MASH Drug Development Enters a New Era

Key Takeaways

• Resmetirom and semaglutide have established treatment options, while confirmatory studies must determine their effects on serious liver outcomes.

• Steatohepatitis resolution, fibrosis improvement, imaging changes, and clinical-event prevention are distinct measures of benefit.

• Incretin-based therapies, FGF21 analogues, and broader pathway interventions offer different development strategies with different evidence requirements.

• Combination regimens need direct evidence of added benefit; activity alongside stable background medication does not establish the value of initiating two agents together.

• Noninvasive patient identification and response monitoring must accommodate imperfect classification and uncertain treatment-response thresholds.

Metabolic dysfunction-associated steatohepatitis (MASH) brings together two closely connected treatment challenges: liver disease that can progress to serious complications and metabolic conditions that shape patients’ broader health needs. Fat accumulation and inflammation in the liver can be accompanied by progressive fibrosis, or scarring, while obesity, type 2 diabetes, and dyslipidemia add complexity to treatment selection and management.

The approvals of resmetirom and semaglutide have changed the therapeutic landscape for adults with noncirrhotic MASH and moderate-to-advanced fibrosis. They also establish distinct approaches to treatment: liver-directed thyroid hormone receptor agonism and glucagon-like peptide-1 (GLP-1) receptor agonism with broader metabolic effects. Their availability makes the relationship between hepatic and cardiometabolic benefits increasingly relevant to both prescribing and drug development.

Investigational therapies are broadening those approaches through additional incretin-based mechanisms, fibroblast growth factor 21 (FGF21) analogues, and interventions affecting inflammatory and fibrogenic pathways. For developers, the question is how these strategies can address remaining needs, including fibrosis improvement, treatment of advanced disease, and responses that individual therapies do not consistently achieve. Combination regimens offer another avenue, but their value requires direct clinical evidence.

The development agenda now extends from demonstrating a treatment effect to establishing where a medicine fits: which patients should receive it, how clinicians should assess response, and whether combining mechanisms improves benefit. Longer-term studies must also determine whether improvements measured in liver biopsies translate into fewer cases of cirrhosis, hepatic decompensation, transplantation, and death. Those answers will shape how an expanding range of therapies becomes a durable treatment strategy.

MASH biology extends beyond the amount of fat stored in the liver. Hepatocytes, the liver’s principal functional cells, interact with immune cells, endothelial cells lining blood vessels, and hepatic stellate cells involved in fibrogenic signaling. Researchers at Peking University and collaborating institutions mapped molecular changes across 61 human livers in a study published in Nature Genetics.¹ They identified a fibrosis-associated gene program enriched in advanced MASH, evidence suggesting communication between endothelial and stellate cells within fibrotic regions, and potentially protective functions of lipid-associated macrophages. The findings illustrate the different contributions interacting cell populations can make to disease.

Clinical development must establish what modifying these processes accomplishes. Resolution of steatohepatitis without worsening fibrosis and improvement in fibrosis without worsening steatohepatitis are distinct outcomes. Imaging-based liver-fat reduction provides another measure of activity, while prevention of liver-related clinical events requires longer observation. Success on one measure does not establish success on all of them.^2,3

Comparisons among medicines also require attention to treatment duration, baseline disease stage, placebo response, and handling of missing biopsies. The joint European guidance specifically cautions against comparing resmetirom and semaglutide efficacy directly across their separate pivotal trials.² Response percentages describe findings within a study; they do not establish a ranking across the pipeline.

Resmetirom is an oral, liver-directed thyroid hormone receptor beta (THR-β)-selective agonist. Its approved indication covers adults with noncirrhotic MASH and moderate-to-advanced fibrosis, corresponding to stages F2–F3, alongside diet and exercise.⁴

5 is a phase III placebo-controlled trial evaluating whether resmetirom resolves steatohepatitis and improves fibrosis in adults with biopsy-confirmed disease. Enrollment included fibrosis stages F1B, F2, and F3, a broader range than the approved indication. Investigators from clinical research centers, academic institutions, and Madrigal Pharmaceuticals presented a week-52 primary analysis involving 966 patients.⁵

Steatohepatitis resolution without worsening fibrosis occurred in 25.9% and 29.9% receiving 80 mg and 100 mg, respectively, versus 9.7% receiving placebo. Improvement in fibrosis by at least one stage without worsening the nonalcoholic fatty liver disease activity score occurred in 24.2% and 25.9%, versus 14.2%. Resmetirom also lowered low-density lipoprotein cholesterol, while diarrhea and nausea were more frequent than with placebo.

These histological improvements occurred without meaningful weight reduction. Earlier experimental work provides context: researchers reported in 2021 that resmetirom improved steatosis and disease activity in a mouse model without changing body weight.⁶ Reduced expression of fibrogenesis-related genes accompanied these effects. The experimental findings support the preclinical rationale without establishing the contribution of each pathway to human efficacy.

The European guidance suggests that resmetirom may be prioritized in some individuals without obesity and type 2 diabetes, or when GLP-1 receptor agonist treatment is already established or poorly tolerated.² These are practical recommendations rather than validated predictions of which drug will produce the best liver response in an individual.

Medication management also matters. Resmetirom increases exposure to certain statins, and some interacting drugs require avoidance or dose adjustment. Its clinical use must therefore fit into a regimen that may already address several cardiometabolic conditions.

Semaglutide has established that a GLP-1 receptor agonist can improve both major histological endpoints used in noncirrhotic MASH development. ESSENCE is a phase III placebo-controlled trial evaluating semaglutide’s effects on liver histology and longer-term outcomes in patients with biopsy-defined MASH and F2–F3 fibrosis. Investigators, including researchers at Virginia Commonwealth University and Novo Nordisk, published a planned week-72 analysis of the first 800 participants.⁷

Steatohepatitis resolution without worsening fibrosis occurred in 62.9% receiving semaglutide 2.4 mg weekly versus 34.3% receiving placebo. Fibrosis reduction without worsening steatohepatitis occurred in 36.8% versus 22.4%. Mean weight change was −10.5% versus −2.0%.

Investigational agents broaden receptor activity in different ways. Tirzepatide combines glucose-dependent insulinotropic polypeptide and GLP-1 receptor agonism. SYNERGY-NASH was a phase II dose-finding trial evaluating whether tirzepatide could resolve MASH without worsening fibrosis in adults with F2–F3 disease over 52 weeks. Researchers reported that the 15-mg dose produced this response in 62% of participants versus 10% receiving placebo.⁸ Fibrosis improvement without worsening MASH, a key secondary endpoint, occurred in 51% versus 30%.

Survodutide and pemvidutide instead combine GLP-1 and glucagon receptor agonism. A 48-week phase II placebo-controlled survodutide trial evaluated histological improvement in MASH without worsening fibrosis among adults whose fibrosis ranged from earlier-stage disease through advanced noncirrhotic disease demonstrated benefit on that primary endpoint.⁹ The endpoint measured improvement rather than complete MASH resolution.

IMPACT is a phase IIb placebo-controlled trial evaluating pemvidutide’s effects on MASH resolution and fibrosis improvement in F2–F3 disease. Its reported 24-week assessment met the MASH-resolution endpoint but not the fibrosis-improvement endpoint, establishing an early steatohepatitis response while leaving longer-term fibrosis efficacy unresolved.¹⁰

Mechanistic research is also examining changes associated with treatment. In a study published in 2025 in Nature Medicine, researchers at Novo Nordisk and collaborating academic institutions identified circulating proteins associated with both semaglutide treatment and MASH resolution, including proteins linked to metabolism, inflammation, and fibrosis.¹¹ These exploratory associations provide research directions, rather than a validated response test or proof that particular protein changes cause the clinical effect.

The ability to sustain treatment is another consideration. Gastrointestinal adverse events were prominent in the incretin trials. The European guidance also recommends nutritional assessment and attention to muscle mass and function during semaglutide treatment, particularly with rapid, substantial weight reduction.² Treatment implementation must accommodate these needs alongside metabolic and hepatic objectives.

FGF21 analogues offer another approach to metabolic function and liver disease. Experimental research supports effects involving multiple tissues, while analogue engineering makes sustained pharmacological exposure possible. Different metabolic effects of FGF21 can have different tissue requirements, underscoring the limitations of attributing all activity to a single organ or downstream mediator.¹²

Efruxifermin combines a modified human FGF21 sequence with an antibody-derived region that helps extend its time in circulation. Its modifications also enhance binding to the β-klotho coreceptor. This engineering supports prolonged exposure to a molecule designed to engage the FGF21 pathway.¹³

Pegozafermin is another long-acting FGF21 analogue. ENLIVEN was a phase IIb placebo-controlled trial evaluating its effects on fibrosis improvement and steatohepatitis resolution in adults with biopsy-confirmed F2–F3 disease over 24 weeks.¹⁴ Fibrosis improvement without worsening steatohepatitis occurred in 26% receiving 30 mg weekly and 27% receiving 44 mg every two weeks, versus 7% receiving placebo. Nausea and diarrhea were the most common treatment-associated adverse events.

HARMONY was a phase IIb placebo-controlled trial evaluating efruxifermin’s safety and histological efficacy in F2–F3 MASH, with a primary fibrosis endpoint at week 24 and treatment continuing to week ^96.15 At week 96, fibrosis improvement without MASH worsening occurred in 49% receiving 50 mg versus 19% receiving placebo in the modified intention-to-treat population. The result extends the evidence beyond early treatment response, although larger studies must establish the clinical role and durability of benefit.

Broader pathway interventions remain relevant as well. Lanifibranor is a pan-peroxisome proliferator-activated receptor agonist affecting metabolic, inflammatory, and fibrogenic pathways. NATIVE was a phase IIb placebo-controlled trial assessing whether 24 weeks of treatment reduced histological disease activity without worsening fibrosis in noncirrhotic disease.¹⁶ Investigators found that 1,200 mg met the primary endpoint, while 800 mg did not. Peripheral edema, anemia, weight gain, and gastrointestinal events occurred more frequently with treatment.

NATiV3 is the phase III trial evaluating lanifibranor in adults with noncirrhotic MASH and F2–F3 fibrosis. Inventiva reported in September 2026 that the final participant had completed the 72-week visit.¹⁷ The phase III program is intended to test whether the earlier efficacy findings hold in a larger study.

Results in F2–F3 disease cannot establish efficacy in compensated cirrhosis. SYMMETRY was a phase IIb placebo-controlled trial testing whether efruxifermin could improve fibrosis without worsening MASH in patients with biopsy-confirmed compensated cirrhosis.¹⁸ The trial found no significant improvement in the primary endpoint at week 36. At week 96, a secondary assessment found improvement in 29% receiving 50 mg versus 11% receiving placebo. The later result warrants further investigation while remaining qualified by the failed primary endpoint.

Belapectin approaches advanced disease through galectin-3 inhibition and a different clinical objective. NAVIGATE was a phase IIb placebo-controlled trial evaluating whether treatment could prevent development of esophageal varices over 18 months in patients with MASH cirrhosis and portal hypertension who had no varices at baseline.^19,20 Researchers, found a numerical reduction with the lower belapectin dose, but the full-analysis comparison was not statistically significant. Composite-endpoint comparisons were also nonsignificant. A favorable per-protocol result had an unadjusted p-value and does not override those findings.

Combination development begins with a plausible reason to intervene at more than one point in disease biology. Establishing benefit requires evidence about the actual regimen, population, doses, and outcomes.

Stable background medication and deliberately initiated combination therapy answer different questions. MAESTRO-NASH included patients receiving established GLP-1 receptor agonist treatment, and subgroup evidence supported resmetirom activity in that setting.⁵ The European guidance nevertheless states that first-line initiation of resmetirom and semaglutide together cannot currently be recommended.2 Background-treatment findings do not establish the incremental efficacy of starting both as a MASH regimen.

Direct testing has produced an important caution. A phase II dose-ranging trial evaluated whether zalfermin combined with semaglutide improved fibrosis without worsening MASH over 52 weeks in patients spanning F2 fibrosis through compensated cirrhosis. Investigators reported that zalfermin 30 mg plus semaglutide 2.4 mg did not significantly improve the primary endpoint versus placebo: 24% versus 16%.²¹ The result limits conclusions about that regimen without determining the outcome of every FGF21–incretin combination.

DUET was a 12-week phase IIa trial evaluating the THR-β agonist TERN-501 alone or with the farnesoid X receptor agonist TERN-101 in presumed MASH.²² Its primary objective was to assess liver-fat reduction with TERN-501 monotherapy using magnetic resonance imaging (MRI), and the study demonstrated dose-dependent liver-fat reductions with monotherapy. The study provides an early pharmacological assessment, rather than established combination benefit on fibrosis or clinical events.

For developers, the central question is what a second component contributes beyond the individual treatments. That assessment must encompass efficacy, tolerability, and the ability to maintain the regimen. A combination that addresses complementary pathways still needs a clinically useful reason to expose patients to both agents.

Identifying a treatment candidate and determining whether treatment is working are separate tasks. The European guidance favors noninvasive tests for treatment selection and considers biopsy unnecessary for most treatment initiations. It also acknowledges that these tests can misclassify fibrosis stage and that repeat or confirmatory testing can improve confidence. Clinical pathways must therefore accommodate uncertain or discordant results.

Response monitoring presents a related challenge. A retrospective analysis pooled 150 participants from three interventional trials to assess whether MRI changes reflected steatohepatitis resolution without fibrosis worsening.²³ Investigators found that changes in iron-corrected T1 and MRI-measured liver fat each distinguished responders from nonresponders with an area under the curve of 0.72, indicating useful but imperfect discrimination.

Failure to cross an improvement threshold also does not necessarily establish treatment failure. The guidance permits consideration of continued therapy in stable disease without demonstrated fibrosis improvement, although the recommendation rests on limited evidence. Decisions concerning semaglutide may additionally involve cardiometabolic benefits outside the liver.

Longer-term programs address whether treatment changes the course of disease. SYNERGY-Outcomes is a phase III master-protocol study evaluating tirzepatide and retatrutide against placebo for prevention of major adverse liver outcomes in high-risk metabolic dysfunction-associated steatotic liver disease.²⁴ Participants are identified through noninvasive tests, extending investigation beyond the biopsy-confirmed MASH populations used in earlier histology trials.

ENLIGHTEN-Fibrosis, a phase III pegozafermin trial in F2–F3 MASH, includes week-52 histological endpoints and assessment of disease progression.²⁵ The phase III SYNCHRONY program evaluates efruxifermin across biopsy-defined noncirrhotic disease, noninvasively diagnosed disease, and cirrhosis.²⁶ These designs extend the evidence sought across different stages and clinical settings.

The next phase of development must connect treatment effects with decisions throughout care: whom to treat, how to recognize a useful response, and when to continue or change therapy. Longer-term evidence must then establish whether those decisions prevent serious liver complications. Answering these questions will determine how an expanding therapeutic repertoire becomes an effective treatment strategy.

1. Li, Ziyu, et al. “Spatially resolved multi-omics of human metabolic dysfunction-associated steatotic liver disease.” Nature Genetics. 57: 3112–3125 (2025).

2. European Association for the Study of the Liver, European Association for the Study of Diabetes, and European Association for the Study of Obesity. “EASL-EASD-EASO guidance on the use of resmetirom and semaglutide as MASH-targeted therapy.” Journal of Hepatology. 29 Sep. 2026.

3. “Ongoing | Non-malignant Hematological, Neurological, and Other Disorder Indications Accelerated Approvals.” U.S. Food and Drug Administration. Accessed 06 Nov. 2026.

4. “REZDIFFRA (resmetirom) tablets, for oral use.” Madrigal Pharmaceuticals, Inc. Revised Jul. 2026; published on DailyMed 5 Aug. 2026.

5. Harrison, Stephen A, et al. “A Phase 3, Randomized, Controlled Trial of Resmetirom in NASH with Liver Fibrosis.” New England Journal of Medicine. 390: 497–509 (2024).

6. Kannt, Aimo, et al. “Activation of thyroid hormone receptor-β improved disease activity and metabolism independent of body weight in a mouse model of non-alcoholic steatohepatitis and fibrosis.” British Journal of Pharmacology. 178: 2412–2423 (2021).

7. Sanyal, Arun J, et al. “Phase 3 Trial of Semaglutide in Metabolic Dysfunction-Associated Steatohepatitis.” New England Journal of Medicine. 392: 2089–2099 (2025).

8. Loomba, Rohit, et al. “Tirzepatide for Metabolic Dysfunction-Associated Steatohepatitis with Liver Fibrosis.” New England Journal of Medicine. 391: 299–310 (2024).

9. Sanyal, Arun J, et al. “A Phase 2 Randomized Trial of Survodutide in MASH and Fibrosis.” New England Journal of Medicine. 391: 311–319 (2024).

10. Noureddin, Mazen, et al. “Safety and efficacy of weekly pemvidutide versus placebo for metabolic dysfunction-associated steatohepatitis (IMPACT): 24-week results from a multicentre, randomised, double-blind, phase 2b study.” The Lancet. 406: 2644–2655 (2025).

11. Jara, Maximilian, et al. “Modulation of metabolic, inflammatory and fibrotic pathways by semaglutide in metabolic dysfunction-associated steatohepatitis.” Nature Medicine. 31: 3128–3140 (2025).

12. BonDurant, Lucas D, et al. “FGF21 Regulates Metabolism Through Adipose-Dependent and -Independent Mechanisms.” Cell Metabolism. 25: 935–944.e4 (2017).

13. Harrison, Stephen A, et al. “A randomized, double-blind, placebo-controlled phase IIa trial of efruxifermin for patients with compensated NASH cirrhosis.” JHEP Reports. 5: 100563 (2023).

14. Loomba, Rohit, et al. “Randomized, Controlled Trial of the FGF21 Analogue Pegozafermin in NASH.” New England Journal of Medicine. 389: 998–1008 (2023).

15. Noureddin, Mazen, et al. “Safety and efficacy of once-weekly efruxifermin versus placebo in metabolic dysfunction-associated steatohepatitis (HARMONY): 96-week results from a multicentre, randomised, double-blind, placebo-controlled, phase 2b trial.” The Lancet. 406: 719–730 (2025).

16. Francque, Sven M, et al. “A Randomized, Controlled Trial of the Pan-PPAR Agonist Lanifibranor in NASH.” New England Journal of Medicine. 385: 1547–1558 (2021).

17. “Inventiva Announces Last Patient Visit in NATiV3 Phase 3 Clinical Trial of Lanifibranor in MASH.” Inventiva. 2 Sep. 2026.

18. Noureddin, Mazen, et al. “Efruxifermin in Compensated Liver Cirrhosis Caused by MASH.” New England Journal of Medicine. 392: 2413–2424 (2025).

19. Chalasani, Naga, et al. “Effects of Belapectin, an Inhibitor of Galectin-3, in Patients With Nonalcoholic Steatohepatitis With Cirrhosis and Portal Hypertension.” Gastroenterology. 158: 1334–1345.e5 (2020).

20. Chalasani, Naga, et al. “Efficacy and safety of belapectin for the prevention of esophageal varices in patients with MASH cirrhosis: The randomized, placebo-controlled NAVIGATE trial.” Hepatology. 1 May 2026.

21. Loomba, Rohit, et al. “Efficacy and safety of zalfermin co-administered with semaglutide in participants with fibrosis and cirrhosis due to metabolic dysfunction-associated steatohepatitis: a phase 2, dose-ranging, double-blind, randomised controlled trial.” The Lancet Gastroenterology & Hepatology. 11: 797–811 (2026).

22. Noureddin, Mazen, et al. “TERN-501 monotherapy and combination therapy with TERN-101 in metabolic dysfunction-associated steatohepatitis: the randomized phase 2a DUET trial.” Nature Medicine. 31: 2297–2305 (2025).

23. Alkhouri, Naim, et al. “Decreases in cT1 and liver fat content reflect treatment-induced histological improvements in MASH.” Journal of Hepatology. 82: 438–445 (2025).

24. “A Master Protocol of Multiple Agents in Adults With Metabolic Dysfunction-Associated Steatotic Liver Disease (SYNERGY-Outcomes).” NCT07165028. University of California San Diego.  Updated 7 Oct. 2026.

25. “Phase III: Pegozafermin in Metabolic Dysfunction-Associated Steatotic Liver Disease With Fibrosis (ENLIGHTEN-Fibrosis).” Genentech. Accessed 06 Nov. 2026.

26. “Clinical Trials.” Akero Therapeutics. Accessed 06 Nov. 2026.