Competition in MASH is Heating Up as GLP-1s Gate-Crash the Party

Digital composite of highlighted red painful liver of woman | Image credit: ©mi_viri -stock.adobe.com

Metabolic dysfunction-associated steatohepatitis (MASH) is a type of non-alcoholic fatty liver disease (NAFLD) affecting more than 250 million people worldwide, and the number of cases in advanced stages is expected to double by 2030. Underlying conditions such as obesity, type 3 diabetes, and metabolic syndrome can increase the risk of MASH. For many years, MASH has been difficult to treat, and several products have failed in clinical development, including Genfit’s peroxisome proliferator-activated receptor (PPAR) agonist elafibranor, Gilead's ASK1 inhibitor selonsertib, Intercept Pharmaceuticals' farnesoid X receptor (FXR) agonist obeticholic acid, and Novartis/Conatus' pan-caspase inhibitor emricasan.

What are some recent product approvals?

In the past few years, significant progress has been made, and new products have entered the MASH market. In March 2024, the US Food and Drug Administration (FDA) approved Madrigal Pharmaceuticals’ orally active, selective thyroid hormone receptor (THR)-β agonist, Rezdiffra (resmetirom), for adults with MASH with moderate to advanced liver scarring (fibrosis), alongside diet and exercise (1). In June 2025, the European Medicines Agency’s (EMA’s) Committee for Medicinal Products for Human Use (CHMP) recommended granting conditional marketing authorization for Rezdiffra in MASH (2). On 19 Aug. 2026, the European Commission approved Rezidiffra, and the company is planning its first European launch in Germany in the fourth quarter of 2025 (4).

In August 2025, Novo Nordisk received FDA approval for its injectable weight-loss drug Wegovy (semaglutide) for patients with MASH and moderate to advanced liver fibrosis, without cirrhosis, in combination with a reduced-calorie diet and exercise (4). The conditional clearance was based on Phase III results, where the glucagon-like peptide-1 receptor agonist (GLP-1RA) demonstrated improved liver scarring without worsening the condition and resolved MASH without making scarring worse (5,6). Eli Lilly is also seeking approval for its injectable dual-action gastric inhibitory polypeptide (GIP)/GLP-1RA, Zepbound (tirzepatide), based on its Phase II SYNERGY-MASH trial in patients with and without type 2 diabetes, and with stage 2 or 3 fibrosis (scarring) (7,8).

What investments are Big Pharma making in MASH?

MASH is seen as the next frontier in metabolic diseases, and numerous clinical trials are underway evaluating hormone analogs, receptor agonists, and enzyme inhibitors (Table I). MASH drug development has attracted significant interest from pharma and private investors. In the GLP-1 space, Boehringer Ingelheim has teamed up with UK-based Zealand Pharma to develop survodutide. This dual glucagon/GLP-1 agonist has demonstrated a placebo-adjusted 64.8% improvement in fatty liver disease (9).

Table I. Clinical development of therapies targeting Metabolic dysfunction-associated steatohepatitis (MASH).

Table I. Clinical development of therapies targeting Metabolic dysfunction-associated steatohepatitis (MASH) (Continued).

In May 2025, GSK acquired Boston Pharmaceuticals' lead asset efimosfermin for US$1.2 billion plus US$800 million in milestone payments. Efimosfermin is a novel, once-monthly fibroblast growth factor 21 (FGF21) analog therapeutic in Phase II clinical development for the treatment of MASH (10). US-based Akero Therapeutics and 89bio are also developing FGF21 analogs, efruxifermin and pegozafermin, respectively (11, 12).

Which European frontrunners are targeting MASH?

Several European biotechs are developing innovative approaches to target the underlying cause of MASH and liver fibrosis. These include:

• Inventiva, France, focuses on developing novel small-molecule therapies targeting fibrosis, lysosomal storage disorders, and oncology. Its lead program, lanifibranor (IVA337), is an orally active pan-PPAR agonist. It demonstrated promising results in a Phase IIb placebo-controlled trial in patients with active MASH, improving the resolution of MASH without worsening fibrosis (13). Lanifibranor is currently being evaluated in NATiV3, a pivotal Phase III clinical trial in patients with MASH and fibrosis stages F2 and F3; the trial is due to complete in September 2026 (14).
• Enyo Pharma, France, is a clinical-stage biopharmaceutical company specializing in fibrolytic and anti-inflammatory diseases. Its lead compound, Vonafexor, is an orally active, non-steroidal agonist of NR1H4 (FXR, or bile acid receptor). In the Phase II LIVIFY study, Vonafexor significantly reduced liver fibrosis and inflammation markers, decreased liver fat and weight, and improved liver and kidney functions (15). In January 2024, the company raised €39 million (US$45.39 million) in Series C funding to develop Vonafexor further (16).
• Zealand Pharma, Denmark, is a biotechnology company focused on discovering and developing innovative peptide-based medicines. It has created several candidates targeting the metabolic brain axis, including Survodutide, a glucagon/GLP-1 dual agonist, which is being developed with Boehringer Ingelheim for MASH (Phase II) and obesity (Phase II), and petrelintide, an amylin analogue that it is co-developing with Roche. This compound could represent a new class of treatment for obesity (17).

In the United States, several biotech companies are working on MASH candidates, including MetaVia, which is developing DA-1726, a novel oxyntomodulin (OXM) analogue that functions as a glucagon-like peptide-1 receptor (GLP1R) and glucagon receptor (GCGR) dual agonist (18).

MASH diagnostics coming online

Additionally, significant progress has been made in developing biomarkers and diagnostics to identify patients at risk of MASH. For example, France-based Genfit has created a non-invasive diagnostic program that includes an in vitro test to detect NIS4+ and NIS2+. At the same time, Nordic Bioscience has identified biomarkers targeting neo-epitopes of collagen fragments that can be used to risk-stratify patients. (19, 20).

Future of MASH

The global MASH market was valued at US$7.9 billion in 2024 and is forecast to grow to US$31.8 billion by 2033, with a compound annual growth rate of 17.7% from 2025 to 2033 (21). After many failed attempts, the industry has finally identified new ways to reduce liver fat buildup. While Madrigal's orally active Rezdiffra was the first to enter the US and European Union markets, it now faces competition from Novo’s injectable Wegovy, and Eli Lilly is not far behind. It will be interesting to see how the MASH landscape evolves and whether new approaches, such as oxyntomodulin analogues and gene silencing agents, can capture a share of this lucrative market in the future.

References

1. FDA. FDA Approves First Treatment for Patients with Liver Scarring Due to Fatty Liver Disease. Press Release. 14 Mar. 2024.
2. EMA. Rezdiffra. Ema.europa.eu. 20 June 2025
3. Madrigal Pharmaceuticals. Madrigal Receives European Commission Approval for Rezdiffra™ (resmetirom) for the Treatment of MASH with Moderate to Advanced Liver Fibrosis. Press Release. 19 Aug. 2025.
4. Madrigal Pharmaceuticals. Madrigal Pharmaceuticals Reports Second-Quarter 2025 Financial Results and Provides Corporate Updates. Press Release. 5 Aug. 2025.
5. FDA. FDA Approves Treatment for Serious Liver Disease Known as ‘MASH’. Press Release. 15 Aug. 2025
6. Sanyal, A. J.; Newsome, P. N.; Kliers, I.; et al. Phase 3 Trial of Semaglutide in Metabolic Dysfunction-Associated Steatohepatitis. The New England Journal of Medicine, 2025 392(21), 2089–2099.
7. Novo Nordisk. Semaglutide 2.4 mg Demonstrates Superior Improvement in Both Liver Fibrosis and MASH Resolution in the ESSENCE Trial. Press Release. 1 Nov. 2024.
8. Loomba, R.; Hartman, M. L.; Lawitz, E. J.; et al. (2024). Tirzepatide for Metabolic Dysfunction-Associated Steatohepatitis with Liver Fibrosis. The New England Journal of Medicine, 2024 391(4), 299–310.
9. Boehringer Ingelheim. Survodutide US FDA Breakthrough Therapy Phase 3 Trials MASH. Press Release. 8 Oct. 2024.
10. GSK. GSK to Acquire Efimosfermin, a Phase III-Ready Potential Best-in-Class Specialty Medicine to Treat and Prevent Progression of Steatotic Liver Disease (SLD). Press Release. 14 May 2025.
11. Akero Therapeutics. Efruxifermin for MASH. akerotx.com/clinical-trials (accessed 20 Aug. 2025).
12. 89bio. 89bio Receives EMA PRIME Status for Pegozafermin in the Treatment of Metabolic Dysfunction-Associated Steatohepatitis (MASH) with Fibrosis and Compensated Cirrhosis. Press Release. 27 Mar. 2024.
13. Francque, S. M.; Bedossa, P.; Ratziu, V.; et al.. A Randomized, Controlled Trial of the Pan-PPAR Agonist Lanifibranor in NASH. The New England Journal of Medicine, 2021 385(17), 1547–1558.
14. ClinicalTrials.gov. Study Details | A Phase 3 Study Evaluating Efficacy and Safety of Lanifibranor Followed by an Active Treatment Extension in Adult Patients With (NASH) and Fibrosis Stages F2 and F3 ( NATiV3 ) (accessed 21 August 2025).
15. Ratziu, V.; Harrison, S. A.; Loustaud-Ratti; et al. Hepatic and Renal Improvements with FXR Agonist Vonafexor in Individuals with Suspected Fibrotic NASH. Journal of Hepatology, 2023 78(3), 479–492.
16. ENYO Pharma. ENYO Pharma Announces a €39 Million Series C Financing and FDA Clearance to Advance Vonafexor in a Phase 2 Clinical Trial for Patients with Alport syndrome. Press Release. 3 Jan. 2024.
17. Zealand Pharma. H1 2025 Presentation. Zealandpharma.com. 14 Aug. 2025.
18. MetaVia. MetaVia Doses First Patient in the 48 mg MAD Cohort of Its Phase 1 Clinical Trial Evaluating DA-1726 for the Treatment of Obesity to Further Explore Maximum Tolerated Dose. Press Release. 9 July 2025
19. Genfit. Diagnostics. Genfit.com (accessed 21 Aug. 2025).
20. Nordic Bioscience. MASLD, SLD, and MASH. nordicbioscience.com (accessed 21 Aug. 2025).
21. Data Intelligence. Nash Or Mash Treatment Market Growth Rate, Industry Insights and Forecast 2025-2033. April 2025.

About the author

Cheryl Barton, PhD, is founder and director of PharmaVision, Pharmavision.co.uk.