For years, patients with metabolic dysfunction-associated steatohepatitis (MASH) faced a frustrating lack of therapeutic options, with clinical management limited to lifestyle interventions such as diet and exercise. This stalemate was not broken until March 2024, when Madrigal’s selective thyroid hormone receptor β agonist, Resmetirom, received FDA approval, marking a historic milestone and opening a new chapter for MASH pharmacotherapy.

The approval of Resmetirom not only validated MASH as a viable and attractive drug development arena, it also accelerated capital and R&D focus toward next-generation mechanisms with broader metabolic benefits. Against this backdrop, targets capable of improving steatosis, inflammation, and systemic metabolic dysfunction have drawn intense interest, with fibroblast growth factor 21 (FGF21) emerging as one of the most closely watched pathways in the metabolic disease pipeline.

In 2025, a wave of capital interest around FGF21 surged. Novo Nordisk announced a USD 5.2 billion acquisition of Akero Therapeutics, bringing its lead asset—Efruxifermin, a once-weekly FGF21 analogue—into its portfolio. Previously, Roche and GSK had already moved into the field, acquiring FGF21 pipelines from 89bio and Boston Pharmaceuticals in deals worth USD 3.5 billion and USD 2.0 billion, respectively.

While no recombinant FGF21 or its analog has yet received global market approval, the competitive landscape is intensifying rapidly. Currently, more than 10 candidate drugs have already progressed into clinical development phases worldwide.

FGF21: An Intelligent Regulator of Systemic Metabolism

Fibroblast growth factor 21 (FGF21) is a member of the human FGF superfamily primarily secreted by the liver in response to fasting and involved in the maintenance of metabolic homeostasis. Unlike traditional growth factors that promote cell proliferation and depend on heparin, FGF21 does not require heparin binding. Instead, it precisely regulates systemic glucose, lipid, and energy homeostasis, earning it a reputation as a “universal regulator” in the field of metabolic disease.

FGF21 exerts its biological effects by forming a stable signalling complex with fibroblast growth factor receptors (FGFR1c, FGFR2c and FGFR3c) and the transmembrane co-receptor β-Klotho. β-Klotho acts as a high-affinity docking partner for FGF21, binding its C-terminal region, while the N-terminal region engages FGFRs. Together, this FGF21/β-Klotho/FGFR trimeric complex activates downstream receptor tyrosine kinase signalling pathways. Through this mechanism, native FGF21 acts primarily on adipose tissue to enhance glucose uptake, promote adiponectin secretion and modulate lipid metabolism.

Figure 1. Mechanism of Action of FGF21 analogues. Source: reference 3

FGF21 stands out due to its dual therapeutic profile, which has made it a key focus in MASH drug development.

On the one hand, FGF21 analogues deliver broad metabolic benefits. They can simultaneously improve glycemic control, lipid profiles, and body weight, aligning well with current treatment strategies that emphasize combined benefits in weight loss, glucose lowering, and cardio-renal protection.

On the other hand, FGF21 also exerts direct anti-MASH and anti-fibrotic effects. Beyond reducing liver burden through systemic metabolic improvement, FGF21 binds to receptors on hepatic stellate cells and inhibits their activation into myofibroblasts, which drive fibrosis formation. In this way, FGF21 directly targets the core pathological processes of MASH—chronic inflammation and progressive fibrosis.

Clinical Progress: Long-Acting FGF21 Analogs for MASH

Although endogenous FGF21 shows strong potential in metabolic regulation, its native form has a very short half-life in humans—approximately 30 minutes to 2 hours—which severely limits its clinical utility. To overcome this hurdle, current research is focused on protein engineering strategies, such as Fc-fusion and PEGylation, to develop long-acting FGF21 analogues. These approaches have successfully extended the half-life to several days or even weeks, making once-weekly or even once-monthly dosing regimens achievable and opening a new competitive track in MASH therapy.

At present, two non-FGF21 drugs—Resmetirom and semaglutide—have been approved globally for the treatment of MASH. However, FGF21 analogues, which combine direct anti-fibrotic activity with broad metabolic benefits, have quickly become the next strategic focus for multinational pharmaceutical companies.

2.1 Efruxifermin: Leading the field with the first signals of cirrhosis reversal

Efruxifermin is an Fc-FGF21 fusion protein with a half-life of around three days and is administered once weekly by subcutaneous injection. Among FGF21-targeted therapies, it currently has the most advanced clinical profile. Its value has been demonstrated in two phase 2b studies, which also formed the key rationale behind Novo Nordisk’s USD 5.2 billion acquisition of its developer, Akero Therapeutics.

In patients with compensated cirrhosis (F4):

In the SYMMETRY study, 96-week data showed that 39% of patients in the 50 mg Efruxifermin group achieved at least a one-stage improvement in liver fibrosis with no worsening of MASH, compared with 15% in the placebo group. This represents the first positive signal of potential cirrhosis reversal seen among MASH drug candidates in clinical development.

In patients with F2/F3 fibrosis:

In the HARMONY study, 96-week results demonstrated that 75% of patients receiving the 50 mg dose met the same primary endpoint, further confirming the strong anti-fibrotic efficacy of Efruxifermin across earlier stages of disease.

2.2 Pegozafermin: A potential “best-in-class” contender

Pegozafermin, acquired by Roche in a USD 3.5 billion deal, is a PEGylated FGF21 analogue that has emerged as a strong competitor with “best-in-class” potential. Its developer, 89bio, has highlighted several dimensions in which Pegozafermin may hold an edge over other agents in the same class.

Efficacy profile:

In a phase 2b clinical trial, Pegozafermin achieved a 3.5-fold relative risk reduction in fibrosis progression, compared with 2.0-fold for Efruxifermin (EFX) and 2.1-fold for Resmetirom. These results suggest a potentially stronger impact on fibrosis improvement within the FGF21 and non-FGF21 MASH treatment landscape.

Safety and tolerability:

Pegozafermin has shown a lower incidence of gastrointestinal adverse events, such as nausea and vomiting, than EFX. In addition, no meaningful effects on bone health or blood pressure have been observed to date—an important consideration for patients requiring long-term, chronic therapy.

Pharmacologic advantages:

According to available data, Pegozafermin offers higher drug exposure and a more balanced agonist activity across FGFRs, which may translate into superior clinical efficacy and a differentiated profile among long-acting FGF21 analogues.

2.3 Efimosfermin: Advancing convenience with once-monthly dosing

Efimosfermin alfa, acquired by GSK in a USD 2.0 billion transaction, is another Fc-fusion FGF21 analogue, but it is differentiated by its ultra-long half-life of around 21 days. This profile supports a once-monthly subcutaneous dosing schedule, offering a clear advantage in treatment convenience and patient adherence.

Phase 2 clinical data showed that, after 24 weeks of treatment, 45% of patients with F2/F3 MASH achieved a meaningful improvement in liver fibrosis. GSK plans to combine Efimosfermin alfa with its investigational siRNA therapy GSK4532990 to build a “fibrosis-targeting + gene regulation” combination regimen aimed at later-stage fatty liver disease.

Summary

Thanks to its dual advantages—broad metabolic benefits and direct anti-fibrotic activity—the FGF21 pathway offers therapeutic potential that goes beyond single-mechanism drugs in the MASH field. Long-acting engineering strategies have largely overcome the developability challenges of native FGF21.

First-wave, late-stage molecules such as Efruxifermin, Pegozafermin, and Efimosfermin alfa have already delivered consistently positive clinical data, demonstrating robust efficacy and a high likelihood of successful approval. Together, these programmes signal that FGF21-based therapies are well positioned to reshape the future treatment landscape of MASH.

References:
1.Sanyal, A. J., et al. (2024). "Efruxifermin in non-alcoholic steatohepatitis: a randomized phase 2b trial." Nature Medicine.
2.Lai, Z., et al. (2025). "A Phase 2 Study of Mazdutide in Patients with Metabolic Dysfunction-Associated Steatohepatitis." Presented at EASL Congress.
3. FGF21 agonists: An emerging therapeutic for metabolic dysfunction-associated steatohepatitis and beyond. Harrison, Stephen A. et al. Journal of Hepatology, Volume 81, Issue 3, 562 - 576
4.ClinicalTrials.gov: NCT05468385 (Efruxifermin Phase 3), NCT05602610 (Mazdutide Phase 3).
5.Tan, Huiling et al. “Targeting FGF21 in cardiovascular and metabolic diseases: from mechanism to medicine.” International journal of biological sciences vol. 19,1 66-88. 1 Jan. 2023, doi:10.7150/ijbs.73936
6.https://ir.akerotx.com
7.https://ir.89bio.com/