Efficacy and safety of beloranib for weight loss in obese adults: a randomized controlled trial

Kim, D.D.; Krishnarajah, Janakan; Lillioja, Stephen; Looze, Fred de; Marjason, Joanne; Proietto, Joseph; Shakib, Sepehr; Stuckey, Bronwyn; Vath, James E.; Hughes, Thomas E.

doi:10.1111/dom.12457

Cited by 54 publications

(56 citation statements)

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“…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].…”

Section: Discussionsupporting

confidence: 86%

“…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.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2018

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Aims/hypothesis This multicentre randomised double-blind placebo-controlled clinical trial assessed the efficacy and safety of a methionine aminopeptidase 2 (MetAP2) inhibitor, beloranib, in individuals with obesity (BMI ≥30 kg/m 2 ) and type 2 diabetes (HbA 1c 53-97 mmol/mol [7-11%] and fasting glucose <15.6 mmol/l). Methods Participants were randomised (via a centralised interactive web response system) to placebo, 1.2 or 1.8 mg beloranib s.c. twice weekly for 26 weeks. Participants, investigators and the sponsor were blinded to group assignment. The primary endpoint was the change in weight from baseline to week 26. The trial was terminated early when beloranib development was stopped because of an imbalance of venous thromboembolism events in beloranib-treated individuals vs placebo that became evident during late-stage development of the drug. Results In total, 153 participants were randomised, 51 to placebo, 52 to 1.2 mg beloranib and 50 to 1.8 mg beloranib. In participants who completed week 26, the least squares mean ± SE weight change (baseline 111 kg) was −3.1 ± 1.2% with placebo (n = 22) vs −13.5 ± 1.1% and −12.7 ± 1.3% with 1.2 and 1.8 mg beloranib, respectively (n = 25; n = 19; p < 0.0001). The change in HbA 1c (baseline 67 mmol/mol [8.3%]) was −6.6 ± 2.2 mmol/mol (−0.6 ± 0.2%) with placebo vs −21.9 ± 2.2 mmol/mol (−2.0 ± 0.2%) or −21.9 ± 3.3 mmol/mol (−2.0 ± 0.3%) with 1.2 or 1.8 mg beloranib (p < 0.0001), respectively. The most common beloranib adverse events were sleep related. One beloranib-treated participant experienced a non-fatal pulmonary embolism.Electronic supplementary material The online version of this article (https://doi.org/10.1007/s00125-018-4677-0) contains peer-reviewed but unedited supplementary material, which is available to authorised users.

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Section: Discussionsupporting

confidence: 86%

Section: Introductionmentioning

confidence: 99%

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

et al. 2018

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“…A follow up, Phase II double-blind, randomized, placebo-controlled study investigated the efficacy, safety and tolerability of a beloranib suspension (0.6, 1.2 and 2.4 mg, SC) in obese women for 12 wk (Kim et al, 2015). At wk 12, beloranib resulted in dose-dependent weight loss of 5-10% compared to 0.3% with placebo.…”

Section: Pharmacotherapies For Obesitymentioning

confidence: 99%

Obesity: Current and potential pharmacotherapeutics and targets

Narayanaswami

Dwoskin

2017

Pharmacology & Therapeutics

152

121

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Obesity is a global epidemic that contributes to a number of health complications including cardiovascular disease, type 2 diabetes, cancer and neuropsychiatric disorders. Pharmacotherapeutic strategies to treat obesity are urgently needed. Research over the past two decades has increased substantially our knowledge of central and peripheral mechanisms underlying homeostatic energy balance. Homeostatic mechanisms involve multiple components including neuronal circuits, some originating in hypothalamus and brain stem, as well as peripherally-derived satiety, hunger and adiposity signals that modulate neural activity and regulate eating behavior. Dysregulation of one or more of these homeostatic components results in obesity. Coincident with obesity, reward mechanisms that regulate hedonic aspects of food intake override the homeostatic regulation of eating. In addition to functional interactions between homeostatic and reward systems in the regulation of food intake, homeostatic signals have the ability to alter vulnerability to drug abuse. Regarding the treatment of obesity, pharmacological monotherapies primarily focus on a single protein target. FDA-approved monotherapy options include phentermine (Adipex-P®), orlistat (Xenical®), lorcaserin (Belviq®) and liraglutide (Saxenda®). However, monotherapies have limited efficacy, in part due to the recruitment of alternate and counter-regulatory pathways. Consequently, a multi-target approach may provide greater benefit. Recently, two combination products have been approved by the FDA to treat obesity, including phentermine/topiramate (Qsymia®) and naltrexone/bupropion (Contrave®). The current review provides an overview of homeostatic and reward mechanisms that regulate energy balance, potential therapeutic targets for obesity and current treatment options, including some candidate therapeutics in clinical development. Finally, challenges in anti-obesity drug development are discussed.

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“…A phase 2 trial in hypothalamic injury-associated obesity, which affects only about 500 patients each year has been completed [34]. Although not the target market, 'normal' obese patients treated for 12 weeks with beloranib at its highest dose level lost 10.5 kg more body weight than patients treated with placebo [35]. This is significantly more than most anti-obesity drugs have achieved (Table 1).…”

Section: Beloranib and Prader-willi Syndromementioning

confidence: 99%

Horizons in the Pharmacotherapy of Obesity

Arch

2015

Curr Obes Rep

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Abstract:Obesity drugs have had a chequered history. In the recent past, only the low efficacy, pancreatic lipase inhibitor orlistat was available worldwide and it was little used. The 5HT2C agonist lorcaserin, and two combinations of old drugs have been approved in the United States but not in Europe. The diabetes drug liraglutide has been approved in both the US and Europe and seems likely to be most widely accepted. In view of regulators' caution in approving obesity drugs, some (like beloranib) may initially be progressed for niche obesity markets. New drug targets have been identified in brown adipose tissue with the aim of not only activating thermogenesis but also increasing the capacity for thermogenesis in this tissue. Attempts are being made to match the efficacy of bariatric surgery by mimicking multiple gut hormones. Unapproved pharmacotherapies are tempting for some patients. Others remain optimistic about more conventional routes to pharmacotherapy.3

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Efficacy and safety of beloranib for weight loss in obese adults: a randomized controlled trial

Cited by 54 publications

References 31 publications

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

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

Obesity: Current and potential pharmacotherapeutics and targets

Horizons in the Pharmacotherapy of Obesity

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