Clinical Trial: Phase 3 Trial of Resmetirom Versus Placebo in Metabolic Dysfunction‐Associated Steatohepatitis—Reanalysis of Fibrosis Stage 2–3 Subset

ABSTRACT

Background

Resmetirom is an oral thyroid hormone receptor beta agonist clinically used to treat metabolic dysfunction‐associated steatohepatitis (MASH) among adults with stage F2 or F3 fibrosis.

Aims

Because the pivotal, 52‐week, randomized, controlled, phase 3 MAESTRO‐NASH trial (once‐daily oral resmetirom 80 or 100 mg or placebo) included patients with F1, F2, or F3 fibrosis, we conducted a post hoc analysis aimed at assessing treatment response in the subset of patients with stages F2 and F3 fibrosis, consistent with the approved label population.

Methods

Co‐primary end points were MASH resolution (hepatocellular ballooning score 0, lobular inflammation score ≤ 1, and ≥ 2‐point nonalcoholic fatty liver disease activity score [NAS] reduction from baseline) with no fibrosis worsening, and ≥ 1‐stage fibrosis improvement with no NAS worsening at Week 52.

Results

Among 917 patients with F2 or F3 fibrosis, metabolic risk factor prevalence was high (hypertension, 78.0%; dyslipidemia, 71.1%; type 2 diabetes, 67.0%). MASH resolution was achieved by 25.7% in the 80‐mg group, 29.9% in the 100‐mg group, and 9.5% in the placebo group (p < 0.0001 for both comparisons with placebo). Respective percentages with fibrosis improvement were 26.5%, 28.9%, and 17.3% (p < 0.01 for both comparisons). From baseline to Week 24, low‐density lipoprotein cholesterol decreased by 11.7% and 13.7% in the 80‐ and 100‐mg resmetirom groups, respectively, and increased by 2.3% with placebo (p < 0.0001 for both comparisons). No new safety signals emerged.

Conclusion

Results among patients with F2 and F3 fibrosis were consistent with the primary MAESTRO‐NASH analysis population, demonstrating efficacy and safety of resmetirom after 52 weeks.

Results among patients with F2 and F3 fibrosis were consistent with the primary MAESTRO‐NASH analysis population, demonstrating the efficacy and safety of resmetirom after 52 weeks.

1. Introduction

Metabolic dysfunction‐associated steatohepatitis (MASH), previously known as nonalcoholic steatohepatitis (NASH), is a progressive liver disease characterized by ≥ 5% hepatic steatosis plus inflammation and hepatocellular damage, in the absence of heavy alcohol consumption [1, 2, 3]. MASH affects a significant portion of the population worldwide, with an estimated global prevalence of ~4%–7% [4, 5] and an extensive associated socioeconomic burden [6, 7].

In patients with MASH, impaired hepatic thyroid hormone receptor beta (THR‐β) function leads to reduced mitochondrial activity and fatty acid β‐oxidation that causes lipid accumulation and eventual fibrosis [8]. The extent of fibrosis is highly predictive of disease impact: risk of adverse clinical outcomes increases substantially once MASH has progressed to fibrosis stage F2 or F3 (on a scale from F0 [no fibrosis] to F4 [cirrhosis]) [9, 10].

Resmetirom (Rezdiffra, Madrigal Pharmaceuticals Inc., West Conshohocken, PA, USA) is an oral, liver‐directed, THR‐β–selective agonist indicated in conjunction with diet and exercise for the treatment of adults with noncirrhotic MASH with moderate to advanced liver fibrosis (stages F2 or F3) [11, 12]. Resmetirom was granted accelerated approval by the United States Food and Drug Administration (FDA) in 2024 and a conditional marketing authorization by the European Medicines Agency (EMA) in 2025 [8, 11, 13]. Conditional FDA approval was based on results from the ongoing MAESTRO‐NASH phase 3 study, which showed a significant effect of resmetirom 80 and 100 mg orally once daily on the dual primary end points of resolution of steatohepatitis without worsening of fibrosis and one stage improvement in fibrosis without worsening of steatohepatitis, on post‐baseline liver biopsies collected at 12 months, consistent with FDA‐recommended end points [14, 15, 16].

The prespecified primary analysis population of MAESTRO‐NASH included adults with biopsy‐confirmed MASH with stage F1B, F2, or F3 fibrosis [16]. Upon regulatory submission of resmetirom for approval to treat MASH in the European Union, the EMA requested reanalysis of the primary results within the subset of patients with only stage F2 and F3 fibrosis, the patient population represented in the US label [11]. Thus, here we report the results of this post hoc analysis in the subset of patients with F2 and F3 fibrosis in MAESTRO‐NASH, with the aim of presenting consolidated results for the patient population that is included in the current US FDA and EMA labels for resmetirom [11, 13].

2. Materials and Methods

2.1. Trial Design and Oversight

MAESTRO‐NASH (NCT03900429) is an ongoing phase 3, double‐blind, randomized, placebo‐controlled trial conducted at 245 sites across 15 countries. Full details of the trial methodology have been previously published. Briefly, the planned trial duration is 54 months, with assessment of the 2 histological primary end points after 52 weeks and assessment of the clinical‐outcome primary end point at the end of the study. The trial was approved by the institutional review board and ethics committee at each participating site and was conducted in accordance with the principles of the Declaration of Helsinki, the International Council for Harmonization Good Clinical Practice guidelines, and all relevant regulations. All patients provided written informed consent [16].

2.2. Patients

Full inclusion and exclusion criteria for MAESTRO‐NASH have been described previously. Eligible patients were ≥ 18 years old, had ≥ 3 out of 5 metabolic risk factors based on modified International Diabetes Foundation criteria for the metabolic syndrome, were at a stable weight, had a controlled attenuation parameter (CAP) of ≥ 280 dB per meter, and had a liver‐stiffness measurement of ≥ 8.5 kPa [16, 17]. Patients were required to have histologic evidence of MASH and a nonalcoholic fatty liver disease (NAFLD) activity score (NAS) of ≥ 4 (on a scale of 0 [lowest severity] to 8 [highest severity]), with a score of ≥ 1 for each component of steatosis (ranked from 0 to 3), lobular inflammation (ranked from 0 to 3), and hepatocellular ballooning (ranked from 0 to 2). In addition, at least 50% of the enrolled population was required to have fibrosis stage F3, and no more than 15% were permitted to have a fibrosis stage of F1 (primarily F1B; a stage of F1B indicated moderate fibrosis, pericentral area only) [16]. The current post hoc analysis included only patients with fibrosis stages F2 and F3, consistent with the approved label population [11, 13].

2.3. Procedures

Patients were randomized 1:1:1 to receive 80 mg or 100 mg resmetirom (Rezdiffra, Madrigal Pharmaceuticals Inc) or placebo once daily by mouth. Randomization was conducted via an interactive web‐response system and stratified by the presence or absence of type 2 diabetes and by fibrosis stage [16]. Biopsies performed at screening and Week 52 were independently evaluated by expert pathologists to assess NAS and fibrosis stage per MASH Clinical Research Network criteria, as previously described [16, 18].

2.4. End Points

A complete listing of primary and secondary end points has been published previously [16]. The prespecified co‐primary end points were (1) MASH resolution (i.e., hepatocellular ballooning score of 0, lobular inflammation score of 0 or 1, and NAS reduction of ≥ 2 points) with no worsening of fibrosis at Week 52, and (2) reduction in fibrosis by ≥ 1 stage with no worsening of NAS at Week 52. A key secondary end point was percent change from baseline in low‐density lipoprotein (LDL) cholesterol level at Week 24. Additional secondary end points included the percent change from baseline to Week 24 in high‐density lipoprotein (HDL) and non‐HDL cholesterol, triglycerides, apolipoprotein B, and lipoprotein(a); the relative percent change from baseline to Week 48 in magnetic resonance imaging proton density fat fraction; and the percent change from baseline to Week 48 in liver enzymes (alanine aminotransferase, aspartate aminotransferase, and γ‐glutamyl transferase). Safety end points included adverse events (AEs) and biochemical and clinical assessments [16].

2.5. Statistical Analysis

The methods for prespecified sample size determination in MAESTRO‐NASH were previously described. This analysis was conducted in the subset of patients with fibrosis stages F2 or F3 within the modified intent‐to‐treat (mITT) population enrolled as of July 31, 2021. Primary end point analyses were performed on the Week 52 liver biopsy mITT population, which included all patients in the Week 52 mITT population that did not have a missing Week 52 liver biopsy as a result of study discontinuation due to the COVID‐19 pandemic. Patients who had no valid biopsy during Week 52 were considered non‐responders for the purposes of the analysis.

Differences in MASH resolution and fibrosis improvement at Week 52 between each resmetirom group and the placebo group were statistically analysed using the Cochran–Mantel–Haenszel test, stratified by screening biopsy stage and presence/absence of diabetes. Patients with missing Week 52 biopsies were treated as nonresponders, and partial credit was applied via statistical modelling to any case in which pathologists disagreed on response status. Sensitivity analyses of missing histologic response data were conducted using placebo‐based multiple imputation and missing‐at‐random (MAR) multiple imputation approaches. For each imputation approach, treatment effects for MASH resolution and fibrosis improvement were summarized as risk differences for resmetirom 80 mg and 100 mg versus placebo, with corresponding 95% confidence intervals and nominal p‐values.

Liver enzyme data at each post‐baseline visit were evaluated using an analysis of covariance (ANCOVA) model including a fixed effect for treatment and a covariate for baseline value. Least square means (LSMs) and p‐values were generated for changes from baseline. Lipid data at each post‐baseline visit were analysed using a similar ANCOVA model employing a multiple imputation procedure to estimate missing values for each test and for each patient separately. All reported p‐values are 2‐sided. As reported previously in the primary analysis population of MAESTRO‐NASH, the prespecified co‐primary end points and the key secondary end point, percent change from baseline in LDL cholesterol level, at Week 24, were statistically significant when compared to placebo. End points not included in the hierarchical plan are presented alongside 95% confidence intervals but without p‐values; these were not used in lieu of hypothesis testing.

3. Results

3.1. Patients

A total of 1050 patients were randomized from March 2019 through July 2021 (Figure 1). Of these, 917 had a fibrosis stage of F2 or F3 at randomization and were therefore included in the current analysis (306 in the 80‐mg resmetirom group, 308 in the 100‐mg resmetirom group, and 303 in the placebo group). A subset of 758 patients had biopsies at both baseline and Week 52 (253 in the 80‐mg resmetirom group, 241 in the 100‐mg resmetirom group, and 264 in the placebo group). A total of 125 (13.6%) patients discontinued from the study prior to Week 52 (37 [12.1%], 54 [17.5%], and 34 [11.2%] in the 80‐mg resmetirom, 100‐mg resmetirom, and placebo groups, respectively). Reasons for study discontinuation overall included withdrawal by the patient for reasons other than AEs (47.2%), AEs (24.8%), loss to follow‐up (20.8%), protocol deviation (2.4%), investigator discretion (for reasons other than AEs; 2.4%), and other (2.4%) (Figure 1). Patient withdrawals for reasons other than AEs accounted for the highest proportion of discontinuations in all groups (resmetirom 80 mg, 51.4%; resmetirom 100 mg, 40.7%; placebo, 52.9%). Discontinuations due to AEs were more frequent in the 100‐mg resmetirom (37.0%) versus 80‐mg (10.8%) and placebo (20.6%) groups, whereas loss to follow‐up was more common in the 80‐mg resmetirom group (35.1% vs. 13.0% and 17.6% in the 100‐mg resmetirom and placebo groups, respectively).

FIGURE 1.

Patient Disposition in the Fibrosis Stages F2 and F3 Patient Subset. ^†Refers to patients in the mITT population who had F1 fibrosis stage at randomization and were therefore excluded from the post hoc analysis. AE, adverse event; ID, investigator discretion; LTFU, lost to follow‐up; mITT, modified intent‐to‐treat; PD, protocol deviation; WD, withdrawal.

Demographic and clinical characteristics were similar across treatment groups (Table 1). At enrollment, the mean ± standard deviation (SD) age of the current analysis population was 56.7 ± 10.8 years, with a mean ± SD body mass index of 35.6 ± 6.7 kg/m². The majority of patients (89.2%) were White, 1.7% were Black, and 3.1% were Asian; 21.4% of patients identified as Hispanic. Patients had a high prevalence of metabolic risk factors including 78.0% with hypertension, 71.1% with dyslipidemia, and 67.0% with type 2 diabetes. Regarding MASH severity, 84.0% of patients had a baseline NAS of ≥ 5; 34.8% and 63.6% of patients had baseline fibrosis stages F2 and F3, respectively.

TABLE 1.

Demographic and clinical characteristics of the patients at baseline (fibrosis stages F2 and F3 subset). ^a

Characteristic	Resmetirom, 80 mg (N = 306)	Resmetirom, 100 mg (N = 308)	Placebo (N = 303)
Age, years	55.9 ± 11.2	57.0 ± 10.8	57.2 ± 10.4
Male, n (%) b	133 (43.5)	134 (43.5)	132 (43.6)
Race or ethnic group, n (%) b
White	277 (90.5)	276 (89.6)	265 (87.5)
Black	4 (1.3)	5 (1.6)	7 (2.3)
Asian	10 (3.3)	9 (2.9)	9 (3.0)
Other c	12 (3.9)	11 (3.5)	18 (5.9)
Missing data	3 (1.0)	7 (2.3)	4 (1.3)
Hispanic or Latino ethnic group, n (%) b	68 (22.2)	79 (25.6)	49 (16.2)
Body weight, kg	100.2 ± 22.3	101.8 ± 22.8	99.5 ± 22.7
Body mass index	35.6 ± 6.4	36.1 ± 7.2	35.2 ± 6.4
Type 2 diabetes, n (%)	213 (69.6)	201 (65.3)	200 (66.0)
Hypertension, n (%)	230 (75.2)	242 (78.6)	243 (80.2)
Dyslipidemia, n (%)	216 (70.6)	224 (72.7)	212 (70.0)
Hypothyroidism, n (%) d	38 (12.4)	43 (14.0)	43 (14.2)
History of ASCVD, n (%)	18 (5.9)	20 (6.5)	13 (4.3)
Estimated 10‐year risk of ASCVD, % e	14.7 ± 12.2	14.4 ± 12.0	15.6 ± 11.5
FibroScan liver‐stiffness measurement, kPa f
Mean ± SD	13.5 ± 6.8	13.7 ± 7.2	13.0 ± 5.6
Median (Q1, Q3)	11.5 (9.6, 15.0)	12.0 (9.5, 16.0)	11.8 (9.5, 14.9)
FibroScan controlled attenuation parameter, dB/m g	346.1 ± 37.4	349.3 ± 38.8	347.1 ± 37.3
MRI‐PDFF, % h	18.2 ± 6.8	17.3 ± 6.7	17.8 ± 6.9
Liver stiffness on MRE, kPA	3.5 ± 1.0	3.7 ± 1.1	3.5 ± 1.0
Fibrosis‐4 index score i	1.4 ± 0.7	1.5 ± 0.7	1.5 ± 0.7
Enhanced Liver Fibrosis score	9.7 ± 0.9	9.8 ± 0.9	9.8 ± 0.9
LDL cholesterol level, mg/dL	107.2 ± 37.1	103.4 ± 37.3	107.6 ± 41.6
HDL cholesterol level, mg/dL	43.6 ± 12.6	44.0 ± 13.1	43.6 ± 12.7
Non‐HDL cholesterol level, mg/dL	3.5 ± 1.1	3.5 ± 1.2	3.6 ± 1.3
Alanine aminotransferase level, U/L	53.1 ± 27.5	56.2 ± 33.6	54.9 ± 33.9
Aspartate aminotransferase level, U/L	38.5 ± 19.6	42.7 ± 25.3	40.8 ± 23.9
γ‐Glutamyl transferase level, U/L	86.5 ± 113.7	86.6 ± 100.9	76.3 ± 85.7
Liver biopsy findings, n (%)
NAS ≥ 5 j	255 (83.3)	276 (89.6)	239 (78.9)
Fibrosis stage k
F2	98 (32.0)	98 (31.8)	95 (31.4)
F3	187 (61.1)	186 (60.4)	181 (59.7)

Abbreviations: ASCVD, atherosclerotic cardiovascular disease; HDL, high‐density lipoprotein; LDL, low‐density lipoprotein; MRE, magnetic resonance elastography; MRI‐PDFF, magnetic resonance imaging proton density fat fraction; NAS, nonalcoholic fatty liver disease activity score; Q1, quartile 1; Q3, quartile 3.

^a Values are mean ± SD unless otherwise specified.

^b Sex, race, and ethnic group were patient‐reported characteristics.

^c Includes American Indian or Alaska Native, Native Hawaiian or other Pacific Islander, or any other race or ethnic group.

^d Patients were considered to have hypothyroidism if they were receiving thyroxine‐replacement therapy.

^e Overall cardiovascular event risk determined based on age, sex, race, systolic blood pressure, diastolic blood pressure, total cholesterol, HDL cholesterol, LDL cholesterol, history of diabetes, smoking status, hypertension treatment, statin treatment, and aspirin therapy. An estimated 10‐year risk of ASCVD < 5% is low, 5 to 7.4% is borderline, 7.5 to 19.9% is intermediate, and ≥ 20% is high [19].

^f Liver stiffness was measured using vibration‐controlled transient elastography. Values > 8 kPa indicate fibrosis stage F2, F3, or F4 [2].

^g Controlled attenuation parameter measurements are noninvasive assessments of steatosis based on increased ultrasound wave attenuation during travel through steatotic tissue compared with normal liver tissue. Readings of ≥ 280 dB/m (out of 400 dB/m maximum) were considered consistent with elevated liver fat [16].

^h MRI‐PDFF is a quantitative biomarker that noninvasively measures liver fat. Readings ≥ 5% are considered consistent with elevated liver fat [20].

ⁱ Fibrosis‐4 index score is determined based on platelet count, aspartate aminotransferase level, age, and alanine aminotransferase level. Scores > 2.67 indicate high risk of advanced fibrosis (F3‐F4) and liver‐related events [2].

^j NAS is on a scale of 0 to 8 where higher scores indicate greater disease severity; score is determined based on steatosis (on a scale from 0 to 3), lobular inflammation (on a scale from 0 to 3), and hepatocellular ballooning (on a scale from 0 to 2). NAS ≥ 4 indicates that an individual is high risk for developing metabolic dysfunction‐associated steatohepatitis [18].

^k Fibrosis stage at randomization. Five patients in each group were categorized as F3 at eligibility screening and F4 at baseline screening by at least one pathologist; these patients were assigned as F3.

3.2. Efficacy

Among randomized patients with F2 and F3 fibrosis, 159 (17.3%) patients (53 [17.3%] in the resmetirom 80‐mg group, 67 [21.8%] in the resmetirom 100‐mg group, and 39 [12.9%] in the placebo group) had no biopsy at Week 52 and were treated as nonresponders in the primary end point analyses. Significantly greater percentages of those receiving resmetirom (25.7% in the 80‐mg group and 29.9% in the 100‐mg group) achieved MASH resolution with no worsening of fibrosis at Week 52 compared with those receiving placebo (9.5%; p < 0.0001 for both comparisons with placebo) (Table 2 and Figure 2A). In addition, significantly greater percentages of patients in the resmetirom 80‐mg (26.5%) and 100‐mg (28.9%) groups achieved ≥ 1‐stage improvement in fibrosis stage with no worsening of NAS at Week 52 compared with patients in the placebo group (17.3%; p = 0.0017 for 80 mg and p < 0.0001 for 100 mg compared with placebo) (Table 2 and Figure 2B). MAESTRO‐NASH included a consensus read of biopsy specimens for which the primary pathologists disagreed on response status for either primary end point; for these cases, two pathologists who were blinded to biopsy timepoint and patient identification code independently reviewed digitized images to reach a consensus determination of response [16]. When response status from this consensus read was used and missing biopsies were handled by placebo‐based or MAR multiple imputation, the risk difference for resmetirom compared with placebo improved for both end points (Table 3).

TABLE 2.

Biopsy end points (fibrosis stages F2 and F3 patient subset).

End point	Resmetirom, 80 mg (N = 300)	Resmetirom, 100 mg (N = 306)	Placebo (N = 300)	Difference Between 80 mg Resmetirom and Placebo (95% CI)		Difference Between 100 mg Resmetirom and Placebo (95% CI)
	Percent with response			Percentage points	p	Percentage points	p
Primary end points
MASH resolution with no worsening of fibrosis	25.7	29.9	9.5	16.4 (10.8–21.9)	< 0.0001	20.7 (15.2–26.3)	< 0.0001
Fibrosis improvement by ≥ 1 stage with no worsening of NAS	26.5	28.9	17.3	9.4 (3.5–15.3)	0.0017	11.8 (5.9–17.6)	< 0.0001
Other end points
≥ 2‐point improvement in NAS, including ≥ 1‐point improvement in hepatocellular ballooning or lobular inflammation, with no worsening of fibrosis	41.3	44.6	21.7	19.9 (13.3–26.4)	< 0.0001	23.0 (16.4–29.5)	< 0.0001
≥ 2‐point improvement in NAS, including ≥ 1‐point improvement in hepatocellular ballooning or lobular inflammation, with improvement in fibrosis	19.2	21.2	8.7	10.7 (5.8–15.5)	< 0.0001	12.7 (7.9–17.5)	< 0.0001
Improvement in each component of NAS	23.3	28.4	7.2	16.3 (11.2–21.3)	< 0.0001	21.4 (16.2–26.6)	< 0.0001
Improvement in fibrosis by ≥ 2 stages	10.3	11.9	4.8	5.4 (1.9–9.0)	0.0020	7.0 (3.3–10.7)	0.0002
Both MASH resolution and fibrosis improvement by ≥ 1 stage	15.5	17.5	5.7	10.0 (5.6–14.4)	< 0.0001	12.1 (7.7–16.6)	< 0.0001

Abbreviations: MASH, metabolic dysfunction‐associated steatohepatitis; NAS, nonalcoholic fatty liver disease activity score.

FIGURE 2.

Primary and Key Secondary End Points in the Fibrosis Stages F2 and F3 Patient Subset. Analysis in panels A and B was conducted on the Week 52 Liver Biopsy mITT population; patients with no valid biopsy during Week 52 were considered non‐responders for the primary end point analysis. LDL, low‐density lipoprotein; mITT, modified intent‐to‐treat; NAFLD, nonalcoholic fatty liver disease; MASH, metabolic dysfunction‐associated steatohepatitis.

TABLE 3.

Biopsy end points (fibrosis stages F2 and F3 patient subset): sensitivity analyses.

End point	Resmetirom, 80 mg (N = 300)	Resmetirom, 100 mg (N = 306)	Placebo (N = 300)	Difference between 80 mg resmetirom and placebo (95% CI)		Difference between 100 mg resmetirom and placebo (95% CI)
	Percent with response			Percentage points	Nominal p	Percentage points	Nominal p
Placebo‐based multiple imputation
MASH resolution
SAP‐based	28.1	32.7	11.3	17.0 (10.8–23.1)	< 0.0001	21.8 (15.6–28.0)	< 0.0001
Consensus‐based	26.1	29.9	9.1	17.3 (11.0–23.5)	< 0.0001	21.4 (15.1–27.7)	< 0.0001
Fibrosis improvement
SAP‐based	27.9	30.1	17.3	10.9 (4.5–17.2)	0.0017	12.8 (6.5–19.1)	0.0002
Consensus‐based	27.3	29.5	15.0	12.5 (5.5–19.5)	0.0011	14.6 (7.7–21.4)	0.0001
Missing‐at‐random multiple imputation
MASH resolution
SAP‐based	30.6	36.0	13.5	17.3 (10.7–23.8)	< 0.0001	23.0 (16.2–29.7)	< 0.0001
Consensus‐based	29.6	36.2	9.1	20.8 (14.3–27.4)	< 0.0001	27.9 (20.9–34.8)	< 0.0001
Fibrosis improvement
SAP‐based	32.0	35.7	21.8	10.5 (3.7–17.3)	0.0049	14.3 (7.3–21.2)	0.0001
Consensus‐based	29.9	33.8	15.1	15.0 (7.8–22.2)	0.0002	18.8 (11.5–26.1)	< 0.0001

Note: Adapted from European Medicines Agency Committee for Medicinal Products for Human Use (CHMP). Assessment Report: Rezdiffra. Accessed July 16, 2026. https://www.ema.europa.eu/en/documents/assessment‐report/rezdiffra‐epar‐public‐assessment‐report_en.pdf. EMA 2026.

Abbreviations: MASH, metabolic dysfunction‐associated steatohepatitis; SAP, statistical analysis plan.

From baseline to Week 24, LDL cholesterol decreased numerically by 11.7% in the 80‐mg resmetirom group and 13.7% in the 100‐mg resmetirom group, compared with a slight increase (by 2.3%) in the placebo group (p < 0.0001 for both comparisons with placebo) (Table 4 and Figure 2C). After 24 weeks, levels of triglycerides, apolipoprotein B, and lipoprotein(a) also showed numerically greater reductions from baseline among patients in either the 80‐ or 100‐mg resmetirom groups compared with those in the placebo group (Table 4). At Week 48, levels of alanine aminotransferase, aspartate aminotransferase, and γ‐glutamyl transferase had also declined among patients in the resmetirom groups compared with placebo (Table 4).

TABLE 4.

Key secondary and other secondary end points (Fibrosis stages F2 and F3 patient subset). ^a

Measurement	Resmetirom, 80 mg (N = 306)	Resmetirom, 100 mg (N = 308)	Placebo (N = 303)	Difference between 80 mg resmetirom and placebo (95% CI) b	Difference between 100 mg resmetirom and placebo (95% CI) b
	LS mean percent change from baseline			Percentage points
LDL cholesterol level at Week 24 c	−11.7 (−14.6 to −8.9)	−13.7 (−16.5 to −10.9)	2.3 (−0.5 to 5.1)	−14.1 (−17.9 to −10.2)	−16.0 (−19.8 to −12.2)
HDL cholesterol level at Week 24	3.6 (1.3 to 5.9)	3.0 (0.7 to 5.3)	2.8 (0.4 to 5.1)	0.9 (−2.3 to 4.0)	0.2 (−2.9 to 3.4)
Non‐HDL cholesterol level at Week 24	−14.1 (−16.6 to −11.6)	−16.1 (−18.6 to −13.6)	1.3 (−1.1 to 3.8)	−15.4 (−18.8 to −12.0)	−17.4 (−20.8 to −14.0)
Apolipoprotein B level at Week 24	−15.6 (−17.8 to −13.5)	−17.7 (−19.9 to −15.6)	1.1 (−1.0 to 3.2)	−16.7 (−19.6 to −13.8)	−18.8 (−21.7 to −15.9)
Triglyceride level at Week 24	−14.2 (−19.0 to −9.4)	−14.1 (−19.0 to −9.2)	6.2 (1.5 to 11.0)	−20.4 (−26.9 to −13.9)	−20.4 (−26.9 to −13.8)
Lipoprotein(a) level at Week 24	−22.1 (−33.9 to −10.3)	−30.4 (−40.3 to −20.4)	3.0 (−6.4 to 12.3)	−25.1 (−40.3 to −9.8)	−33.3 (−46.5 to −20.2)
MRI‐PDFF at Week 52	−31.2 (−36.2 to −26.1)	−40.7 (−45.7 to −35.6)	−7.1 (−12.2 to −2.1)	−24.1 (−30.9 to −17.2)	−33.6 (−40.4 to −26.8)
Alanine aminotransferase level at Week 48	−17.2 (−23.5 to −10.9)	−22.5 (−29.1 to −16.0)	1.0 (−5.4 to 7.5)	−18.2 (−27.1 to −9.5)	−23.6 (−32.5 to −14.7)
Aspartate aminotransferase level at Week 48	−13.8 (−20.0 to −7.6)	−18.7 (−25.0 to −12.3)	3.6 (−2.5 to 9.7)	−17.4 (−25.7 to −9.1)	−22.2 (−30.7 to −13.8)
γ‐Glutamyl transferase level at Week 48	−21.8 (−28.9 to −14.7)	−27.4 (−34.7 to −20.0)	5.7 (−1.2 to 12.5)	−27.5 (−36.8 to −18.1)	−33.0 (−42.7 to −23.4)

Abbreviations: HDL, high‐density lipoprotein; LDL, low‐density lipoprotein; MRI‐PDFF, magnetic resonance imaging proton density fat fraction.

^a Lipids and liver enzymes were assessed using multiple imputation analyses.

^b Widths of CIs were not adjusted for multiplicity and were not used for hypothesis testing.

^c Key secondary end point.

3.3. Safety

Similar percentages of patients experienced ≥ 1 adverse event (AE) across the 80‐mg resmetirom (92.2%), 100‐mg resmetirom (91.2%), and placebo groups (92.4%) (Table 5). Most AEs (> 75% in each group) were mild or moderate in severity, with the most commonly reported AEs across the 3 treatment groups being diarrhoea, COVID‐19, and nausea (Table 5). Diarrhoea, nausea, pruritus, and vomiting were more common in both resmetirom groups compared with placebo; other types of AEs occurred with similar frequencies across groups.

TABLE 5.

Safety summary (fibrosis stages F2 and F3 patient subset).

Event	Resmetirom, 80 mg (N = 306)	Resmetirom, 100 mg (N = 308)	Placebo (N = 303)
≥ 1 Adverse event	282 (92.2)	281 (91.2)	280 (92.4)
Maximum severity
Grade 1: mild	69 (22.5)	64 (20.8)	75 (24.8)
Grade 2: moderate	172 (56.2)	173 (56.2)	155 (51.2)
Grade 3 or higher: severe	41 (13.4)	44 (14.3)	50 (16.5)
≥ 1 Adverse event considered by investigator to be related to resmetirom or placebo	119 (38.9)	127 (41.2)	85 (28.1)
≥ 1 Serious adverse event	33 (10.8)	39 (12.7)	36 (11.9)
≥ 1 Serious adverse event considered by investigator to be related to resmetirom or placebo	2 (0.7)	0 (0.0)	1 (0.3)
Adverse event leading to trial discontinuation before Week 52 a	4 (1.3)	20 (6.5)	7 (2.3)
Diarrhoea	1 (0.3)	6 (1.9)	1 (0.3)
Nausea	2 (0.7)	3 (1.0)	0
Vomiting	1 (0.3)	2 (0.6)	1 (0.3)
Abdominal pain	2 (0.7)	0	1 (0.3)
Abdominal discomfort	0	2 (0.6)	0
Obesity	1 (0.3)	1 (0.3)	0
Pruritus	0	1 (0.3)	1 (0.3)
Rash	0	1 (0.3)	1 (0.3)
Adverse event leading to trial discontinuation during entire treatment period b	7 (2.3)	23 (7.5)	11 (3.6)
Fatal adverse event	0 (0.0)	2 (0.6)	1 (0.3)
Major cardiovascular event c	1 (0.3)	1 (0.3)	1 (0.3)
Other cardiovascular event c	0 (0.0)	1 (0.3)	3 (1.0)
Adverse events occurring in > 10% of patients within any treatment group
Diarrhoea	83 (27.1)	102 (33.1)	47 (15.5)
COVID‐19	65 (21.2)	50 (16.2)	61 (20.1)
Nausea	67 (21.9)	58 (18.8)	37 (12.2)
Arthralgia	47 (15.4)	34 (11.0)	38 (12.5)
Back pain	33 (10.8)	25 (8.1)	35 (11.6)
Fatigue	33 (10.8)	25 (8.1)	27 (8.9)
Urinary tract infection	31 (10.1)	26 (8.4)	25 (8.3)
Pruritus	24 (7.8)	35 (11.4)	20 (6.6)
Vomiting	28 (9.2)	34 (11.0)	16 (5.3)

Note: Values expressed as n (%) of patients.

^a Includes adverse events that led to trial discontinuation prior to Week 52 in at least 0.2% of the overall trial population.

^b For discontinuations that occurred after the first resmetirom or placebo dose and within 30 days after the last resmetirom or placebo dose.

^c Nonfatal strokes, nonfatal myocardial infarctions, or death from cardiovascular cause were considered major cardiovascular events; all cardiovascular events were adjudicated.

Percentages of patients reporting ≥ 1 serious AE were 10.8%, 12.7%, and 11.9% in the 80‐mg resmetirom, 100‐mg resmetirom, and placebo groups, respectively (Table 5). Two patients in the 80‐mg resmetirom group and 1 patient in the placebo group reported ≥ 1 serious AE that was considered by the investigator to be potentially related to treatment, and no treatment‐related serious AEs occurred in the 100‐mg resmetirom group. Trial discontinuations owing to AEs were more frequent in the 100‐mg resmetirom group (6.5%) than in either the 80‐mg resmetirom group (1.3%) or the placebo group (2.3%). The most common AEs leading to discontinuation in the overall trial population included diarrhoea (0.9%), nausea (0.5%), vomiting (0.4%), abdominal pain (0.3%), abdominal discomfort (0.2%), obesity (0.2%), pruritus (0.2%), and rash (0.2%); among these, gastrointestinal AEs were more frequent with resmetirom 100 mg and/or 80 mg versus placebo (Table 5).

One patient in each of the 3 groups experienced a major cardiovascular event. Two patients in the 100‐mg resmetirom group experienced fatal AEs; one died due to an intracardiac thrombus related to a prosthetic valve, and the other experienced cholestasis relating to a recurrent, preexisting lymphoma and died subsequent to the Week 52 analysis cutoff date. One patient in the placebo group died due to unknown causes, with the exact cause of death undetermined because the family did not provide additional information. None of the fatal AEs were considered related to study drug by the Investigator.

4. Discussion

This post hoc analysis aims to provide a consolidated report that bridges the results from the prespecified patient population in the randomized MAESTRO‐NASH study with the population included in the FDA and EMA labels for resmetirom (i.e., the subset of patients who had stage F2 or F3 fibrosis) [11, 13]. Results of this analysis were entirely consistent with previously published results from the primary analysis population [16], demonstrating that primary efficacy and key secondary end points were met among this patient subset. These data are important for future meta‐analyses comparing results across therapies among patients with stage 2 or 3 fibrosis with MASH.

Both evaluated doses of resmetirom were associated with MASH resolution with no worsening of fibrosis and an improvement in fibrosis by ≥ 1 stage with no worsening of the NAS by Week 52. In addition, both doses were associated with significantly greater declines in LDL‐cholesterol levels by Week 24 relative to placebo and reductions in cardiovascular risk markers including triglycerides, apolipoprotein B, and lipoprotein(a). Per FDA guidance, these results are reasonably likely to predict clinical benefit for patients with MASH, which will be determined at the conclusion of the 54‐month MAESTRO‐NASH clinical trial [14, 16]. The prevalence of cardiometabolic risk factors was nearly identical between the FDA and EMA label populations (78.1% vs. 78.0% with hypertension, 71.3% vs. 71.1% with dyslipidemia, and 67.0% vs. 67.0% with type 2 diabetes, respectively) [16], a notable consideration given the association of these factors with mortality and disease progression in MASH.

Safety results were also consistent between the primary analysis population and the FDA label population, supporting previous data from phase 2 and 3 trials indicating an acceptable tolerability profile [16, 21, 22]. Diarrhoea, nausea, pruritus, and vomiting were more frequently reported among patients who received resmetirom than among those who received placebo, but overall percentages of patients who experienced AEs and serious AEs were similar across resmetirom and placebo groups.

After trial completion at 54 months, we will be able to evaluate longer‐term safety in addition to all‐cause mortality, liver transplant, and other significant hepatic events, histological progression to cirrhosis, and Model for End Stage Liver Disease (MELD) score increase in order to confirm treatment benefit [16].

Results support the continued indication of resmetirom specifically for adults with MASH and stages F2 and F3 fibrosis, consistent with current US and EU labeling [11, 13]. While the conclusions are consistent between this post hoc analysis and the original MAESTRO‐NASH report, this report aims to bridge prespecified pivotal trial evidence and regulatory label information, providing consistent medical education for healthcare professionals managing treatment of adults with noncirrhotic MASH.

Author Contributions

Jörn M. Schattenberg: writing – review and editing. David Schneider: writing – review and editing. Krishna Padmanabhan: formal analysis, writing – review and editing. Rohit Loomba: conceptualization, formal analysis, writing – original draft, writing – review and editing. Maria Mironova: formal analysis, writing – review and editing.

Funding

This study was supported by Madrigal Pharmaceuticals. RL also receives funding support from NIDDK (P30DK120515) and John C Martin Foundation (RP124). [Correction added on 18 August 2026, after first online publication: The Funding section has been revised in this version].

Conflicts of Interest

M.M. has no conflicts of interest. K.P. and D.S. are employees and shareholders of Madrigal Pharmaceuticals. J.M.S. declares consultant honoraria from Akero, Alexion, Altimmune, Astra Zeneca, 89Bio, Boehringer Ingelheim, Gilead Sciences, GSK, Ipsen, Inventiva Pharma, Madrigal Pharmaceuticals, Merck Kríya Therapeutics, Echosens, Eli Lilly, E‐Therapeutics, Merck, MSD Sharp & Dohme GmbH, Novo Nordisk, Roche, and Vantage Biosciences LtD; speaker honoraria from AbbVie, Boehringer Ingelheim, Gilead Sciences, Ipsen, Lilly, Madrigal Pharmaceuticals, MSD, Novo Nordisk, and Opella; travel support from Boerhringer Ingelheim, and IPSEN; and stockholder options with Hepta Bio, and HeapCure Pharma. R.L. serves as a consultant to Aardvark Therapeutics, Altimmune, Arrowhead Pharmaceuticals, AstraZeneca, Cascade Pharmaceuticals, Eli Lilly, Gilead, Glympse bio, Inipharma, Intercept, Inventiva, Ionis, Janssen Inc., Lipidio, Madrigal, Neurobo, Novo Nordisk, Merck, Pfizer, Sagimet, 89 bio, Takeda, Terns Pharmaceuticals, and Viking Therapeutics. R.L. has stock options in Sagimet biosciences. In addition, his institution received research grants from Arrowhead Pharmaceuticals, Astrazeneca, Boehringer‐Ingelheim, Bristol‐Myers Squibb, Eli Lilly, Galectin Therapeutics, Gilead, Intercept, Hanmi, Intercept, Inventiva, Ionis, Janssen, Madrigal Pharmaceuticals, Merck, Novo Nordisk, Pfizer, Sonic Incytes, and Terns Pharmaceuticals. R.L. is a co‐founder of LipoNexus Inc.

Mironova M., Padmanabhan K., Schneider D., Schattenberg J. M., and Loomba R., “Clinical Trial: Phase 3 Trial of Resmetirom Versus Placebo in Metabolic Dysfunction‐Associated Steatohepatitis—Reanalysis of Fibrosis Stage 2–3 Subset,” Alimentary Pharmacology & Therapeutics 64, no. 7 (2026): 919–929, 10.1111/apt.70888.

Data Availability Statement

The data that support the findings of this study are available from the corresponding author upon reasonable request.