pf-05231023 and Diabetes-Mellitus--Type-2

FGF21 plays a central role in energy, lipid, and glucose homeostasis. To characterize the pharmacologic effects of FGF21, we administered a long-acting FGF21 analog, PF-05231023, to obese cynomolgus monkeys. PF-05231023 caused a marked decrease in food intake that led to reduced body weight. To assess the effects of PF-05231023 in humans, we conducted a placebo-controlled, multiple ascending-dose study in overweight/obese subjects with type 2 diabetes. PF-05231023 treatment resulted in a significant decrease in body weight, improved plasma lipoprotein profile, and increased adiponectin levels. Importantly, there were no significant effects of PF-05231023 on glycemic control. PF-05231023 treatment led to dose-dependent changes in multiple markers of bone formation and resorption and elevated insulin-like growth factor 1. The favorable effects of PF-05231023 on body weight support further evaluation of this molecule for the treatment of obesity. Longer studies are needed to assess potential direct effects of FGF21 on bone in humans.

Topics: Adolescent; Adult; Aged; Animals; Anti-Obesity Agents; Antibodies, Monoclonal, Humanized; Blood Glucose; Body Weight; Diabetes Mellitus, Type 2; Drug Evaluation, Preclinical; Female; Fibroblast Growth Factors; Gene Expression; Humans; Insulin; Lipid Metabolism; Macaca fascicularis; Male; Middle Aged; Obesity; Subcutaneous Fat; Weight Loss; Young Adult

The aim of the present study was to evaluate the pharmacokinetics/pharmacodynamics (PK/PD), safety and tolerability of single intravenous (IV) doses of PF-05231023, a long acting fibroblast growth factor 21 (FGF21) analogue being developed for the treatment of type 2 diabetes mellitus (T2DM).. T2DM subjects (glycosylated haemoglobin: 7.0-10.5%; on stable metformin therapy and/or diet and exercise) were randomized to receive a single dose of placebo or PF-05231023 (0.5-200 mg). Safety evaluations were performed up to 14 days after dosing. PK and PD endpoints were measured and a PK/PD model was developed for triglyceride - an early marker of drug activity.. No antidrug antibody or serious adverse events (AEs) were observed. The most frequent AEs were gastrointestinal but were generally mild. Plasma PF-05231023 levels peaked immediately post-IV dosing, with mean terminal half-lives of 6.5-7.7 h and 66.5- 96.6 h for intact C- and N-termini, respectively. Intact C-terminus exposures increased proportionally with increasing dose, whereas N-terminus exposures appeared to trend higher than dose-proportionally. Although no apparent effect on plasma glucose was seen, dose-dependent decreases in triglyceride were observed, with a maximum reduction of 48.5 ± 10.0% (mean ± standard deviation) for the 200 mg dose compared with a reduction of 19.1 ± 26.4% for placebo, demonstrating proof of pharmacology. Moreover, a reduction in total cholesterol and low-density lipoprotein cholesterol and an increase in high-density lipoprotein cholesterol were observed in the high-dose groups.. Single IV doses of PF-05231023 up to 200 mg were generally safe and well tolerated by subjects with T2DM. The observed early sign of pharmacology supports further clinical testing of PF-05231023 upon repeated administration.

Topics: Administration, Intravenous; Antibodies, Monoclonal, Humanized; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Female; Fibroblast Growth Factors; Humans; Hypoglycemic Agents; Male; Middle Aged; Triglycerides

Fibroblast growth factor 21 (FGF21) is known as a potent metabolic regulator but its protective mechanisms against lipotoxicity-induced β-cell dysfunction and apoptosis remain elusive. Here, we aimed to examine the regulatory pathways whereby FGF21 mediates islet lipid metabolism in lipotoxicity-treated cells and animal models. Rat β-cell line (INS-1E cells) and islets isolated from C57/BL6J mice were exposed to palmitic acid (PA) with/without FGF21, mimicking lipotoxic conditions. Resultant insulin secretion and intracellular signaling were analyzed with Western blotting and RNA-seq. C57/BL6J and global FGF21 knockout (KO) mice were fed with a high-fat diet (HFD) to induce lipotoxicity and given with a long-acting mimetic of FGF21. Insulin resistance and β-cell function were then assessed using homeostasis model assessment of insulin resistance (HOMA-IR) and insulinogenic index. FGF21 ameliorated PA-induced lipid accumulation, reversed cell apoptosis, and enhanced glucose-stimulated insulin secretion (GSIS) as impaired by lipotoxicity in islet β-cells. Mechanistically, FGF21 exerted its beneficial effects through activation of AMPK-ACC (acetyl-CoA carboxylase) pathway and peroxisome proliferation-activated receptors (PPARs) δ/γ signaling, thus increasing the levels of carnitine palmitoyltransferase-1A (CPT1A) and leading to increased fatty acid (FA) oxidation and reduced lipid deposition in β-cells. Interestingly, FGF21 reduced PA-induced cell death via restoration of the expression of apoptosis inhibitor Birc3. In vivo studies further showed that FGF21 is critical for islet insulinogenic capacity and normal function in the context of HFD-treated animals. FGF21 down-regulates islet cell lipid accumulation, probably via activation of AMPK-ACC and PPARδ/γ signaling, and reduces cell death under lipotoxicity, indicating that FGF21 is protective against lipotoxicity-induced β-cell dysfunction and apoptosis.

Topics: Acetyl-CoA Carboxylase; AMP-Activated Protein Kinases; Animals; Antibodies, Monoclonal, Humanized; Apoptosis; Cell Line, Tumor; Diabetes Mellitus, Type 2; Diet, High-Fat; Disease Models, Animal; Fibroblast Growth Factors; Insulin; Insulin Resistance; Insulin-Secreting Cells; Male; Mice, Inbred C57BL; Mice, Knockout; Obesity; Palmitic Acid; PPAR gamma; Rats; Receptors, Cytoplasmic and Nuclear; Signal Transduction