PF-05231023 / Pfizer - LARVOL DELTA

FGF21 analogue PF-05231023 on alcohol consumption and neuronal activity in the nucleus accumbens. (PubMed, Neuropsychopharmacology) - "PF-05231023 reduced alcohol intake and preference in a dose- and sex-specific manner; diminished approach behaviours following an alcohol but not sucrose cue; and decreased lever-pressing under a progressive-ratio schedule, both alone and when combined with the Glucagon-like peptide-1 (GLP-1) agonist Exendin-4; it did not reduce lever-pressing for sucrose in alcohol-naïve mice. These findings demonstrate that PF-05231023 broadly suppresses alcohol-motivated behaviours without impacting natural reward and that targeting FGF21 signaling in combination with GLP-1 agonists may enhance therapeutic efficacy. Mechanistically, the observed reductions in alcohol consumption following PF-05231023 may involve diminished alcohol palatability and modulation of neuronal activity from distinct subsets of Acb neurons."

Journal • FGF21

PF-05231023 reduces lipid deposition in apolipoprotein E-deficient mice by inhibiting the expression of lipid synthesis genes. (PubMed, Front Vet Sci) - "Transcriptome analysis of adipose tissue showed that PF-05231023 treatment downregulated the expression of lipid synthesis-related genes and inhibited the sterol regulatory element binding transcription factor 1 gene, thereby improving lipid deposition. PF-05231023 effectively improved the lipid metabolism of Apoe -/- mice, demonstrating an anti-atherosclerotic effect and providing a scientific basis and experimental foundation for the clinical treatment of cardiovascular diseases by using long-acting FGF21 analogs."

Journal • Preclinical • Atherosclerosis • Cardiovascular • Dyslipidemia • Metabolic Disorders • APOE • FGF21

Fibroblast Growth Factor 21 in the Diagnosis and Treatment of Metabolic Disorders (ENDO 2024) - "Since native FGF21 has poor pharmacodynamic properties (e.g., short half-life and proteolytic cleavage by proteases), long-acting FGF21 analogs (e.g., LY2405319, PF-05231023, pegozafermin, AKR-001, and LLF580) have been synthesized and tested in clinical trials for the treatment of obesity, NAFLD, dyslipidemia, and type 2 diabetes. FGF21 is a predominantly liver-derived peptide hormone regulating energy expenditure and metabolism of lipids and glucose. Serum FGF21 levels are increased in several metabolic disorders including obesity, NAFLD, dyslipidemia, and type 2 diabetes. FGF21 is an attractive target for the treatment of these metabolic disorders."

Cardiovascular • Diabetes • Dyslipidemia • Genetic Disorders • Hepatology • Infectious Disease • Metabolic Disorders • Metabolic Dysfunction-Associated Steatotic Liver Disease • Nephrology • Obesity • Renal Disease • Septic Shock • Type 2 Diabetes Mellitus • FGF21

Epigenetic regulation of GABA catabolism in iPSC-derived neurons: the molecular links between FGF21 and histone methylation. (PubMed, Mol Metab) - P=N/A | "Our results highlight a significant role in the epigenetic regulation of genes involved in GABA catabolism related to FGF21 action. (The ClinicalTrials.gov Identifier: NCT00662571)."

Epigenetic controller • Journal • Addiction (Opioid and Alcohol) • FGF21

Improvement situation on indexes of the zebrafish disease model of non-alcoholic fatty liver disease with FGF21 analogues (PubMed, Zhonghua Gan Zang Bing Za Zhi) - "The addition of PF-05231023 reduced oleic acid-induced lipid and triglyceride levels in HepG2 cells. FGF21 analogue addition can improve indexes in the zebrafish disease model of non-alcoholic fatty liver disease."

Journal • Hepatology • Inflammation • Metabolic Disorders • Non-alcoholic Fatty Liver Disease • FGF21

Epigenetic Regulation Of GABA Catabolism In IPSC - Derived Neurons: The Role Of FGF21 (CINP 2023) - "Aims and Objectives: We set out to identify molecular mechanisms for both the naïve form of FGF21 and a long-acting FGF21 molecule (PF-05231023) in iPSC-derived neurons... Our results highlight a significant role in the epigenetic regulation of genes involved in GABA catabolism related to FGF21 action."

Addiction (Opioid and Alcohol) • FGF21

Hepatoprotective effects of the long-acting FGF21 analogue PF-05231023 in the GAN diet-induced obese and biopsy-confirmed mouse model of NASH. (PubMed, Am J Physiol Gastrointest Liver Physiol) - "Improvements in NASH and fibrosis severity were supported by reduced quantitative histological markers of steatosis, inflammation and fibrogenesis as well as improvements in disease-associated liver transcriptome signatures. PF-05231023 reduces NASH and fibrosis severity in a translational biopsy-confirmed mouse model of NASH, supporting development of FGF21 analogues for the treatment of NASH."

Biopsy • Journal • Preclinical • Fibrosis • Hepatology • Immunology • Inflammation • Liver Cirrhosis • Metabolic Disorders • Non-alcoholic Fatty Liver Disease • Non-alcoholic Steatohepatitis • Obesity • FGF21

Metabolic, biochemical, histopathological and transcriptomic effects of long-acting FGF21 analogue in the GAN diet-induced obese and biopsy-confirmed mouse model of NASH (EASL-ILC 2022) - "The long-acting FGF21 analogue efruxifermin has in a recent phase 2 clinical trial (BALANCED) demonstrated promising efficacy for both NASH resolution and improvement in fibrosis stage as compared to placebo controls (Harrison et al. Long-acting FGF21 analogue PF-05231023 improved metabolic, biochemical and liver histological markers of steatosis, inflammation and fibrogenesis in biopsy-confirmed DIO-NASH mice. Consistent with clinical findings, PF-05231023 improved NAS and Fibrosis Stage. These findings further validate clinical translatability of the GAN DIO-NASH mouse model."

Preclinical • Fibrosis • Hepatology • Immunology • Inflammation • Non-alcoholic Steatohepatitis • Obesity • FGF21

METABOLIC, BIOCHEMICAL, HISTOLOGICAL, AND TRANSCRIPTOMIC EFFECTS OF A LONG-ACTING FGF- 21 ANALOGUE IN THE GAN DIET-INDUCED OBESE AND BIOPSY-CONFIRMED MOUSE MODEL OF NASH (NASH-TAG 2022) - "The long-acting FGF-21 analogue efruxifermin has in a recent phase 2 clinical trial (BALANCED) demonstrated promising efficacy for both NASH resolution and improvement in fibrosis stage as compared to placebo controls (Harrison et al. The long-acting FGF-21 analogue PF-05231023 improved metabolic, biochemical, and liver histological markers of steatosis, inflammation and fibrogenesis in biopsy-confirmed DIO- NASH mice. Furthermore, PF-05231023 treatment improved clinical- derived endpoints for NAS and Fibrosis Stage. These findings highlight FGF21 as a promising therapeutic agent for fibrosing NASH and further validate clinical translatability of the GAN DIO-NASH mouse model."

Preclinical • Fibrosis • Hepatology • Immunology • Inflammation • Metabolic Disorders • Non-alcoholic Fatty Liver Disease • Non-alcoholic Steatohepatitis • Obesity • FGF • FGF21

Fibroblast growth factors in control of lipid metabolism: from biological function to clinical application. (PubMed, Curr Opin Lipidol) - "Clinical trials with FGF-based drugs report beneficial effects in lipid and bile acid metabolism, with clinical improvements in dyslipidemia, steatosis, weight loss, and liver damage. In contrast, glucose-lowering effects, as observed in preclinical models, are currently lacking."

Clinical • Journal • Cholestasis • Diabetes • Dyslipidemia • Genetic Disorders • Hepatology • Metabolic Disorders • Non-alcoholic Fatty Liver Disease • Non-alcoholic Steatohepatitis • Obesity • Type 2 Diabetes Mellitus

Glyco-engineered Long Acting FGF21 Variant with Optimal Pharmaceutical and Pharmacokinetic Properties to Enable Weekly to Twice Monthly Subcutaneous Dosing. (PubMed, Sci Rep) - "PF-06645849 also caused greater body weight loss in DIO mice at lower and less frequent SC doses, compared to previous FGF21 analogue PF-05231023. In summary, the overall PK/PD and pharmaceutical profile of PF-06645849 offers great potential for development as weekly to twice-monthly SC administered therapeutic for chronic treatment of metabolic diseases."

Journal • PK/PD data