ckd732 and Weight-Loss

Recently, the recognition of obesity as a complex disease that requires chronic management has become more widespread. There has also been a movement away from a focus on body mass index alone, and toward the management of obesity-related comorbidities as well as excess weight. This article examines the current and emerging pharmacological options for weight management in people with overweight or obesity who have, or are at a high risk of, weight-related comorbidities. In the USA, the current options for pharmacological weight management are phentermine (indicated for short-term use only), orlistat, combined phentermine/topiramate extended release, lorcaserin, naltrexone/bupropion and liraglutide 3.0 mg. Currently, orlistat, naltrexone/bupropion and liraglutide 3.0 mg are approved in Europe. All of the above-mentioned medications have shown weight-loss efficacy versus placebo. Those approved for long-term weight management have also been associated with improvements in weight-related comorbidities, such as hypertension, prediabetes, diabetes or dyslipidaemia, or related biomarkers. As with all drugs, the safety and tolerability profiles of medications for weight management should be considered alongside their efficacy to ensure correct use. Additional medications for weight management that are in clinical development include bupropion/zonisamide and beloranib. The field of obesity treatment is advancing with a number of medications being recently approved, and with other pharmacological options emerging.

Topics: Anti-Obesity Agents; Bupropion; Cinnamates; Comorbidity; Cyclohexanes; Diabetes Mellitus; Dyslipidemias; Epoxy Compounds; Humans; Hypertension; Isoxazoles; Obesity; Overweight; Prediabetic State; Sesquiterpenes; Weight Loss; Zonisamide

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.

Topics: Adipose Tissue, Brown; Anti-Obesity Agents; Appetite Depressants; Benzazepines; Cinnamates; Clinical Trials as Topic; Cyclohexanes; Drug Approval; Drug Combinations; Epoxy Compounds; Europe; Humans; Lactones; Liraglutide; Molecular Targeted Therapy; Obesity; Orlistat; Sesquiterpenes; Thermogenesis; United States; Weight Loss

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.. MetAP2 inhibitors represent a novel mechanism for producing meaningful weight loss and improvement in HbA. ClinicalTrials.gov NCT02324491 FUNDING: The study was funded by Zafgen, Inc.

Topics: Adolescent; Adult; Aged; Aminopeptidases; Anti-Obesity Agents; Blood Glucose; Body Weight; Cinnamates; Cyclohexanes; Diabetes Mellitus, Type 2; Double-Blind Method; Epoxy Compounds; Female; Glucose; Glycated Hemoglobin; Glycoproteins; Humans; Hypoglycemic Agents; Male; Metalloendopeptidases; Methionyl Aminopeptidases; Middle Aged; Obesity; Sesquiterpenes; Weight Loss; Young Adult

There are no treatments for the extreme hyperphagia and obesity in Prader-Willi syndrome (PWS). The bestPWS clinical trial assessed the efficacy, safety and tolerability of the methionine aminopeptidase 2 (MetAP2) inhibitor, beloranib.. Participants with PWS (12-65 years old) were randomly assigned (1:1:1) to biweekly placebo, 1.8 mg beloranib or 2.4 mg beloranib injection for 26 weeks at 15 US sites. Co-primary endpoints were the changes in hyperphagia [measured by Hyperphagia Questionnaire for Clinical Trials (HQ-CT); possible score 0-36] and weight by intention-to-treat. ClinicalTrials.gov registration: NCT02179151.. One-hundred and seven participants were included in the intention-to-treat analysis: placebo (n = 34); 1.8 mg beloranib (n = 36); or 2.4 mg beloranib (n = 37). Improvement (reduction) in HQ-CT total score was greater in the 1.8 mg (mean difference -6.3, 95% CI -9.6 to -3.0; P = .0003) and 2.4 mg beloranib groups (-7.0, 95% CI -10.5 to -3.6; P = .0001) vs placebo. Compared with placebo, weight change was greater with 1.8 mg (mean difference - 8.2%, 95% CI -10.8 to -5.6; P < .0001) and 2.4 mg beloranib (-9.5%, 95% CI -12.1 to -6.8; P < .0001). Injection site bruising was the most frequent adverse event with beloranib. Dosing was stopped early due to an imbalance in venous thrombotic events in beloranib-treated participants (2 fatal events of pulmonary embolism and 2 events of deep vein thrombosis) compared with placebo.. MetAP2 inhibition with beloranib produced statistically significant and clinically meaningful improvements in hyperphagia-related behaviours and weight loss in participants with PWS. Although investigation of beloranib has ceased, inhibition of MetAP2 is a novel mechanism for treating hyperphagia and obesity.

Topics: Adolescent; Adult; Aminopeptidases; Appetite Depressants; Body Mass Index; Cinnamates; Cyclohexanes; Dose-Response Relationship, Drug; Double-Blind Method; Early Termination of Clinical Trials; Epoxy Compounds; Female; Glycoproteins; Humans; Hyperphagia; Intention to Treat Analysis; Male; Methionyl Aminopeptidases; Obesity; Prader-Willi Syndrome; Protease Inhibitors; Sesquiterpenes; Severity of Illness Index; Venous Thrombosis; Weight Loss; Young Adult

Hypothalamic injury-associated obesity (HIAO) results from damage to the hypothalamus that often occurs with surgical removal/radiation therapy of tumours in the hypothalamic region, such as craniopharyngioma. There is currently no rigorously studied pharmaceutical treatment for the intractable weight gain and cardiometabolic consequences that occur in patients with HIAO. We aimed to assess efficacy, safety and tolerability of beloranib treatment for 4 to 8 weeks in patients with HIAO.. This Phase 2a, double-blind, placebo-controlled study included 14 patients with HIAO, randomized to receive beloranib 1.8 mg or placebo subcutaneously twice weekly for 4 weeks with an optional 4-week open-label extension in which all patients received beloranib. The primary endpoint was change in weight from baseline to Week 4.. Participants were 64% female, with a mean (SD) age of 32 (9) years, BMI of 43 (7) kg/m. Beloranib treatment resulted in progressive weight loss in patients with HIAO that was comparable to that observed with beloranib in patients with exogenous obesity. These findings indicate a novel mechanism for treating obesity in patients with HIAO.

Topics: Adult; Aminopeptidases; Appetite Depressants; Biomarkers; Body Mass Index; Cardiovascular Diseases; Cinnamates; Cohort Studies; Cyclohexanes; Double-Blind Method; Enzyme Inhibitors; Epoxy Compounds; Female; Follow-Up Studies; Glycoproteins; Humans; Hypothalamus; Injections, Subcutaneous; Male; Metabolic Syndrome; Methionyl Aminopeptidases; Obesity, Morbid; Proof of Concept Study; Risk; Sesquiterpenes; Weight Loss; Young Adult

To assess the efficacy, safety and tolerability of beloranib treatment for obesity.. This phase II, double-blind, randomized study investigated the effects of beloranib suspension (0.6, 1.2 and 2.4 mg) or placebo, administered subcutaneously, for 12 weeks in 147 participants (primarily white women) with obesity. No diet or exercise advice was administered.. At week 12, beloranib resulted in dose-dependent progressive weight loss of -5.5 ± 0.5, -6.9 ± 0.6 and -10.9 ± 1.1 kg for the 0.6, 1.2 and 2.4 mg beloranib doses, respectively, compared with -0.4 ± 0.4 kg with placebo (all p < 0.0001 vs placebo). Weight loss with beloranib was associated with corresponding reductions in waist circumference and body fat mass, as well as improvements in lipids, high-sensitivity C-reactive protein and blood pressure. Sleep disturbance and gastrointestinal adverse events were more common with beloranib than with placebo; these were generally mild to moderate, transient and dose-related, and led to more early study withdrawals in participants in the group with the highest dose of beloranib.. In this 12-week phase II study, beloranib produced clinically and statistically significant weight loss and corresponding improvements in cardiometabolic risk factors. Beloranib appeared safe, and the 0.6 and 1.2 mg doses were generally well tolerated. The 2.4 mg dose was associated with increased sleep latency and mild to moderate gastrointestinal adverse events over the first month of treatment. These findings represent a novel mechanism for producing clinically meaningful weight loss.

Topics: Adolescent; Adult; Aged; Aminopeptidases; Anti-Obesity Agents; Blood Pressure; Body Mass Index; C-Reactive Protein; Cinnamates; Cyclohexanes; Dose-Response Relationship, Drug; Double-Blind Method; Dyssomnias; Epoxy Compounds; Female; Gastrointestinal Diseases; Humans; Lipids; Male; Metalloendopeptidases; Middle Aged; Obesity; Risk Factors; Sesquiterpenes; Waist Circumference; Weight Loss; Young Adult