A Long-Acting FGF21 Molecule, PF-05231023, Decreases Body Weight and Improves Lipid Profile in Non-human Primates and Type 2 Diabetic Subjects

Abstract

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.

Role of Circulating Fibroblast Growth Factor 21 Measurement in Primary Prevention of Coronary Heart Disease Among Chinese Patients With Type 2 Diabetes Mellitus

“…Treatment with FGF21 conferred beneficial effects on body weight, glucose, and lipid metabolism in animal studies,2 and similar benefits were demonstrated in humans treated with FGF21 analogues 3, 4. On the other hand, raised FGF21 levels have been found in various cardiometabolic conditions in clinical studies, suggesting a reactive change to FGF21 resistance or the underlying metabolic disturbances 1.…”

A common allele in FGF21 associated with preference for sugar consumption lowers body fat in the lower body and increases blood pressure

“…Some of these therapies have reached early clinical trials and suggest that FGF21 mimetics can induce weight loss and reduce insulin resistance [7][8][9]. Whilst there is no direct evidence for the function of the rs838133 variant (or one in strong linkage disequilibrium), the A allele is very likely to represent a loss of FGF21 function, because it is very robustly associated with higher sugar and alcohol preference in people, a finding that is completely consistent with the genetic and pharmacological effects of FGF21 lowering in animal models, including non-human primates [1,2].…”

“…An early trial showed lipid lowering effects in people with type 2 diabetes and obesity but there was only suggestive evidence for effects on weight and glucose tolerance [7]. A recent study suggested that FGF21 analogues may alter blood pressure in humans [8], although changes in blood pressure were not observed in a previous trial [9]. Pre-clinical evidence of FGF21's potential role in metabolism includes resistance to diet induced obesity in mice overexpressing FGF21 [3] and improved glucose tolerance in obese mice through administration of recombinant FGF21 [3].…”

“…http://dx.doi.org/10.1101/214700 doi: bioRxiv preprint first posted online Nov. 6, 2017; blood pressure in humans [8], although changes in blood pressure were not observed in a previous trial [9]. Pre-clinical evidence of FGF21's potential role in metabolism includes resistance to diet induced obesity in mice overexpressing FGF21 [3] and improved glucose tolerance in obese mice through administration of recombinant FGF21 [3].…”

“…We used a well-validated and freely available R package called GGIR (v1. [5][6][7][8][9][10][11][12] to process these files, made available to researchers, in order to extract measures of physical activity and sleep. For this study, we used three derived measures of activity and one measure of sleep timing (L5 time).…”