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Clinical Trial
. 2023 Nov;29(11):2919-2928.
doi: 10.1038/s41591-023-02603-1. Epub 2023 Oct 16.

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

Stephen A Harrison  1 , Rebecca Taub  2 , Guy W Neff  3 , K Jean Lucas  4 , Dominic Labriola  2 , Sam E Moussa  5 , Naim Alkhouri  6 , Mustafa R Bashir  7
Affiliations
Clinical Trial

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

Stephen A Harrison et al. Nat Med. 2023 Nov.

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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Conflict of interest statement

S.A.H. reports grant/research support from 89 Bio, Boehringer Ingelheim, Akero, Altimmune, Axcella, Corcept, Cymabay, Enyo, Galectin, Galmed, Genentech, Genfit, Gilead, Hepion, Hightide, Intercept, Madrigal, Metacrine, NGM Bio, NorthSea, Poxel, Sagimet and Viking; advisory/consulting fees from Akero, Altimmune, AstraZeneca, Axcella, Chronic Liver Disease Foundation, Echosens, Genfit, Gilead, GSK, Hepion, Hepta Bio, Hightide, HistoIndex, Intercept, Madrigal, Medpace, NGM Bio, Northsea, Novartis, Novo Nordisk, Perspectum, Poxel, Sagimet, Sonic Incytes, Terns and Viking; and is the owner of Pinnacle Clinical Research. R.T. is an employee and stockholder at Madrigal Pharmaceuticals. G.W.N. reports advisory/consulting fees from Boehringer Ingelheim; grant/research support from Madrigal Pharmaceuticals; and speaker’s fees from Intercept Pharmaceuticals. K.J.L. reports grant/research support from Madrigal Pharmaceuticals. D.L. is an employee at Madrigal Pharmaceuticals. S.E.M. reports grant/research support from Madrigal Pharmaceuticals; owns stock in Madrigal Pharmaceuticals. N.A. reports grant/research support from 89Bio, AbbVie/Allergan, Akero, Better Therapeutics, Boehringer Ingelheim, Bristol-Myers Squibb, Corcept, DSM, Galectin, Genentech, Genfit, Gilead, Hepagene, Healio, Intercept, Inventiva, Ionis, Madrigal, Merck, NGM, Noom, NorthSea, Novo Nordisk, Perspectum, Pfizer, Poxel, Viking and Zydus; speaker’s fees from AbbVie/Allergan, Alexion, Echosens, Eisai, Exelixis, Gilead, Intercept, Perspectum, Salix and Theratechnologies; Consultant for AbbVie/Allergan, Echosens, Fibronostics, Gilead, Intercept, Madrigal, Novo Nordisk, Perspectum, Pfizer and Zydus. M.R.B. reports grant/research support from Carmot Therapeutics, Corcept Therapeutics, Madrigal Pharmaceuticals, Metacrine, NGM Biopharmaceuticals, Pinnacle Clinical Research, ProSciento and Siemens Healthineers; and advisory/consulting fees from Medpace.

Figures

Fig. 1
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. 2
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. 3
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.
Extended Data Fig. 1
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. 2
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. 3
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. 4
Extended Data Fig. 4. Hierarchical testing procedure.
Hierarchical testing procedure for key secondary end points.
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