FGF-21 (Fibroblast Growth Factor 21)
/ Endogenous fibroblast growth factor 21; beta-Klotho/FGFR1c receptor complex agonistALIAS · FGF-21 · Fibroblast growth factor 21 · Recombinant FGF-21
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Tier 2. FGF-21 analog programs (efruxifermin from Akero Therapeutics, pegbelfermin from Bristol-Myers Squibb, and earlier candidates) reached Phase 2 in metabolic dysfunction-associated steatohepatitis (MASH, formerly NASH) and type 2 diabetes with positive signals on liver fat, fibrosis, and lipid endpoints. None are FDA-approved as of 2026; efruxifermin Phase 3 SYMMETRY and SYNCHRONY programs in MASH are ongoing.
FGF-21 is an atypical member of the fibroblast growth factor family - secreted as a true endocrine hormone (rather than acting locally like canonical FGFs) and signalling through a heterodimeric receptor complex of FGFR1c with the obligate co-receptor beta-Klotho (KLB). Tissue specificity is determined by KLB expression, which is largely restricted to liver, adipose tissue, and pancreas.
Hepatic FGF-21 secretion increases in response to fasting, ketogenic states, mitochondrial stress, and PPAR-alpha activation. Endocrine actions include increased insulin sensitivity, increased adiponectin secretion from white adipose tissue, increased thermogenesis in brown adipose tissue, suppressed sweet-taste preference and alcohol intake (CNS actions via beta-Klotho expression in the suprachiasmatic nucleus and area postrema), and beneficial lipid-profile shifts including lowered triglycerides.
The metabolic-disease therapeutic rationale derives from the combination of insulin-sensitisation, adipose-tissue browning, and hepatic lipid-handling improvements - all relevant to MASH and type 2 diabetes. Engineered analogs with extended half-life (efruxifermin, an Fc-fusion bivalent FGF-21 analog; pegbelfermin, a PEGylated FGF-21 analog) are the clinical-stage molecules; the native peptide has too short a half-life to be a practical therapeutic.
Tier 2. Phase 2 trials of efruxifermin in MASH (HARMONY, BALANCED) reported significant reductions in liver fat (MRI-PDFF) and improvements in fibrosis and steatohepatitis on biopsy at 24 and 96 weeks (Harrison 2023 Lancet, Rinella 2024 Hepatology). Pegbelfermin Phase 2 (Charles 2019 Hepatology) reported liver fat reduction; subsequent fibrosis-endpoint results were less robust and BMS deprioritised the program. Efruxifermin Phase 3 SYMMETRY in compensated MASH cirrhosis and SYNCHRONY in pre-cirrhotic MASH are ongoing as of 2026.
Class adverse effects of FGF-21 analogs include increased frequency of bone-mineral-density signals (FGF-21 effects on bone metabolism are an active area of investigation), gastrointestinal effects (nausea, diarrhoea), and injection-site reactions. Long-term safety data accumulate as Phase 3 programs progress. Native FGF-21 has very short plasma half-life and is not administered as a therapeutic.
Regulatory status
- FDA status:
- Not FDA-approved
The translation from rodent FGF-21 pharmacology to human clinical effect has been complicated - early mouse data suggested very large weight-loss effects that have not been reproduced in human Phase 2 (where weight loss is modest) but the liver-disease efficacy signal has held up. The class is primarily a MASH / liver-disease story rather than an obesity story.
Vendor-sold 'FGF-21' research material is typically a recombinant native protein with native-form pharmacokinetics - it is not interchangeable with efruxifermin (an Fc-fusion) or pegbelfermin (a PEGylated form). The half-life difference is roughly 1000-fold.