cetilistat and Obesity

Topics: Anti-Obesity Agents; Appetite; Appetite Depressants; Benzazepines; Benzoxazines; Bupropion; Clinical Trials as Topic; Drug Approval; Drug Combinations; Drug Discovery; Energy Metabolism; Enzyme Inhibitors; Fructose; Glucagon-Like Peptide 1; Humans; Hypothalamus; Lactones; Lipase; Liraglutide; Metabolic Syndrome; Naltrexone; Obesity; Orlistat; Phentermine; Topiramate

Worldwide obesity prevalence has nearly doubled since 1980. Due to numerous co-morbidities, obesity represents a serious health and socioeconomic problem worldwide. Pharmacotherapy should be an integral part of comprehensive obesity management. Drug therapy can assist in weight loss and its maintenance in those individuals who do not achieve appropriate weight loss through lifestyle interventions alone. After the withdrawal of sibutramine from the market in 2010, orlistat, a lipase inhibitor, was the only remaining prescription drug approved for the long-term treatment of obesity. In 2012, phentermine/topiramate extended-release (PHEN/TPM ER) combination and lorcaserin were approved by the US FDA as novel medications for long-term weight management. Three major phase III trials conducted with each drug confirmed their efficacy in terms of weight loss/maintenance and improvement of cardiometabolic risks. No head-to-head studies between the two new anti-obesity drugs have been carried out. However, in the existing studies PHEN/TPM ER had a superior weight loss profile to lorcaserin but the incidence of adverse effects was lower with lorcaserin. Both drugs were well-tolerated, and adverse events were modest in intensity, dose dependent, rather rare, and tended to decrease with the duration of treatment. Major safety concerns regarding PHEN/TPM ER include elevations in resting pulse rate, teratogenicity, mild metabolic acidosis, and psychiatric and cognitive adverse events. Valvulopathy, cognitive impairment, psychiatric disorders, and hypoglycemia represent major safety concerns for lorcaserin. Although existing trials have not demonstrated any significant issues with PHEN/TPM ER-induced heart rate elevation and lorcaserin-induced valvulopathy, all safety concerns should be seriously taken into account in patients treated with either of these novel anti-obesity medications.

Topics: Anti-Obesity Agents; Benzazepines; Benzoxazines; Bupropion; Chemistry, Pharmaceutical; Drug-Related Side Effects and Adverse Reactions; Fructose; Glucagon-Like Peptide 1; Humans; Liraglutide; Naltrexone; Obesity; Phentermine; Topiramate

A short overview of new drugs approved for the treatment of obesity (lorcaserin, phentermine/topiramate combination) as well as those with a perspective for approval as antiobesity drugs (cetilistat, naltrexone/bupropion combination, liraglutide) is presented. All these drugs produce significant weight loss accompanied by reductions in cardiometabolic health risks. Although the adverse events were rather rare and tended to decrease with the duration of treatment with most of these medications, the drug-specific safety concerns should be seriously considered. In order to ensure an appropriate, efficient and safe implementation of novel antiobesity drugs into the comprehensive treatment of obesity, it will be necessary to establish a network of physicians and other health-care providers well educated in obesity management.

Topics: Anti-Obesity Agents; Benzazepines; Benzoxazines; Bupropion; Drug Combinations; Fructose; Glucagon-Like Peptide 1; Humans; Liraglutide; Naltrexone; Obesity; Phentermine; Topiramate; Weight Loss

Currently, obesity presents one of the biggest health problems. Management strategies for weight reduction in obese individuals include changes in life style such as exercise and diet, behavioral therapy, and pharmacological treatment, and in certain cases surgical intervention. Diet and exercise are best for both prevention and treatment, but both require much discipline and are difficult to maintain. Drug treatment of obesity offer a possible adjunct, but it may only have modest results, limited by side effects; furthermore, the weight lowering effects last only as long as the drug is being taken and, unfortunately, as soon as the administration is stopped, the weight is regained. These strategies should be used in a combination for higher efficacy. Drugs used to induce weight loss have various effects: they increase satiety, reduce the absorption of nutrients or make metabolism faster; but their effect is usually moderate. In the past, several drugs were used in the pharmacological therapy of weight reduction including thyroid hormone, dinitrophenol, amphetamines and their analogues, e.g. fenfluramine, At present, only orlistat is available in the long term treatment (≥ 24 weeks) of obesity as sibutramine and rimonabant were withdrawn form the market. Several new anti-obesity drugs are being tested at present, and liraglutide, a GLP-1 analogue (incretin mimetic), is the most promising one.

Topics: Amides; Anti-Obesity Agents; Anticonvulsants; Antidepressive Agents; Basal Metabolism; Benzazepines; Benzoxazines; Body Mass Index; Bridged Bicyclo Compounds, Heterocyclic; Ciliary Neurotrophic Factor; Clinical Trials as Topic; Combined Modality Therapy; Cyclobutanes; Dexfenfluramine; Fatty Acids; Female; Fenfluramine; Glucagon-Like Peptide 1; Human Growth Hormone; Humans; Intestinal Absorption; Lactones; Leptin; Life Style; Liraglutide; Male; Norepinephrine; Obesity; Obesity, Morbid; Orlistat; Piperidines; Pyrazoles; Pyridines; Receptor, Melanocortin, Type 4; Rimonabant; Satiation; Serotonin; Sodium-Glucose Transport Proteins; Sucrose; Thyroid Hormones

The prevalence of obesity is rising worldwide, with the U.K. having the highest prevalence in Europe. Obesity is associated with significant morbidity and has substantial healthcare implications, with current projections estimating that by 2030 obesity will cost the NHS approximately pounds 2 billion each year. Lifestyle modification remains the cornerstone of anti-obesity treatment, but drugs can be introduced as adjuncts to assist and maintain weight loss. Some 1.45 million obesity-related prescriptions were dispensed in 2009, highlighting the high demand for obesity pharmacotherapy. At present, the lipase inhibitor orlistat (Xenical) is the only UK-approved long-term medical therapy for obesity. Double-blind clinical trials have shown that orlistat significantly increases weight loss compared to placebo, but the array of adverse side effects associated with orlistat limits its tolerability. The need for more effective and better-tolerated anti-obesity medications is clear and six therapies have reached phase-III trials.

Topics: Anti-Obesity Agents; Benzazepines; Benzoxazines; Bupropion; Clinical Trials as Topic; Drug Combinations; Fructose; Glucagon-Like Peptide 1; Humans; Lactones; Life Style; Liraglutide; Naltrexone; Obesity; Orlistat; Phentermine; Topiramate; Weight Loss

Alizyme plc, in collaboration with Takeda Pharmaceutical Co Ltd in Japan, is developing cetilistat, an oral non-absorbed synthetic lipase inhibitor, derived from Alizyme's pancreatic lipase inhibitor research program, for the potential treatment of obesity in patients with or without diabetes. It is also under investigation for the potential management of type 2 diabetes. Several phase II clinical trials for obesity have been completed. Phase III trials were in preparation at the time of publication.

Topics: Animals; Anti-Obesity Agents; Benzoxazines; Drug Evaluation, Preclinical; Enzyme Inhibitors; Humans; Lipase; Molecular Structure; Obesity; Patents as Topic; Structure-Activity Relationship; Treatment Outcome

The objective of this multicenter, randomized, double-blind study was to determine the efficacy and safety of cetilistat and orlistat relative to placebo in obese patients with type 2 diabetes, on metformin. Following a 2-week run-in, patients were randomized to placebo, cetilistat (40, 80, or 120 mg three times daily), or orlistat 120 mg t.i.d., for 12 weeks. The primary endpoint was absolute change in body weight from baseline. Secondary endpoints included other measures of obesity and glycemic control. Similar reductions in body weight were observed in patients receiving cetilistat 80 or 120 mg t.i.d. or 120 mg t.i.d. orlistat; these reductions were significant vs. placebo (3.85 kg, P = 0.01; 4.32 kg, P = 0.0002; 3.78 kg, P = 0.008). In the 40 mg t.i.d. and placebo groups, reductions were 2.94 kg, P = 0.958 and 2.86 kg, respectively. Statistically significant reductions in glycosylated hemoglobin (HbA(1c)) were noted. Cetilistat was well tolerated, and showed fewer discontinuations due to adverse events (AEs) than in the placebo and orlistat groups. Discontinuation in the orlistat group was significantly worse than in the 120 mg cetilistat and placebo groups and was entirely due to gastrointestinal (GI) AEs. Treatment with cetilistat 80 or 120 mg t.i.d., or with orlistat 120 mg t.i.d., significantly reduced body weight and improved glycemic control relative to placebo in obese diabetic patients. Cetilistat was well tolerated with the number of discontinuations due to AEs being similar to placebo.

Topics: Adolescent; Adult; Aged; Benzoxazines; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Double-Blind Method; Female; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Intention to Treat Analysis; Lactones; Lipase; Male; Metformin; Middle Aged; Obesity; Orlistat; Patient Selection; Treatment Outcome; Weight Loss

To assess the efficacy, pharmacodynamics, safety and tolerability of a range of doses of cetilistat, a novel inhibitor of gastrointestinal lipases, in healthy volunteers.. Three Phase I, randomized, placebo-controlled, parallel-group studies were conducted. Enrolled subjects in the three studies (n = 99) received a controlled calorie diet (total intake 2160 calories daily, 30% from fat). Twenty-four subjects were randomized to placebo and 66 were randomized to the following cetilistat doses: 50 mg three times daily [t.i.d. (n = 7)], 60 mg t.i.d. (n = 9), 100 mg t.i.d. (n = 7), 120 mg t.i.d. (n = 9), 150 mg t.i.d. (n = 16), 240 mg t.i.d. (n = 9) and 300 mg t.i.d. (n = 9). Nine subjects received the approved orlistat dose (120 mg t.i.d.). Treatment was for 5 days, with a 2-day run-in period and 1-day post-treatment follow-up. The primary outcome measure was daily faecal fat excretion. Secondary outcomes included plasma lipid levels, tolerability [gastrointestinal adverse events (AEs)] and safety.. Cetilistat increased faecal fat excretion relative to baseline at all doses. Cetilistat was well tolerated, with gastrointestinal AEs the most common (51%). Steatorrhoea (oily stool) was more frequent in the orlistat group (4.11 events per subject) than in any cetilistat dose group (0.14-1.81 events per subject). Most AEs (98%) were mild or moderate in intensity.. Cetilistat increased dietary fat excretion in healthy volunteers receiving a controlled calorie diet. Cetilistat was well tolerated at all doses examined and tolerability appeared to be improved relative to orlistat. Faecal fat excretion in the cetilistat groups was at least comparable to the orlistat 120 mg t.i.d. group.

Topics: Adolescent; Adult; Anti-Obesity Agents; Benzoxazines; Dietary Fats; Double-Blind Method; Enzyme Inhibitors; Humans; Intestinal Absorption; Lactones; Lipase; Male; Middle Aged; Obesity; Orlistat; Treatment Outcome; Young Adult

To determine the efficacy, safety and tolerability of cetilistat (ATL-962), a novel inhibitor of gastrointestinal (GI) lipases, in obese patients.. Phase II, multicentre, randomized, placebo-controlled, parallel group study. Enrolled patients (N=442) were advised a hypocaloric diet (deficient by 500 kcal per day, 30% of calories from fat) for a 2-week run-in period. Patients who satisfied the entry criteria (N=371) continued on the hypocaloric diet and were randomized to either placebo or one of three different doses of cetilistat (60 mg three times daily t.i.d., 120 mg t.i.d. and 240 mg t.i.d.) for 12 weeks, followed by a 4-week post-treatment follow-up. Safety, tolerability and body weight were assessed, together with other parameters associated with obesity.. The primary outcome measure was absolute change in body weight from baseline. Secondary outcomes included the proportion of patients achieving pre-defined weight loss targets, changes from baseline in waist circumference and in blood lipids. GI tolerability criteria were specifically assessed, as was safety.. Treatment with cetilistat reduced mean body weight to similar extents at all doses, which were statistically significant compared with placebo (60 mg t.i.d. 3.3 kg, P<0.03; 120 mg t.i.d. 3.5 kg, P=0.02; 240 mg t.i.d. 4.1 kg, P<0.001). Total serum and low-density lipoprotein cholesterol levels were likewise significantly reduced by 3-11% at all doses of cetilistat. Cetilistat was well tolerated. The frequency of withdrawal owing to treatment-emergent adverse events was similar between cetilistat-treated groups (5.3-7.6%) and placebo (7.6%). Adverse events were generally mild to moderate in intensity, occurred on only one occasion and were mostly GI in nature. The incidence of GI adverse events was increased in the cetilistat-treated groups compared to placebo. However, those GI adverse events, such as flatus with discharge and oily spotting, only occurred in 1.8-2.8% of subjects in the cetilistat-treated groups.. Cetilistat produced a clinically and statistically significant weight loss in obese patients in this short-term 12-week study. This was accompanied by significant improvements in other obesity-related parameters. Cetilistat treatment was well tolerated. The risk-benefit demonstrated in this study in terms of weight loss vs intolerable GI adverse effects shows that cetilistat merits further evaluation for the pharmacotherapy of obesity and related disorders.

Topics: Adult; Benzoxazines; Cholesterol; Double-Blind Method; Drug Administration Schedule; Enzyme Inhibitors; Female; Gastrointestinal Diseases; Humans; Lipase; Male; Middle Aged; Obesity; Treatment Outcome; Weight Loss

Topics: Anti-Obesity Agents; Benzazepines; Benzoxazines; Bupropion; Drug Combinations; Drug Labeling; Drugs, Investigational; Fructose; Humans; Naltrexone; Obesity; Phentermine; United States; United States Food and Drug Administration

Obesity is a modern plague in industrialized and developing countries, and currently overweight and obesity cause more deaths worldwide than underweight. Cetilistat is a novel, orally active, gastrointestinal and pancreatic lipase inhibitor. In in vitro studies cetilistat inhibited human pancreatic lipase with an IC50 in the low nanomolar range. In phase II clinical tials in obese patients and in obese patients with type 2 diabetes, cetilistat administered for 12 weeks significantly reduced body weight, serum low-density lipoprotein (LDL) cholesterol and total cholesterol in comparison to placebo. The proportion of obese patients reaching a reduction in baseline body weight of at least 5% was greater in all active arms in comparison to placebo. In obese diabetic patients the levels of glycosylated hemoglobin (HbA1c) were also significatively reduced. Cetilistat showed mild to moderate adverse events, predominantly of gastrointestinal nature (steatorrhea), with an incidence lower than orlistat. It was recently approved in Japan for the treatment of obesity with complications.

Topics: Animals; Anti-Obesity Agents; Benzoxazines; Diabetes Mellitus, Type 2; Humans; Lipase; Obesity; Weight Loss

Cetilistat is a novel inhibitor of pancreatic lipase. The aim of this report is to evaluate the anti-obesity action of cetilistat in diet-induced obesity (DIO) rats. Cetilistat inhibited rat and human pancreatic lipase activity with an IC (50) of 54.8 nmol/l, and 5.95 nmol/l, respectively, meaning that it is 9.2 times more potent for human pancreatic lipase than for that of rat. Cetilistat was orally administered simultaneously with fat emulsion to Sprague-Dawley rats. Plasma triglyceride (TG) concentrations were measured before and after oral fat loading. The elevation in plasma triglyceride concentration by oral fat loading was reduced by cetilistat in a dose-dependent manner at 3, 10, 30, and 100 mg/kg, indicating that cetilistat reduces intestinal fat absorption in rats. Cetilistat was administered to DIO F344 rats as food admixture in a high-fat diet at 4.9, 14.9, or 50.7 mg/kg/day for three weeks. Both triglyceride and nonesterified fatty acid content in the feces were dose-dependently and drastically increased, suggesting the intestinal breakdown of fat and excretion. Body weight (BW) gain and white adipose tissue (WAT) weight were reduced in a dose-dependent manner. In addition, leptin, TG, and total cholesterol (TC) in plasma were reduced and there were no reports of oily stools. These results suggest that cetilistat ameliorates obesity and hyperlipidemia in DIO rats, a plausible animal model of the most common type of human obesity.

Topics: Adipose Tissue; Animals; Anti-Obesity Agents; Benzoxazines; Cholesterol; Diet; Dietary Fats; Dose-Response Relationship, Drug; Enzyme Inhibitors; Feces; Lipid Metabolism; Male; Obesity; Pancreas; Pancrelipase; Rats; Rats, Inbred F344; Triglycerides; Weight Gain