MAESTRO-NASH Results in Detail: Numbers, Subgroups, and Time Course

At a glance

Parameter	Detail
Trial name	MAESTRO-NASH (NCT03900429)
N randomized	966 (intent-to-treat population for 52-week biopsy)
Intervention	Resmetirom 80 mg or 100 mg once daily
Comparator	Matching placebo
Duration	52 weeks (primary biopsy endpoint), with 54-month extension ongoing
Primary endpoints	(1) NASH resolution with no worsening of fibrosis; (2) Improvement in fibrosis by ≥1 stage with no worsening of NAS
Key result	Both doses met both co-primary endpoints (p < 0.001 for all comparisons vs placebo)

Trial Design and Population

MAESTRO-NASH was a phase 3, double-blind, randomized, placebo-controlled trial that enrolled adults with biopsy-confirmed NASH (NAS ≥4) and fibrosis stages F1B through F3. The trial randomized approximately 1,050 patients across three arms (1:1:1) to resmetirom 80 mg, resmetirom 100 mg, or placebo. The primary publication in the New England Journal of Medicine details the 52-week biopsy results from 966 patients in the intent-to-treat population who had evaluable paired biopsies.

Key enrollment criteria included age 18 and older, body mass index between 25 and 45 kg/m², and histologic confirmation of NASH with a NAS of at least 4 (with at least 1 point each in steatosis, lobular inflammation, and hepatocyte ballooning). Patients with cirrhosis (F4) were excluded from the primary efficacy analysis, though a separate safety cohort enrolled compensated cirrhotic patients.

The population was roughly 56% female, had a mean age of approximately 54 years, and a mean BMI near 36 kg/m². About 67% had type 2 diabetes. Fibrosis stage distribution at baseline: approximately 24% F1B, 30% F2, and 46% F3. This heavy weighting toward F3 is clinically important because these patients sit closest to progression into cirrhosis.

Co-Primary Endpoint 1: NASH Resolution

NASH resolution (defined as ballooning score of 0, inflammation score of 0 or 1, and no worsening of fibrosis stage) at week 52 was achieved by:

The number needed to treat (NNT) was approximately 6 for the 80 mg dose and 5 for the 100 mg dose, a meaningful treatment effect for a histological endpoint in a liver disease trial. The placebo response rate of 9.7% aligns with historical placebo rates in NASH biopsy trials, which typically range from 8% to 19% depending on endpoint stringency. The FDA's approval review noted this consistency as supporting the trial's internal validity.

Co-Primary Endpoint 2: Fibrosis Improvement

Fibrosis improvement by at least one stage (with no worsening of NAS) at week 52:

The placebo fibrosis improvement rate of 14.2% reflects the known phenomenon of fibrosis stage regression on serial biopsies, partly real biology and partly sampling variability in a patchy disease. This is exactly why the NASH field moved toward dual co-primary endpoints. Fibrosis regression is harder to separate from noise than NASH resolution, and the confidence intervals here are accordingly wider.

Composite Responder Analysis: Both Endpoints Combined

A secondary analysis examined patients who achieved both NASH resolution and fibrosis improvement simultaneously. This composite outcome captures the patients with the clearest histological benefit:

These composite rates are lower than either individual endpoint, which is expected. Still, tripling the dual-responder rate versus placebo represents a clinically meaningful shift in the proportion of patients experiencing genuine histological improvement across both inflammation and fibrosis axes.

Secondary and Exploratory Endpoints

Liver Fat Reduction (MRI-PDFF)

Resmetirom produced substantial reductions in hepatic fat content measured by MRI-derived proton density fat fraction. At week 52, relative reductions from baseline in liver fat were approximately:

• 80 mg: -32.9% relative change
• 100 mg: -36.0% relative change
• Placebo: -8.1% relative change

The separation between active and placebo arms was apparent by week 12 and widened through week 24 before reaching a plateau. This time-course pattern is consistent with the mechanism of action: resmetirom activates thyroid hormone receptor beta (THR-β) in hepatocytes, increasing mitochondrial fatty acid oxidation and reducing lipotoxic lipid species. The fat reduction occurs upstream of inflammation and fibrosis improvement, which is why imaging changes precede and predict histological changes. As reported in the primary publication, patients who achieved ≥30% relative fat reduction were significantly more likely to meet the co-primary endpoints.

Serum Biomarkers

The LDL and triglyceride reductions are mechanistically expected because THR-β activation in the liver increases LDL receptor expression and promotes triglyceride clearance, the same pathways by which endogenous thyroid hormone regulates lipid metabolism. The SHBG increase is a pharmacodynamic marker of hepatic THR-β engagement and serves as an indirect measure of target activation.

ALT levels decreased significantly from baseline in both resmetirom arms (approximately -20 to -25 U/L) compared with placebo, suggesting reduced hepatocellular injury parallel to the histological improvement.

Subgroup Analyses

Prespecified subgroup analyses from the primary trial report showed generally consistent treatment effects across:

• Fibrosis stage at baseline (F2 vs F3): Both stages showed significant benefit. F2 patients had numerically higher NASH resolution rates. F3 patients showed slightly more fibrosis improvement, likely due to more room for stage regression.
• Diabetes status: Patients with and without type 2 diabetes showed similar histological response rates. This is notable because earlier NASH drug candidates (e.g., pioglitazone) worked primarily through insulin sensitization and showed attenuated effects in non-diabetic populations.
• BMI categories: Treatment effects were consistent across BMI strata, though confidence intervals widened in the <30 and >40 subgroups due to smaller sample sizes.
• Sex: Men and women responded similarly on both co-primary endpoints.
• Baseline NAS score: Patients with NAS ≥5 had higher absolute responder rates than those with NAS 4, but the treatment difference versus placebo was consistent.

The interaction p-values for all major subgroups were non-significant, supporting the conclusion that resmetirom's effect is not driven by a single demographic or clinical subset.

Safety Profile

Diarrhea and nausea were the most common adverse events in the resmetirom arms (approximately 27-33% for GI events combined vs. 17-19% on placebo). Most GI symptoms were mild to moderate, occurred in the first 12 weeks, and attenuated over time. Discontinuation rates due to adverse events were 6.8% (80 mg), 8.6% (100 mg), and 4.5% (placebo).

The safety review also focused on:

• Thyroid function: TSH levels decreased modestly in both active arms (reflecting pituitary THR-β feedback), but free T4 and T3 remained within normal ranges. No clinical thyrotoxicosis was reported.
• Bone density: No significant changes in bone mineral density at 52 weeks. This addresses a theoretical concern given the known skeletal effects of systemic thyroid hormone excess. Resmetirom's 28-fold selectivity for THR-β over THR-α limits extra-hepatic effects.
• Cardiac effects: No increase in atrial fibrillation, heart rate changes, or cardiac events. Heart rate differences between groups were <1 bpm on average.
• Gallbladder events: Slightly higher rates of cholelithiasis in active arms (1.7% vs 0.6%), consistent with increased bile acid flux from hepatic THR-β activation. The FDA label for Rezdiffra includes this as an identified risk.

What the Trial Does Not Tell Us

Several limitations deserve attention for clinical decision-making:

1. No cirrhotic efficacy data yet. F4 patients were enrolled only in a safety cohort. Whether resmetirom can reverse established cirrhosis or prevent decompensation remains unknown until the 54-month extension data reads out.
2. 52-week biopsy window. Fibrosis remodeling is slow. Some patients who did not meet the fibrosis endpoint at 52 weeks may have been on trajectory for improvement. The 54-month data will clarify durability.
3. Histological endpoints vs. clinical outcomes. NASH resolution and fibrosis stage improvement are accepted surrogate endpoints, but the trial was not powered for hard clinical outcomes (liver transplant, liver-related mortality, hepatic decompensation). The AASLD practice guidance on MASLD notes this surrogate-to-outcome gap as a field-wide limitation.
4. Concomitant medications. Patients on GLP-1 receptor agonists, SGLT2 inhibitors, and other metabolic therapies were included but not stratified at randomization. Whether resmetirom's effect is additive with these agents requires dedicated study.
5. Biopsy sampling error. NASH is heterogeneously distributed across the liver. A single core biopsy may not represent global disease status. This affects both arms equally but adds noise to individual-level response classification.

Regulatory Outcome and Clinical Positioning

The FDA granted accelerated approval to resmetirom (brand name Rezdiffra) on March 14, 2024, for adults with non-cirrhotic NASH with moderate-to-advanced fibrosis (F2-F3). This made it the first drug approved specifically for MASH/NASH, after decades of failed trials with other mechanisms (FDA approval announcement). Full approval is contingent on confirmation of clinical benefit in the ongoing extension study.

The accelerated approval pathway reflects confidence in the histological surrogate endpoints but also underscores that the drug's place in therapy will evolve as longer-term outcome data emerge.

Frequently asked questions

›What were the exact co-primary endpoints in MAESTRO-NASH?

The two co-primary endpoints were (1) NASH resolution, defined as hepatocyte ballooning score of 0 and lobular inflammation score of 0 or 1 with no worsening of fibrosis, and (2) improvement of liver fibrosis by at least one stage with no worsening of NAFLD Activity Score. Both were assessed by liver biopsy at 52 weeks and read by a central pathology panel blinded to treatment assignment.

›How large was the treatment effect for resmetirom versus placebo?

For NASH resolution, the absolute difference was 16.2 percentage points for 80 mg and 20.2 percentage points for 100 mg compared to placebo. For fibrosis improvement, the differences were 10.0 and 11.7 percentage points, respectively. All comparisons reached statistical significance with p < 0.001 or p = 0.002.

›Did resmetirom work in patients with and without type 2 diabetes?

Yes. Subgroup analyses showed consistent treatment effects regardless of diabetes status. This distinguishes resmetirom from insulin-sensitizing agents like pioglitazone, which tend to show stronger effects in diabetic NASH populations.

›What were the main side effects of resmetirom in MAESTRO-NASH?

Gastrointestinal symptoms (diarrhea and nausea) were the most frequent adverse events, affecting roughly 27-33% of patients on active drug versus 17-19% on placebo. Most were mild to moderate and occurred early in treatment. Discontinuation rates for adverse events were modestly higher in the active arms (6.8-8.6% vs. 4.5%).

›Does resmetirom affect thyroid function?

Resmetirom modestly lowered TSH through pituitary THR-β feedback, but free T4 and free T3 remained in normal ranges. No clinical thyrotoxicosis was observed. The drug's selectivity for THR-β over THR-α (28-fold) limits systemic thyroid-like effects on heart and bone.

›How quickly did liver fat decrease during MAESTRO-NASH?

MRI-PDFF data showed significant liver fat reduction by week 12, with continued improvement through week 24 and a plateau thereafter. The early fat reduction is mechanistically upstream of the later inflammation and fibrosis improvements observed at the 52-week biopsy.

›Is resmetirom approved for patients with cirrhosis?

No. The FDA's accelerated approval covers non-cirrhotic MASH with fibrosis stages F2 and F3 only. Patients with compensated cirrhosis (F4) were enrolled in a separate safety cohort, and efficacy data for this group will come from the ongoing 54-month extension study.

›What happens after resmetirom's accelerated approval?

Full approval depends on the ongoing MAESTRO-NASH extension study, which evaluates long-term clinical outcomes including progression to cirrhosis, hepatic decompensation, liver transplantation, and liver-related death over 54 months. These hard clinical endpoints will determine whether the histological improvements translate to meaningful clinical benefit.

›How does resmetirom compare to other MASH drug candidates?

Resmetirom is the only FDA-approved MASH therapy as of 2024. Other candidates in late-stage development target different mechanisms (FGF21 analogues, pan-PPAR agonists, GLP-1 receptor agonists with liver-specific effects). No head-to-head trial data exist between resmetirom and these agents.

›Were there any effects on cardiovascular risk markers?

Yes. Resmetirom reduced LDL cholesterol by 13.6-16.3%, triglycerides by 16.5-20.1%, and apolipoprotein B by approximately 12-18% compared with placebo. These lipid effects are driven by hepatic THR-β activation and may offer ancillary cardiovascular benefit in a population with high baseline metabolic risk.

References

1. Harrison SA, Bedossa P, Guy CD, et al. A Phase 3, Randomized, Controlled Trial of Resmetirom in NASH with Liver Fibrosis. N Engl J Med. 2024;390(6):497-509. PubMed
2. U.S. Food and Drug Administration. Rezdiffra (resmetirom) NDA 217785 Approval Package. 2024. FDA
3. U.S. Food and Drug Administration. Rezdiffra Prescribing Information. 2024. Label
4. Rinella ME, Lazarus JV, Ratziu V, et al. A Multi-society Delphi Consensus Statement on New Fatty Liver Disease Nomenclature. Hepatology. 2023;78(6):1966-1986. PubMed
5. Rinella ME, Neuschwander-Tetri BA, Siddiqui MS, et al. AASLD Practice Guidance on the Clinical Assessment and Management of Nonalcoholic Fatty Liver Disease. Hepatology. 2023;77(5):1797-1835. PubMed
6. Harrison SA, Bashir MR, Guy CD, et al. Resmetirom (MGL-3196) for the Treatment of Non-alcoholic Steatohepatitis: A Multicentre, Randomised, Double-blind, Placebo-controlled, Phase 2 Trial. Lancet. 2019;394(10213):2012-2024. PubMed