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Cited by 435Liver Disease Diagnosis and TreatmentHepatitis C virus researchLiver Diseases and Immunity

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Resmetirom for nonalcoholic fatty liver disease: a randomized, double-blind, placebo-controlled phase 3 trial

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Harrison, Stephen A., Taub, Rebecca, Neff, Guy W., Lucas, K. Jean, Labriola, Dominic, Moussa, Sam E., Alkhouri, Naim, Bashir, Mustafa R.·2023·Nature Medicine
DOI 10.1038/s41591-023-02603-1PMC PMC10667098
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Abstract

Nonalcoholic steatohepatitis (NASH) is a progressive liver disease with no approved treatment. MAESTRO-NAFLD-1 was a 52-week randomized, double-blind, placebo-controlled phase 3 trial evaluating the safety of resmetirom in adults with nonalcoholic fatty liver disease and presumed NASH. Patients were randomized to three double-blind arms (100 mg resmetirom (n = 325), 80 mg resmetirom (n = 327) or placebo (n = 320)) or open-label 100 mg resmetirom (n = 171). The primary end point was incidence of treatment-emergent adverse events (TEAEs) over 52 weeks and key secondary end points were LDL-C, apoB, triglycerides (over 24 weeks), hepatic fat (over 16 and 52 weeks) and liver stiffness (over 52 weeks). Resmetirom was safe and well tolerated. TEAEs occurred in 86.5% (open-label 100 mg resmetirom), 86.1% (100 mg resmetirom), 88.4% (80 mg resmetirom) and 81.8% (placebo) of patients. TEAEs in excess of placebo included diarrhea and nausea at the initiation of treatment. Key secondary end points included least square means difference from placebo at 80 mg, 100 mg resmetirom: LDL-C (-11.1%, -12.6%), apoB (-15.6%, -18.0%), triglycerides (-15.4%, -20.4%), 16-week hepatic fat (-34.9%, -38.6%), (P < 0.0001) and liver stiffness (-1.02, -1.70) and 52-week hepatic fat (-28.8, -33.9). These findings demonstrate resmetirom was safe and well tolerated in adults with presumed NASH, supporting a role for further clinical development. (ClinicalTrials.gov identifier NCT04197479 ).

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Fig. 1 Patient composition. Pbo, placebo; rand, randomized; Pt, patient; WD, withdrew; inv, investigator decision; LFTU, lost to follow-up; AE, adverse event; prot dev, protocol deviation.
Fig. 1 Patient composition. Pbo, placebo; rand, randomized; Pt, patient; WD, withdrew; inv, investigator decision; LFTU, lost to follow-up; AE, adverse event; prot dev, protocol deviation.CC BY · PubMed Central
Fig. 2 Resmetirom-mediated changes in atherogenic lipid levels and non-invasive biomarkers. a, Least squares mean %CFB in LDL-C, apoB and TG at week 24 (100 mg OL n = 169; 100 mg DB n = 314; 80 mg DB n = 320; placebo n = 309). TG reported in subgroup with baseline TG levels >150 mg dl−1 (100 mg OL n = 97; 100 mg DB n = 169; 80 mg DB n = 166; placebo n = 163). Data are presented as mean ± s.e.m. b, Median %CFB in hepatic fat (measured by MRI-PDFF) at weeks 16 and week 52 (100 mg OL n = 152; 100 mg DB n = 268; 80 mg DB n = 258; placebo n = 268) as well as mean CFB in FibroScan CAP at week 52 (100 mg OL n = 147; 100 mg DB n = 270; 80 mg DB n = 260; placebo n = 260). c, Percentage of patients whose VCTE results improved or worsened by either ≥2 kPa or ≥30% from baseline at week 52 (100 mg OL n = 50; 100 mg DB n = 102; 80 mg DB n = 83; placebo n = 107) (left). Percent of patients whose MRE results improved or worsened by ≥19% from baseline (right). mITT population. BL, baseline.
Fig. 2 Resmetirom-mediated changes in atherogenic lipid levels and non-invasive biomarkers. a, Least squares mean %CFB in LDL-C, apoB and TG at week 24 (100 mg OL n = 169; 100 mg DB n = 314; 80 mg DB n = 320; placebo n = 309). TG reported in subgroup with baseline TG levels >150 mg dl−1 (100 mg OL n = 97; 100 mg DB n = 169; 80 mg DB n = 166; placebo n = 163). Data are presented as mean ± s.e.m. b, Median %CFB in hepatic fat (measured by MRI-PDFF) at weeks 16 and week 52 (100 mg OL n = 152; 100 mg DB n = 268; 80 mg DB n = 258; placebo n = 268) as well as mean CFB in FibroScan CAP at week 52 (100 mg OL n = 147; 100 mg DB n = 270; 80 mg DB n = 260; placebo n = 260). c, Percentage of patients whose VCTE results improved or worsened by either ≥2 kPa or ≥30% from baseline at week 52 (100 mg OL n = 50; 100 mg DB n = 102; 80 mg DB n = 83; placebo n = 107) (left). Percent of patients whose MRE results improved or worsened by ≥19% from baseline (right). mITT population. BL, baseline.CC BY · PubMed Central
Fig. 3 Resmetirom-mediated changes in markers of liver injury and sex-hormone bindingglobulin. a–d, Mean ALT (a), AST (b) and GGT (c) in the subgroup with baseline ALT levels ≥30 IU l−1 and SHBG (nmol l−1) (d) levels over time. Shown are observed data (100 mg OL n = 83; 100 mg DB n = 157; 80 mg DB n = 169; placebo n = 156). Data are presented as mean ± s.e.m.
Fig. 3 Resmetirom-mediated changes in markers of liver injury and sex-hormone bindingglobulin. a–d, Mean ALT (a), AST (b) and GGT (c) in the subgroup with baseline ALT levels ≥30 IU l−1 and SHBG (nmol l−1) (d) levels over time. Shown are observed data (100 mg OL n = 83; 100 mg DB n = 157; 80 mg DB n = 169; placebo n = 156). Data are presented as mean ± s.e.m.CC BY · PubMed Central
Extended Data Fig. 1 Resmetirom-mediated reduction in hepatic fat. Least squares (LS) mean change from baseline (95% confidence interval (CI)) in hepatic fat (measured by magnetic resonance imaging-proton density fat fraction (MRI-PDFF)) at Week 52 in patient subgroups of the double-blind 100 mg resmetirom and double-blind 80 mg resmetirom arms. Marker shows median. High SHBG, population with ≥120% increase from baseline in SHBG.
Extended Data Fig. 1 Resmetirom-mediated reduction in hepatic fat. Least squares (LS) mean change from baseline (95% confidence interval (CI)) in hepatic fat (measured by magnetic resonance imaging-proton density fat fraction (MRI-PDFF)) at Week 52 in patient subgroups of the double-blind 100 mg resmetirom and double-blind 80 mg resmetirom arms. Marker shows median. High SHBG, population with ≥120% increase from baseline in SHBG.CC BY · PubMed Central
Extended Data Fig. 2 Resmetirom-mediated reduction in proton density fat fraction and liver volume. Least squares (LS) mean change from baseline (95% confidence interval (CI)) in PDFF (a) and liver volume (b) at Week 52 in patient subgroups of the open-label 100 mg resmetirom arm. Marker shows median. High SHBG, population (~two-thirds) with ≥120% increase from baseline in SHBG.
Extended Data Fig. 2 Resmetirom-mediated reduction in proton density fat fraction and liver volume. Least squares (LS) mean change from baseline (95% confidence interval (CI)) in PDFF (a) and liver volume (b) at Week 52 in patient subgroups of the open-label 100 mg resmetirom arm. Marker shows median. High SHBG, population (~two-thirds) with ≥120% increase from baseline in SHBG.CC BY · PubMed Central
Extended Data Fig. 3 Study Design. *Randomization was stratified by type 2 diabetes status and by history of documented atherosclerotic cardiovascular disease. The first 30 patients enrolled in the MAESTRO-NAFLD-1 trial were enrolled in the open-label 100 mg resmetirom (including any patients taking thyroxine >75 mcg). After the first 30 patients were enrolled in the open-label 100 mg resmetirom arm, subsequent patients were randomized 1:1:1:1 to 3 double-blind arms (100 mg resmetirom, 80 mg resmetirom, or placebo) or the open-label 100 mg resmetirom arm. Randomization to the open-label arm was discontinued when the target number of patients was achieved (July 1, 2020). Thereafter, eligible patients were randomized 1:1:1 to the 3 double-blind arms (100 mg resmetirom, 80 mg resmetirom, or placebo).
Extended Data Fig. 3 Study Design. *Randomization was stratified by type 2 diabetes status and by history of documented atherosclerotic cardiovascular disease. The first 30 patients enrolled in the MAESTRO-NAFLD-1 trial were enrolled in the open-label 100 mg resmetirom (including any patients taking thyroxine >75 mcg). After the first 30 patients were enrolled in the open-label 100 mg resmetirom arm, subsequent patients were randomized 1:1:1:1 to 3 double-blind arms (100 mg resmetirom, 80 mg resmetirom, or placebo) or the open-label 100 mg resmetirom arm. Randomization to the open-label arm was discontinued when the target number of patients was achieved (July 1, 2020). Thereafter, eligible patients were randomized 1:1:1 to the 3 double-blind arms (100 mg resmetirom, 80 mg resmetirom, or placebo).CC BY · PubMed Central
Extended Data Fig. 4 Hierarchical testing procedure. Hierarchical testing procedure for key secondary end points.
Extended Data Fig. 4 Hierarchical testing procedure. Hierarchical testing procedure for key secondary end points.CC BY · PubMed Central

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Metadata

Authors
Harrison, S. A., Taub, R., Neff, G. W., Lucas, K. J., Labriola, D., Moussa, S. E., Alkhouri, N., & Bashir, M. R.
Affiliations
  • Pinnacle Clinical Research (US)
  • Madrigal Pharmaceuticals (United States) (US)
  • Lucas Research (US)
  • University of Arizona (US)
  • Arizona Liver Health (US)
  • Duke Medical Center (US)
Corresponding author
Harrison, Stephen A.
ORCID
Venue
Nature Medicine
Publisher
Springer Science and Business Media LLC
Published
2023-10-16
Volume
29
Issue
11
Pages
2919-2928
ISSN
  • 1078-8956 (ISSN-L)
  • 1546-170X
DOI
10.1038/s41591-023-02603-1
PMC
PMC10667098
OpenAlex
W4387666937
Cited by
435
References
18
Citations by year
2026: 108 · 2025: 178 · 2024: 138 · 2023: 11
FWCI
87.06
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Medicine (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Funders
Madrigal Pharmaceuticals
Topics
  • Health Sciences › Medicine › Hepatology › Liver Disease Diagnosis and Treatment
  • Health Sciences › Medicine › Hepatology › Hepatitis C virus research
  • Health Sciences › Medicine › Hepatology › Liver Diseases and Immunity
Keywords
resmetirom, non-alcoholic fatty liver disease, nonalcoholic steatohepatitis, liver fat, liver stiffness, LDL cholesterol, apolipoprotein B, triglycerides, treatment-emergent adverse events, drug safety and tolerability
MeSH terms
Adult, Apolipoproteins B, Double-Blind Method, Humans, Cholesterol, LDL, Liver, Pyridazines, Triglycerides, Uracil, Treatment Outcome, Non-alcoholic Fatty Liver Disease

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