Ascending dose‐controlled trial of beloranib, a novel obesity treatment for safety, tolerability, and weight loss in obese women

Abstract

Objective: Evaluate the safety and tolerability of beloranib, a fumagillin-class methionine aminopetidase-2 (MetAP2) inhibitor, in obese women over 4 weeks. Design and Methods: Thirty-one obese (mean BMI 38 kg/m 2 ) women were randomized to intravenous 0.1, 0.3, or 0.9 mg/m 2 beloranib or placebo twice weekly for 4 weeks (N ¼ 7, 6, 9, and 9). Results:The most frequent AEs were headache, infusion site injury, nausea, and diarrhea. Nausea and infusion site injury occurred more with beloranib than placebo. The most common reason for discontinuation was loss of venous access. There were no clinically significant abnormal laboratory findings. In subjects completing 4 weeks, median weight loss with 0.9 mg/m 2 beloranib was À3.8 kg (95% CI À5.1, À0.9; N ¼ 8) versus À0.6 kg with placebo (À4.5, À0.1; N ¼ 6). Weight change for 0.1 and 0.3 mg/m 2 beloranib was similar to placebo. Beloranib (0.9 mg/m 2 ) was associated with a significant 42 and 18% reduction in triglycerides and LDL-cholesterol, as well as improvement in C-reactive protein and reduced sense of hunger. Changes in b-hydroxybutyrate, adiponectin, leptin, and fibroblast growth factor-21 were consistent with the putative mechanism of MetAP2 inhibition. Glucose and blood pressure were unchanged. Conclusions: Beloranib treatment was well tolerated and associated with rapid weight loss and improvements in lipids, C-reactive protein, and adiponectin.

Efficacy and safety of methionine aminopeptidase 2 inhibition in type 2 diabetes: a randomised, placebo-controlled clinical trial

“…Importantly, other MetAP2 inhibitors were recently shown to have similar beneficial effects on body weight and glycaemic control, but with a substantially improved safety profile compared with beloranib [7]. Injection-site erythema 1 (2) 2 (4) In addition to reductions in body weight and HbA 1c , improvements in waist and hip circumference, fat mass, lipids, hsCRP, leptin and adiponectin (ESM Table 2) are consistent with previous observations of beloranib [3][4][5][6] and likely result from rapid weight loss as well as other weight-independent effects of MetAP2 inhibition. MetAP2 inhibitors are hypothesised to reduce body weight by increasing fat mobilisation and oxidation [2] and reducing food intake-beloranib produces a marked but transient reduction in food intake in preclinical studies [2] and improves measures of hunger and prospective food intake in obese individuals [3][4][5] and hyperphagia in PWS [6].…”

“…In preclinical models of obesity and diabetes, MetAP2 inhibitors produce weight loss characterised by markedly reduced adiposity and increased glycaemic control, as well as transiently reduced food intake [1,2]. The MetAP2 inhibitor beloranib has demonstrated consistent and substantial weight loss and glucose-lowering effects in clinical studies of general obesity, hypothalamicinjury-associated obesity and Prader-Willi syndrome (PWS) [3][4][5][6]. This phase 2 clinical trial is the first to study the effects of MetAP2 inhibition with beloranib compared with placebo on glycaemic control and body weight in individuals with type 2 diabetes and obesity.…”

Weight Management in Type 2 Diabetes: Current and Emerging Approaches to Treatment

“…Another agent under clinical investigation as an antiobesity agent is beloranib, a fumagillin-class methionine aminopeptidase-2 inhibitor that has recently completed phase 2 trials (110). Because beloranib treatment is associated with rapid weight loss and improvements in lipids (110), beloranib could likely also have a beneficial effect in the treatment of overweight/obese patients with type 2 diabetes.…”

“…Because beloranib treatment is associated with rapid weight loss and improvements in lipids (110), beloranib could likely also have a beneficial effect in the treatment of overweight/obese patients with type 2 diabetes.…”

Discovery of Novel Antigiardiasis Drug Candidates

“…For killing the Giardia trophozoites that attach to the intestinal lumen and do not invade cells, the lack of oral availability is advantageous because the high drug concentration in the intestinal lumen can combat the parasite locally, whereas the severe systemic toxic effects associated with injection or infusion may be avoided. More recently, fumagillin has been shown to impair diet-induced obesity in mice treated by oral gavage with doses of 1 mg/kg/day (32), and an orally administered fumagillin derivative, beloranib, has reached human clinical trials as treatment for obesity (33).…”