The FGF21 field is welcoming its dawn. This year, three giants — Novo Nordisk, Roche and GSK — have placed heavy bets in this area, each spending billions to acquire FGF21 drugs. Although business development (BD) transactions have occurred sporadically in this space before, such crowded, large-scale acquisitions are unprecedented.
M&A Deals in the FGF21 Field
The three recently acquired FGF21 drugs are at advanced stages of development, indicating that the challenges in druggability for this target are nearly overcome. Once successfully launched, they will be the first to revolutionise treatment in the field of metabolic dysfunction-associated steatohepatitis (MASH).
More surprises may be yet to come as FGF21 and GLP-1 complement and synergise with each other, opening the possibility to further expand the treatment landscape to include obesity. This evinces the potential rise of another super field in metabolism after GLP-1.
Blockbuster Potential
The FGF21 target might be unfamiliar to many. FGF21 (fibroblast growth factor 21) was first discovered in mouse liver and thymus in 2000 [1]. Subsequent research gradually revealed that it is widely expressed in various metabolically active tissues and organs such as liver, adipose tissue, skeletal muscle and pancreas [2], deeply involved in regulatory processes.
As an important metabolic regulator, FGF21 has two relatively critical and clear functions: regulating glucose and lipid metabolism, which also gives it transformative potential in treating obesity and related metabolic syndromes [3]. To some extent, the development path of FGF21 mirrors that of the already mature GLP-1, reflecting a broad potential indication space with blockbuster potential.
In the pathological environment of MASH, FGF21 drugs can exert effects through multiple mechanisms: first, direct anti fibrotic effects; second, improving hepatic steatosis and cell stress; third, systemic metabolic regulation, improving conditions such as insulin sensitivity and dyslipidaemia [4]. This multipronged activity makes FGF21 drugs quite competitive against MASH.
Globally, there are currently only two truly innovative therapies approved for MASH: Madrigal Pharmaceuticals' THR-β agonist resmetirom and Novo's GLP-1R agonist semaglutide.
Resmetirom got first green light globally in March 2024, a landmark drug filling the treatment gap in the MASH field. Matching its significant clinical value is its strong commercial performance: it sold USD 350 million in the H1 2025, aiming for USD 800 million for the full year, with some analysts predicting the drug's sales peak will exceed USD 5 billion.
From resmetirom's sales figures, it is possible to glimpse at the huge prospects of the MASH market, and the emergence of FGF21 drugs might further revolutionise the MASH treatment landscape.
It is important to know that both resmetirom and semaglutide are currently limited to non-cirrhotic MASH patients with moderate-to-severe liver fibrosis (stage F2 F3), while FGF21 drugs are expected to have better efficacy in treating stage F4 cirrhosis. This may also be an important factor pushing Big Pharma to rush into the FGF21 field through large-scale M&A.
Giants Enter the Arena, Competi.
Giants Enter the Arena, Competing for BIC Molecules
As pharmaceutical giants enter the race, the competitive landscape of the FGF21 field has begun to take shape. The three currently leading candidates — pegozafermin, efimosfermin alfa and efruxifermin — each have unique features in molecular design, distinct clinical performances and a claim to best-in-class (BIC) status.
Pegozafermin employs polyethylene glycol (PEG) modification technology, connecting a PEG chain to the FGF21 molecule to extend its half-life to enable a dosing frequency of once every two weeks (Q2W). The Phase II ENLIVEN study showed that both once weekly (Q1W) and Q2W dosing regimens of pegozafermin effectively reduced liver fibrosis in MASH patients
Efimosfermin alfa and efruxifermin utilise Fc fusion protein technology, linking two site-mutated FGF21 molecules via a human IgG1 Fc fragment, effectively extending the drug's in vivo circulation time. The Phase II BOS 580 201 study showed that after 24 weeks of treatment with efimosfermin alfa, 45% of MASH patients had significant improvement in liver fibrosis, and nearly 70% of patients achieved MASH symptom resolution
More importantly, efimosfermin alfa has the potential for once monthly (Q1M) dosing and is currently the only FGF21 monthly formulation in advanced development. For chronic diseases like MASH that require long-term management, optimising dosing frequency holds significant clinical importance.
Efruxifermin also demonstrated excellent liver fibrosis improvement and MASH resolution effects in clinical studies. In the Phase II HARMONY study, over half of the patients in the 50 mg dose group achieved at least a one-stage fibrosis improvement and MASH resolution at 96 weeks [7,8]. It is worth mentioning that efruxifermin has shown potential to reverse stage-4 fibrosis. In the Phase II SYMMETRY study, 39% of F4 patients in the 50 mg dose group achieved at least one-stage fibrosis improvement without MASH worsening at 96 weeks
From existing data, all three candidates can achieve efficacy comparable to or even surpassing approved drugs. More importantly, the smooth progression of these drugs indicates that the challenges of drugging the FGF21 target have been practically overcome.
However, true superiority still requires head-to-head studies for final validation. The ultimate outcome of this BIC molecule battle will be determined in future clinical trials.
Towards Iterative Evolution
Although the first FGF21 drug has not yet truly arrived, the R&D layout for next-generation drugs has long been underway. It can be roughly categorised that first-generation drugs are mainly FGF21 analogues, while iterative drugs are evolving towards dual-target and multi-target approaches.
According to the PharmCube's NextBiopharm® database, there are 23 innovative drugs under research targeting FGF21 as a single target, and 17 multi-target drugs. Among them, the most common pairing is with GLP-1/1R, with related drugs advancing fastest to Phase II stage, led by HEC ChangJiang Pharma's FGF21/GLP-1 dual agonist HEC88473, Doer Biologics' FGF21R/GLP-1R/GCGR triple agonist DR10624 and Minwei Biotech's GLP-1/GIP/FGF21 triple activity fusion protein MWN105.
Many players have adopted the strategy of co-developing FGF21 with GLP-1/1R, likely based on two main considerations. On one hand, they hope to enhance the therapeutic effect on MASH through mechanism complementarity. On the other hand, they aim to expand the scope of indications, especially entering the obesity field.
Although GLP-1 drugs have shown excellent effects in weight loss, they still have limitations in aspects such as lipid metabolism regulation and energy consumption improvement, which are precisely the differentiated advantages of the FGF21 target. The combination of the two is expected to create a more potent and longer lasting weight-loss solution.
Looking ahead, the development path of the FGF21 field is becoming increasingly clear. In the short term, the currently leading single-target molecules will validate the target's value in the MASH market; in the medium to long term, FGF21 multi-target drugs carry the expectation of breaking through the ceiling of existing therapies and reshaping the treatment landscape of metabolic diseases.