ckd732 and Obesity

Despite the introduction of various pharmaceutical therapies for treating obesity, selecting the optimal treatment remains challenging for both patients and physicians. Therefore, in this network meta-analysis (NMA), we aim to simultaneously compare the available drugs for treating obesity to determine the most effective treatment options.. International databases, including PubMed, Web of Science, Scopus, Cochrane Library, and Embase, were searched for studies published from database inception to April 2023. The consistency assumption was evaluated using by the loop-specific and design × treatment interaction approaches. The effects of treatment in the NMA were summarized using mean differences based on a change score analysis. The random-effects model was used to report the results. Results were reported with 95% CIs.. Of 9519 retrieved references, 96 randomized controlled trials, including 68 with both men and women, 23 with women only, and 5 with men only, met the eligibility criteria for this study. There were 4 treatment networks in the trials of both men and women, 4 in the trials of women only, and 1 in the trials of men only. The best-ranked treatments in the network in the trials of both men and women were (1) semaglutide, 2.4 mg (P-score = 0.99); (2) hydroxycitric acid, 4667 mg 3 times daily, supervised walking, and 2000-kcal/d diet (P-score = 0.92); (3) phentermine hydrochloride and behavioral therapy (P-score = 0.92); and (4) liraglutide plus advice to diet and exercise (P-score = 1.00). In women, the best-ranked treatments were beloranib (P-score = 0.98) and sibutramine, metformin, and hypocaloric diet (P-score = 0.90). In men, there was no significant difference among treatments.. According to the results of this NMA, semaglutide seems to be an effective treatment option for both men and women, whereas beloranib appears to be particularly effective for women with obesity and overweight, but its production has been stopped since 2016 and is not available.

Topics: Diet, Reducing; Female; Humans; Male; Network Meta-Analysis; Obesity; Pharmaceutical Preparations; Randomized Controlled Trials as Topic

Fumagillin, an antimicrobial compound first isolated in 1949 from the fungus Aspergillus fumigatus, four decades later was unexpectedly found to inhibit angiogenesis. Interest in developing angiogenesis inhibitor drugs as possible treatments for cancer led to the synthesis of analogs of fumagillin. Preclinical studies of various analog drugs confirmed that they inhibited angiogenesis, but they also were associated with weight loss as an adverse effect. Because adipose tissue can grow and regress throughout adulthood, is highly vascularized, and has angiogenic properties, interest in investigating anti-angiogenic agents in animal models of obesity found that fumagillin analogs caused dose-dependent reversible weight reduction and adipose tissue loss. Beloranib, a fumagillin analog that is an angiogenesis inhibitor and associated with decreased adiposity in animals, has been studied in phase I clinical trials for cancer. It is currently being investigated for the treatment of obesity and related conditions. Three phase I and three phase II studies found significant degrees of weight loss and acceptable tolerability for beloranib compared to placebo, justifying further clinical development of the drug for obesity.

Topics: Angiogenesis Inducing Agents; Animals; Anti-Obesity Agents; Aspergillus; Cinnamates; Cyclohexanes; Epoxy Compounds; Fatty Acids, Unsaturated; Humans; Mice; Obesity; Sesquiterpenes

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

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

Methionine aminopeptidase 2 (MetAP2) inhibition is a promising approach to treating diabetes, obesity, and associated metabolic disorders. Beloranib, a MetAP2 inhibitor previously investigated for treatment of Prader-Willi syndrome, was associated with venous thrombotic adverse events likely resulting from drug effects on vascular endothelial cells (ECs). Here, we report the pharmacological characterization of ZGN-1061, a novel MetAP2 inhibitor being investigated for treatment of diabetes and obesity. Four weeks of subcutaneous administration of ZGN-1061 to diet-induced obese (DIO) insulin-resistant mice produced a 25% reduction in body weight, primarily due to reduced fat mass, that was comparable to beloranib. ZGN-1061 also produced improvements in metabolic parameters, including plasma glucose and insulin, and, in HepG2 cells, initiated gene changes similar to beloranib that support observed in vivo pharmacodynamics. In vitro studies in ECs demonstrated that ZGN-1061 effects on EC proliferation and coagulation proteins were greatly attenuated, or absent, relative to beloranib, due to lower intracellular drug concentrations, shorter half-life of inhibitor-bound MetAP2 complex, and reduced cellular enzyme inhibition. In dogs, ZGN-1061 was more rapidly absorbed and cleared, with a shorter half-life than beloranib. Unlike beloranib, ZGN-1061 did not increase coagulation markers in dogs, and ZGN-1061 had a greatly improved safety profile in rats relative to beloranib. In conclusion, ZGN-1061 and beloranib demonstrated similar efficacy in a mouse model of obesity, while ZGN-1061 had a markedly improved safety profile in multiple in vitro and in vivo models. The lower duration of exposure characteristic of ZGN-1061 is expected to provide a meaningfully enhanced clinical safety profile.

Topics: Aminopeptidases; Animals; Azetidines; Blood Coagulation; Cinnamates; Cyclohexanes; Dogs; Enzyme Inhibitors; Epoxy Compounds; Female; Hep G2 Cells; Humans; Hypoglycemic Agents; Male; Metalloendopeptidases; Mice; Mice, Inbred C57BL; Morpholines; Obesity; Rats; Safety; Sesquiterpenes; Tissue Distribution

Hypothalamic lesions or deficient melanocortin (MC) signaling via MC4 receptor (MC4r) mutations often lead to hyperphagia and severe treatment-resistant obesity. We tested the methionine aminopeptidase 2-inhibitor beloranib (ZGN-440) in 2 male rat models of obesity, one modeling hypothalamic obesity with a combined medial hypothalamic lesion (CMHL) and the other modeling a monogenic form of obesity with MC4r mutations (MC4r knockout [MC4rKO]). In CMHL rats (age 3 months), postsurgery excess weight gain was significantly inhibited (ZGN-440, 0.2 ± 0.7 g/d; vehicle, 3.8 ± 0.6 g/d; P < 0.001) during 12 days of ZGN-440 treatment (0.1 mg/kg daily subcutaneously) together with a 30% reduction of daily food intake vs vehicle injection. In addition, ZGN-440 treatment improved glucose tolerance and reduced plasma insulin, and circulating levels of α-melanocyte stimulating hormone were increased. Serum lipid levels did not differ significantly in ZGN-440-treated vs vehicle-treated rats. Similar results were found in MC4rKO rats: ZGN-440 treatment (14-21 d) was associated with significant reductions of body weight gain (MC4rKO, -1.7 ± 0.6 vs 2.8 ± 0.4 g/d; lean wild-type controls, -0.7 ± 0.2 vs 1.7 ± 0.7 g/d; ZGN-440 vs vehicle, respectively), reduction of food intake (MC4rKO, -28%; lean controls, -7.5%), and insulin resistance, whereas circulating levels of interleukin-1β did not change. In both obesity models, body temperature and locomotor activity were not affected by ZGN-440 treatment. In conclusion, the robust reduction of body weight in response to ZGN-440 observed in rats with severe obesity is related to a strong reduction of food intake that is likely related to changes in the central regulation of feeding.

Topics: Aminopeptidases; Animals; Body Temperature; Body Weight; Cinnamates; Cyclohexanes; Disease Models, Animal; Drug Evaluation, Preclinical; Eating; Epoxy Compounds; Gene Expression; Glucose Tolerance Test; Hyperphagia; Hypothalamus, Middle; Insulin Resistance; Leptin; Lipid Metabolism; Liver; Male; Metalloendopeptidases; Obesity; Rats, Sprague-Dawley; Rats, Transgenic; Receptor, Melanocortin, Type 4; Sesquiterpenes

The systemic treatment with angiogenesis inhibitor has been shown to result in weight reduction and adipose tissue loss in various models of obesity. To verify the mechanism of CKD-732 (TNP-470 analog) against obesity, we evaluated CKD-732's peripheral and central anti-obesity effects. CKD-732 was injected subcutaneously (s.c.) for 7 days in various animal models and intracerebroventricularly (i.c.v.) in arcuate nucleus (ARC) lesion mice, ob/ob mice, and normal littermates. Modulation of the hypothalamic neuropeptide mRNAs after i.c.v. injection was evaluated in ARC lesion mice and normal littermates. A conditioned taste aversion (CTA) was performed using lithium chloride (LiCl) as a positive control agent in Long-Evans Tokushima Otsuka and Otsuka Long-Evans Tokushima fatty (OLETF) rats. As a result, 7 days of CKD-732 s.c. injection reduced the cumulative food intake and the body weight significantly in both treated obese (e.g. 114.8 +/- 13.4 g vs 170.7 +/- 20.6 g, 7.9 +/- 0.5% decrease vs 0.3 +/- 2.2% decrease; in treated OLETF rat versus control OLETF rat, P < 0.01 respectively) and non-obese models. Epididymal and mesenteric fat pads, and the size of adipocytes were significantly decreased in treated rats. A single i.c.v. injection decreased food intake and body weight in ARC lesion mice and ob/ob mice but not in normal littermates. Unexpectedly, the hypothalamic neuropeptide mRNAs were not altered by single i.c.v. injection. CKD-732 also induced a dose-dependent CTA comparable with LiCl injection, which is a commonly used agent to produce a CTA. In conclusion, CKD-732 causes significant body weight and appetite reduction, possibly by decreasing adiposity directly and inducing central anorexia, which is partly explained by a CTA. These results should be carefully verified to assess the utility of CKD-732 as an anti-obesity drug.

Topics: Adipocytes; Adipose Tissue; Animals; Anti-Obesity Agents; Arcuate Nucleus of Hypothalamus; Body Weight; Cell Size; Cinnamates; Cyclohexanes; Eating; Epoxy Compounds; Hypothalamus; Lithium Chloride; Male; Mice; Mice, Obese; Neuropeptides; O-(Chloroacetylcarbamoyl)fumagillol; Obesity; Rats; Rats, Inbred OLETF; Sesquiterpenes; Taste