LY2405319, an Engineered FGF21 Variant, Improves the Metabolic Status of Diabetic Monkeys

Abstract

Fibroblast growth factor 21 (FGF21) is a novel metabolic regulator that represents a promising target for the treatment of several metabolic diseases. Administration of recombinant wild type FGF21 to diabetic animals leads to a dramatic improvement in glycaemia and ameliorates other systemic measures of metabolic health. Here we report the pharmacologic outcomes observed in non-human primates upon administration of a recently described FGF21 analogue, LY2405319 (LY). Diabetic rhesus monkeys were treated subcutaneously with LY once daily for a period of seven weeks. The doses of LY used were 3, 9 and 50 mg/kg each delivered in an escalating fashion with washout measurements taken at 2, 4, 6 and 8 weeks following the final LY dose. LY therapy led to a dramatic and rapid lowering of several important metabolic parameters including glucose, body weight, insulin, cholesterol and triglyceride levels at all doses tested. In addition, we observed favorable changes in circulating profiles of adipokines, with increased adiponectin and reduced leptin indicative of direct FGF21 action on adipose tissue. Importantly, and for the first time we show that FGF21 based therapy has metabolic efficacy in an animal with late stage diabetes. While the glycemic efficacy of LY in this animal was partially attenuated its lipid lowering effect was fully preserved suggesting that FGF21 may be a viable treatment option even in patients with advanced disease progression. These findings support continued exploration of the FGF21 pathway for the treatment of metabolic disease.

FGF21-receptor agonists: an emerging therapeutic class for obesity-related diseases

“…For example, while FGF21-class molecules readily normalize blood glucose levels in mouse models of obesityinduced insulin resistance [14], [15], [16], only a modest glucose lowering effect was observed in human patients with type 2 diabetes [28], [29]. In addition, FGF21-analogs strongly suppress food intake in NHPs [28], [32], while a mild increase in food consumption occurs in mice [15], [16]. Hence, although FGF21-class molecules induced robust weight loss both in NHPs and in diet-induced obese mice, the mechanism of weight loss in NHPs appears to be related to reduction in food consumption [28], [67], while thermogenesis primarily drives weight loss in mice.…”

“…Hence, although FGF21-class molecules induced robust weight loss both in NHPs and in diet-induced obese mice, the mechanism of weight loss in NHPs appears to be related to reduction in food consumption [28], [67], while thermogenesis primarily drives weight loss in mice. The weight-loss induced by FGF21-class molecules in NHPs is accompanied by improvements in various cardiometabolic lipid factors [28], [30], [31], [32]. Whether or not FGF21 activates BAT thermogenesis in NHPs has yet to be determined.…”

“…Circulating adiponectin increases after treatment with native FGF21 protein in mice [48], [49], [50] and in spontaneously obese NHPs [31]. In addition, several engineered FGF21-class molecules increase circulating adiponectin in NHPs and humans [27], [28], [29], [32]. One exception to this FGF21-class effect was demonstrated by a FGF21RA anti-KLB antibody, named mimAb1.…”

Mechanistic Investigation of the Preclinical Pharmacokinetics and Interspecies Scaling of PF-05231023, a Fibroblast Growth Factor 21–Antibody Protein Conjugate

“…Truncation of N termini (NT) by six or more residues, or C termini (CT) by two or more residues, decreased in vitro potency more than 10-fold, suggesting that potent functional activity was derived from both termini of FGF21 (Micanovic et al, 2009;Yie et al, 2009). In diabetic animal models and patients with type 2 diabetes, recombinant fibroblast growth factor 21 (rFGF21) and its analogs demonstrated dose-dependent reductions in low-density lipoprotein cholesterol, apolipoproteins, fasting triglycerides, fasting insulin, and body weight, as well as dose-dependent elevations of high-density lipoprotein cholesterol and adiponectin (Adams et al, 2013;Gaich et al, 2013;Kharitonenkov et al, 2013;Smith et al, 2013). Although dose-dependent reductions in blood glucose have been observed in diabetic rodent and nonhuman primate models, thus far only a trend toward lower fasting blood glucose has been observed in human clinical studies (Gaich et al, 2013).…”

Selective Regulation of FGF19 and FGF21 Expression by Cellular and Nutritional Stress

“…It is interesting that both FGF19 and FGF21 show beneficial effects on obesity and insulin sensitivity (11)(12)(13)(14). Recent studies revealed that a synthetic FGF21 analog improves lipid metabolism in obese humans and monkeys with type 2 diabetes (15,16). These reports suggest FGF19 and FGF21 are attractive therapeutic targets for obesity and diabetes.…”