001) and week 36 (-37.3 resmetirom, -8.5 placebo; -28.8 (-42.0, -15.7), p<0.0001). In patients with elevated baseline lipids, resmetirom compared with placebo reduced low-density lipoprotein cholesterol -22.3%, apolipoprotein B -27.6%, triglycerides -30.8% and lipoprotein(a) -37.9% (p<0.0001 for all lipids). At week 36, resmetirom reduced serum ALT (-35.9 U/L, p=0.004) and fibrosis biomarkers ELF (-0.484, p=0.017) and PRO-C3 (- 21.4 ng/mL, p=0.003). Treatment was associated with a ≥ 2-point improvement in the biopsy NAFLD Activity Score (56% of 73 resmetirom vs 32% of 34 placebo patients, p=0.02) and NASH resolution (27.4% resmetirom vs 6.5% placebo patients, p=0.02) at 36 weeks. Adverse events were mostly mild or moderate and were balanced between groups except a higher incidence of mild transient diarrhea with resmetirom.

Interpretation: Resmetirom treatment resulted in significant reduction in hepatic fat, atherogenic lipids, liver enzymes, fibrosis markers, and improvement in NASH on liver biopsy.

Trial Registration: (NCT02912260).

Funding Statement: The study was funded by Madrigal Pharmaceuticals. It was designed by expert consultants in the NASH field in conjunction with representatives of the funder. Data were collected by investigators, and managed, validated, and analysed by Medpace Research (Cincinnati, OH, USA).

Declaration of Interests: SAH reports grant and research support from Conatus,Galectin, Galmed, Genfit, Gilead, Intercept, Madrigal, NGM Bio, Akero, Axcella, Metacrine, 3V Bio, Enyo, NorthSea, Genentech, Contravir, Cymabay, and Hightide; is a consulting adviser for the Chronic Liver Disease Foundation, Cirius, Echosens, Akero, Galmed, Genfit, Gilead, Intercept, Madrigal, NGM Bio, Novartis, Perspectum, Metacrine, Medpace, 3V Bio, Blade, Viking, Poxel, Axcella, Terns, HistoIndex, Hightide, Contravir, Innovate, CiVi and Prometic. MRB reports grant and research support: General Electric, Madrigal, Metacrine Inc, NGM Bio, Pinnacle Clinical Research, ProSciento Inc, Siemens; is a consulting advisor for MedPace. CDG reports grant and research support from Immuron, Taiwan J, Madrigal, CymaBay, and NGM; is a consulting advisor for Immuron, Taiwan J, Madrigal, CymaBay, and NGM. RZ is an employee of MedPace working under contract with Madrigal. CAM reports grant and research support from Galectin, Intercept, Genfit, Gilead, NGM Bio, TaiwanJ, Novartis, Allergan, Conatus, Immuron, Galmed, BMS, Novo Nordisk, Conatus, Immuron; is consulting advisor for Gilead and NuSirt. JPF reports grant and research support from Akcea, Allergan, BMS, Cirius, Cymabay, Eli Lilly, Genentech, Madrigal, NGM, Novartis, Novo Nordisk, Pfizer, Sanofi, Second Genome, and Theracos; Speakers’ Bureau for Merck, Sanofi; is consulting advisor for Eli Lilly, Gilead, Merck, Novo Nordisk, Sanofi. NA reports grant and research support from Akero, Albireo, Allergan, BMS, Conatus, Enyo, Galectin, Galmed, Genfit, Gilead, Hanmi, Intercept, Madrigal, Novartis, and Poxel; Speakers’ Bureau for Alexion, Gilead, and Intercept; is a consulting adviser for Allergan, Cirius, Gilead, and Pfizer. MBB reports grant and research support from the National Institutes of Health, Intercept, Allergan, Madrigal; is a consulting advisor for Kinetix Group and Boehringer-Ingelheim. SB reports grant and research support from Madrigal; Speakers’ Bureau for Amgen, Lilly, Novo Nordisk and Akcea; is a consulting advisor for Sanofi, Amgen, GLG Group, Guidepoint Global, Regeneron, Novo Nordisk, Novartis and Akcea. BANT reports consulting and advisor relationships with Allergan, Arrowhead, ARTham, Axcella, Blade, Boehringer Ingleheim, BMS, Coherus, Consynance, Durect, Enanta, Fortress, Gelesis, Gilead, Intercept, Lipocine, Madrigal, Medimmune, Merck, Metacrine, Mundipharma, NGM, pH-Pharma, Prometheus, Siemens and institution research support from Allergan, BMS, Cirius, Cymabay, Enanta, Galectin, Genfit, Gilead, Intercept, Madrigal, NGM, and Prometheus. RT is an employee and shareholder of Madrigal. SEM reports research support from Madrigal.

Ethics Approval Statement: Written informed consent was obtained from all patients prior to enrollment, and the study was performed in accordance with ethical principles of the Declaration of Helsinki and was consistent with the International Conference on Harmonisation/Good Clinical Practice, and applicable regulatory requirements. The institutional review board or independent ethics committee of each study center approved the study and all amendments.

Keywords: MGL-319 resmetirom, NASH, non-alcoholic steatohepatitis, NAFLD, non-alcoholic fatty liver disease, lipids

Suggested Citation

Harrison, Stephen and Bashir, Mustafa R. and Guy, Cynthia D. and Zhou, Rong and Moylan, Cynthia A. and Frias, Juan P. and Alkhouri, Naim and Bansal, Meena B. and Baum, Seth and Neuschwander-Tetri, Brent A. and Taub, Rebecca and Moussa, Sam E., Resmetirom (MGL-3196) for the Treatment of Non-Alcoholic Steatohepatitis: A Multicenter, Randomized, Double-Blind, Placebo-Controlled, Phase 2 Trial (July 16, 2019). Available at SSRN: https://ssrn.com/abstract=3420409

Stephen Harrison (Contact Author)

University of Oxford - Radcliffe Department of Medicine ( email )

United Kingdom

Mustafa R. Bashir

Duke University

100 Fuqua Drive
Durham, NC 27708-0204
United States

Cynthia D. Guy

Duke University - Medical Center

100 Fuqua Drive
Durham, NC 27715
United States

Rong Zhou

Medpace

United States

Cynthia A. Moylan

Duke University - Medical Center

100 Fuqua Drive
Durham, NC 27715
United States

Juan P. Frias

University of California, San Diego (UCSD)

9500 Gilman Drive
Mail Code 0502
La Jolla, CA 92093-0112
United States

Naim Alkhouri

University of Texas at San Antonio ( email )

One UTSA Circle
San Antonio, TX 78249
United States

Meena B. Bansal

Mount Sinai Health System - Icahn School of Medicine

One Gustave L. Levy Place
New York, NY 10029-6574
United States

Seth Baum

Florida Atlantic University

Boca Raton, FL 33431
United States

Brent A. Neuschwander-Tetri

Saint Louis University

220 North Grand Boulevard
St. Louis, MO 63103
United States

Rebecca Taub

Madrigal Pharmaceuticals

United States

Sam E. Moussa

University of Arizona

Department of History
Tucson, AZ 85721
United States

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