Objective: To determine the efficacy, safety and tolerability of cetilistat (ATL-962), a novel inhibitor of gastrointestinal (GI) lipases, in obese patients. Design: Phase II, multicentre, randomized, placebo-controlled, parallel group study. Enrolled patients (N ¼ 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 ¼ 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. Outcome measures: 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. Results: 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, Po0.03; 120 mg t.i.d. 3.5 kg, P ¼ 0.02; 240 mg t.i.d. 4.1 kg, Po0.001). 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. Conclusions: 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.

IntroductIonWeight control plays an important role in the management of patients with type 2 diabetes and is typically addressed by lifestyle modifications. These focus on a nutritionally balanced, moderately hypocaloric diet, with a reduced intake of saturated fat and an increase in physical activity (1-6). Current pharmacological options for weight management are limited, with only three agents, orlistat (an inhibitor of gastric and pancreatic lipases) (7-10), sibutramine (a combined reuptake inhibitor of both serotonin and norepinephrine) that acts centrally to enhance satiety (11), and phentermine (a sympathomimetic) currently approved in some countries for use in obese patients with or without diabetes (12-15). Rimonabant (a cannabinoid-1 receptor blocker) was recently removed from the market. Cetilistat is a novel, highly lipophilic benzoxazinone inhibitor of gastrointestinal (GI) and pancreatic lipases, which is currently under development for the management of weight loss in obese patients with or without medical complications. In a 12-week, randomized, placebo-controlled, phase 2 clinical study in obese patients without pharmacologically treated comorbidities, administration of 60, 120, or 240 mg cetilistat three times daily (t.i.d.) in combination with a hypocaloric diet produced significantly greater weight loss than placebo at all doses tested (16). In addition, cetilistat was well tolerated, with a similar proportion of discontinuations due to adverse events (AEs) in both the cetilistat and the placebo groups (16). AEs were predominantly GI in nature and mild or moderate in severity.We report here the results from a randomized, placebocontrolled study investigating the efficacy and tolerability of three cetilistat doses (40, 80, and 120 mg t.i.d.) compared to placebo, in obese patients with type 2 diabetes on metformin. The study also included an active treatment comparator arm, with patients in this group receiving orlistat (120 mg t.i.d. 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. Discontinua...

SUMMARY BackgroundRenzapride, a 5-hydroxytryptamine type-4 (5-HT 4 ) receptor agonist and 5-HT 3 receptor antagonist, has been proposed as a new treatment of irritable bowel syndrome with constipation (IBS-C).

SUMMARY BackgroundRelatively few pharmacological treatment options are available for treating patients with irritable bowel syndrome. New and effective medicines are urgently required.

This was an exploratory study of renzapride in 168 male and female patients with non-D, non-C irritable bowel syndrome (IBS). Patients were randomized to placebo or renzapride (1, 2, or 4 mg/day) for 8 weeks. The primary efficacy variable was patient-reported satisfactory relief of IBS symptoms. Secondary variables included relief of abdominal pain/discomfort. The proportion of patients reporting satisfactory relief of their IBS symptoms for at least 50% of the time did not differ significantly from those on placebo. However, post hoc analysis in women showed differences in responder rate on renzapride versus placebo of 18.2% (95% CI -5% to 42%; P = 0.066) during weeks 1-4 and 6% (95% CI -21% to 33%; P = 0.339) during weeks 5-8. Renzapride was well tolerated and most adverse events were mild to moderate in intensity. Further studies are warranted to determine whether renzapride is beneficial in this patient population.