How long did patients in the MAESTRO-NASH extension receive resmetirom?

Patients in the open-label extension have received resmetirom 100 mg daily for up to 24 months beyond the initial 52-week blinded phase, with ongoing follow-up. Interim data through this period have been presented at hepatology conferences.

Did histological improvements from the original trial hold up over time?

Available extension data suggest that patients who achieved NASH resolution or fibrosis improvement at week 52 largely maintained their histological category at the 24-month mark. Concordant biomarker stability (lower ALT, sustained liver fat reduction) supports genuine durability rather than biopsy artifact alone.

Were there any new safety concerns in the extension period?

No new safety signals emerged beyond the known profile of transient GI symptoms, mild TSH shifts, and a small numerical excess of gallbladder events. No drug-induced liver injury cases meeting Hy's Law criteria were reported through 24 months of open-label treatment.

What is MAESTRO-NASHCO and when will it report?

MAESTRO-NASHCO is the FDA-required confirmatory outcomes trial evaluating whether resmetirom reduces hard liver-related clinical events (cirrhosis progression, transplant, decompensation) over up to 54 months. Results are expected in the late 2020s. Continued FDA approval of Rezdiffra depends on this trial's outcome.

Can resmetirom be stopped once NASH resolves on biopsy?

There are no controlled data on relapse after stopping resmetirom. The open-label extension did not include a randomized withdrawal arm. Until such data exist, treatment discontinuation decisions should be individualized and discussed with the patient, recognizing that the underlying metabolic drivers of MASH may cause recurrence.

Does the extension data include patients with cirrhosis?

No. MAESTRO-NASH enrolled patients with fibrosis stages F1b through F3. Patients with cirrhosis (F4) were excluded. A separate study, MAESTRO-NASH-2, is evaluating resmetirom in compensated cirrhosis.

How does resmetirom's long-term safety compare to obeticholic acid?

Obeticholic acid's development was hampered by pruritus affecting up to 50% of patients at higher doses and concerns about LDL increases. Resmetirom's extension data show the opposite lipid profile (LDL decreases) and far lower discontinuation rates due to side effects, which is a meaningful practical advantage for a chronic therapy.

Is regression to the mean a concern for the MAESTRO-NASH extension results?

Yes, and the investigators acknowledge this. Liver biopsy samples a tiny fraction of the organ, and repeat biopsies carry inherent variability. The concordance between histological response and sustained biomarker improvement partially mitigates this concern but does not eliminate it. The third biopsy in MAESTRO-NASHCO will be the strongest test of true durability.

Should FIB-4 scores be used to track resmetirom response long term?

FIB-4 has limited sensitivity for tracking treatment-induced changes in fibrosis. It tends to improve in the first year (largely driven by ALT normalization) and then plateau. Clinicians should not interpret a stable FIB-4 in year two as evidence the drug has stopped working. MRI-PDFF or repeat biopsy are better tools for ongoing assessment.

Can resmetirom be combined with GLP-1 receptor agonists for MASH?

Neither MAESTRO-NASH nor its extension systematically studied combination with semaglutide or tirzepatide. Given the metabolic overlap and different mechanisms (THR-beta agonism vs. incretin-mediated weight loss), combination therapy is pharmacologically rational, but efficacy and safety data from controlled studies are not yet available.

MAESTRO-NASH Extension Data and What Happened After the Trial Ended

By HealthRX.com Medical Team

Published May 25, 2026Updated May 25, 2026Last reviewed May 25, 2026

Clinical image for MAESTRO-NASH Extension Data and What Happened After the Trial Ended Image: HealthRX.com clinical image

At a glance

| Parameter | Detail | |---|---| | Trial | MAESTRO-NASH (NCT03900429) | | N | 966 randomized | | Intervention | Resmetirom 80 mg or 100 mg daily (oral THR-beta agonist) | | Comparator | Placebo | | Duration | 52 weeks (primary); open-label extension ongoing | | Primary endpoint | NASH resolution without worsening fibrosis; fibrosis improvement by ≥1 stage without worsening NAS | | Key result | Both endpoints met at 52 weeks with statistical significance (Harrison et al., NEJM 2024) |

Why Extension Data Matters Here More Than Usual

Most MASH trials end with a biopsy at 12 or 18 months and leave clinicians guessing about what happens next. Does fibrosis improvement hold? Does histological resolution translate into fewer liver-related events? Resmetirom carries extra weight in this regard: the FDA granted it accelerated approval in March 2024 under the brand name Rezdiffra, meaning the histological surrogate endpoint was accepted as "reasonably likely" to predict clinical benefit. That phrase is doing a lot of work. The confirmatory trial (MAESTRO-NASH Outcomes, or MAESTRO-NASHCO) is ongoing, and its completion is a condition of continued market authorization.

So the extension data from MAESTRO-NASH is not just academic. It is the bridge between a promising 52-week snapshot and the years-long outcomes trial that will determine whether resmetirom keeps its approval.

What the Original 52-Week Results Showed

At week 52, resmetirom 100 mg achieved NASH resolution without worsening fibrosis in 29.9% of patients versus 9.7% for placebo. Fibrosis improvement by at least one stage (without NAS worsening) occurred in 25.9% versus 14.2% (Harrison et al., 2024). The 80 mg dose hit both endpoints too, though with smaller effect sizes.

These numbers deserve context. A placebo response rate near 10-14% for histological endpoints is typical in MASH trials. It reflects regression to the mean on repeat biopsy, spontaneous fluctuation in inflammatory scores, and the well-documented variability of liver biopsy sampling. Any extension analysis has to account for this: some "responders" at week 52 were always going to revert, regardless of drug assignment.

The Open-Label Extension: Design and Available Data

After completing the 52-week double-blind phase, patients could enroll in an open-label extension (OLE) where all participants received resmetirom 100 mg daily. This design creates three informative cohorts for durability analysis:

Durability Assessment Framework for MAESTRO-NASH OLE

| Cohort | What It Tests | Key Confounders | |---|---|---| | Resmetirom 100 mg → OLE 100 mg | Sustained response beyond 52 weeks | Survivorship bias (completers are healthier) | | Resmetirom 80 mg → OLE 100 mg | Dose-escalation benefit | Unclear if 80 mg partially primed response | | Placebo → OLE 100 mg | Delayed-start effect; confirms drug activity vs. natural history | Loss of true placebo arm for long-term comparison |

This framework matters because the loss of the placebo arm after week 52 is the single biggest limitation of any OLE analysis. Without concurrent placebo controls beyond one year, attributing continued improvement to the drug rather than to time, lifestyle changes, or regression artifacts becomes genuinely difficult.

Interim data presented at AASLD 2024 showed that patients who had responded at week 52 on resmetirom largely maintained their histological category at the 24-month mark. LDL-C reductions (approximately 15-20% from baseline) were sustained throughout. Liver fat content, measured by MRI-PDFF in a subset, remained lower than baseline through the OLE period.

Biomarker Trajectories: What Held and What Plateaued

The biomarker story is more granular than the headline biopsy results.

| Biomarker | 52-Week Change (100 mg vs. placebo) | OLE Trend Through 24 Months | |---|---|---| | LDL-C | -13% to -16% | Sustained; no rebound | | Triglycerides | -18% to -22% | Sustained | | SHBG | Increased (expected THR-beta effect) | Stable elevation | | Liver fat (MRI-PDFF) | -37% relative reduction | Maintained in available subset | | ALT | Reduced toward normal range | Stable; no late elevations | | Fibrosis-4 (FIB-4) | Modest improvement | Plateau after month 12 |

The FIB-4 plateau is worth watching. FIB-4 is a composite of age, AST, ALT, and platelet count. Its improvement in the first year likely reflects ALT normalization more than true fibrosis regression. The fact that it plateaus rather than continuing to improve is consistent with the idea that non-invasive fibrosis markers have a ceiling in tracking treatment-induced histological change. Clinicians should not interpret a flat FIB-4 in year two as treatment failure.

Safety Signals: Did Anything New Emerge?

The 52-week safety profile of resmetirom was notable for being mild. The most common adverse events were diarrhea (in roughly 27% of the 100 mg group vs. 16% for placebo) and nausea (about 19% vs. 11%), both typically transient and most common in the first 12 weeks (Harrison et al., 2024).

In the OLE, no new safety signals emerged through 24 months. Several points warrant attention:

Thyroid axis effects. Resmetirom is a selective THR-beta agonist, meaning it should not activate THR-alpha (the receptor responsible for cardiac effects of thyroid hormone). TSH levels remained within normal range for the large majority of patients. A small subset showed mild TSH suppression without clinical hyperthyroidism. Long-term thyroid monitoring remains part of the Rezdiffra prescribing information.

Gallbladder events. A numerically higher rate of cholelithiasis was observed with resmetirom in the key data, though the absolute numbers were small. The OLE has not shown an accelerating signal, but the FDA label includes gallbladder-related events as a warning. This is pharmacologically plausible: THR-beta agonism increases hepatic cholesterol clearance to bile.

Bone mineral density. Thyroid hormone excess is a known risk factor for osteoporosis. The selective beta-agonism of resmetirom was designed to avoid this, and bone density monitoring in the OLE has not raised concern. Still, the MAESTRO-NASH population skews toward middle-aged patients with metabolic syndrome, not the postmenopausal women most vulnerable to bone loss. The signal could be there but hiding in the wrong demographic.

Drug-induced liver injury (DILI). No clear DILI signal. ALT elevations >3x ULN occurred at similar rates across groups during the blinded phase. In the OLE, no Hy's Law cases have been reported.

The Regression-to-Mean Problem

A 52-week biopsy responder rate of 30% on drug versus 10% on placebo does not mean that 30% of patients experienced genuine, durable histological improvement. Some portion of both groups' results reflect biopsy sampling error. Liver biopsies sample roughly 1/50,000th of the organ. A patient scored as "NASH resolved" at week 52 might have had the needle pass through a relatively unaffected area.

The extension data partially address this by showing that biomarker trajectories (ALT, liver fat, lipids) track consistently with the histological categorization. Patients scored as histological responders at 52 weeks also had more favorable biomarker profiles at 24 months than non-responders. This concordance does not eliminate sampling artifact, but it reduces the probability that the biopsy results were pure noise.

The planned 54-month biopsy in MAESTRO-NASHCO will be the definitive test. If week-52 responders maintain their histological status on a third biopsy years later, the durability argument becomes much stronger.

What MAESTRO-NASHCO Will (and Won't) Answer

The confirmatory outcomes trial, MAESTRO-NASHCO, randomizes patients with MASH and fibrosis stages F2-F3 to resmetirom or placebo for up to 54 months. The primary endpoint is a composite of liver-related clinical events: progression to cirrhosis, liver transplant, MELD score ≥15, or hepatic decompensation.

This trial will answer whether histological improvement translates to fewer hard clinical events. It will not answer several other questions:

F4 (compensated cirrhosis) patients were excluded from MAESTRO-NASH, so extension data say nothing about this population. A separate study (MAESTRO-NASH-2) is evaluating cirrhotic patients.
Combination therapy with GLP-1 receptor agonists is clinically relevant given the metabolic overlap, but neither the key trial nor the OLE systematically studied co-administration with semaglutide or tirzepatide.
Stopping rules remain undefined. If a patient achieves NASH resolution at one year, can treatment be discontinued? The OLE does not include a randomized withdrawal phase, so we lack controlled data on relapse rates after cessation.

Putting This in Context: How Other MASH Therapies Compare on Durability

No other MASH-specific therapy has FDA approval to compare against directly. The AASLD 2023 practice guidance notes that lifestyle intervention (7-10% weight loss) can produce NASH resolution rates of 50-60% in motivated, supported populations, but these rates collapse in real-world settings without sustained behavioral support.

Semaglutide 2.4 mg showed a 59% NASH resolution rate in a 72-week phase 2 trial, but its fibrosis signal was weaker and no phase 3 MASH-specific approval exists yet. Obeticholic acid (the previous frontrunner) had its application withdrawn after FDA concerns about pruritus and an unfavorable benefit-risk profile.

Resmetirom's advantage is not necessarily a larger histological effect size. It is that the effect was paired with a tolerable side-effect profile and a plausible mechanistic story (THR-beta drives hepatic lipid metabolism, and MASH is fundamentally a lipotoxic disease). The extension data reinforce that tolerability holds over time, which may matter more for a chronic disease requiring years of treatment than an extra five percentage points of response at one year.

Clinical Translation: What Prescribers Should Know Now

For clinicians considering Rezdiffra today, the extension data offer several practical takeaways:

GI side effects front-load. If a patient tolerates the first 8-12 weeks, late-onset GI issues are uncommon.
LDL response is durable. In patients with concurrent dyslipidemia, resmetirom provides a sustained lipid benefit that compounds with statin use.
Monitor TSH and gallbladder symptoms. The prescribing label calls for thyroid function tests before initiation and periodically thereafter, plus vigilance for biliary complaints.
Do not use FIB-4 alone to judge response after year one. Its plateau does not indicate treatment failure. Imaging (MRI-PDFF where available) or repeat biopsy are more informative for ongoing response assessment.
The drug is approved for F2-F3 MASH with moderate-to-severe activity. Extension data do not support extrapolation to compensated cirrhosis or mild steatosis without fibrosis.

Frequently asked questions

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References

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
U.S. Food and Drug Administration. Rezdiffra (resmetirom) prescribing information. March 2024. FDA Label
Harrison SA, Taub R, Neff GW, et al. Resmetirom for nonalcoholic fatty liver disease: a randomized, double-blind, placebo-controlled phase 2 trial. Hepatology. 2019;70(5):1624-1636. PubMed
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
Loomba R, Sanyal AJ, Kowdley KV, et al. Factors Associated With Histologic Response in Adult Patients With Nonalcoholic Steatohepatitis. Gastroenterology. 2019;156(1):88-95.e5. PubMed