In the Pipeline
In clinical trials for the relatively new antiepileptic zonisamide, an unanticipated effect was weight loss. It has, therefore, been studied for its potential as a weight-loss agent, either in monotherapy or in combination with other agents such as bupropion. Zonisamide has sodium and calcium channel blocking activity, as well as dose-dependent biphasic dopaminergic and serotonergic activity. Empatic™ (made by Orexigen) is a fixed-dose combination of a proprietary formulation of zonisamide SR and bupropion SR.
In trials at Duke University, zonisamide alone with a hypocaloric diet was shown to be more effective in reducing weight than placebo. The same investigators have conducted a short-term, open-label trial of treatment with zonisamide and bupropion, finding that the combination resulted in more weight loss than zonisamide alone. Fatigue, drowsiness, sedation, nausea, and cognitive impairments (difficulty concentrating, memory problems, speech and language difficulties) have all been reported with zonisamide use.
The manufacturer of Empatic recently reported that in phase 2b trials, patients who took the drug for 24 weeks lost 9.9% of their baseline body weight compared with 1.7% for patients taking placebo, without evidence of a plateau. Improvements in waist circumference, triglycerides, fasting insulin, and blood pressure were also reported. Phase 3 trials are now planned.
Tesofensine (made by NeuroSearch) is a triple monoamine reuptake inhibitor that blocks the presynaptic uptake of norepinephrine, dopamine, and serotonin. Originally being studied for neurodegenerative conditions such as Parkinson and Alzheimer diseases, unintended weight loss was observed in individuals treated with the drug.
The mechanisms through which tesofensine leads to weight loss are a pronounced effect on appetite suppression and increased energy expenditure. In phase 2 clinical trials with tesofensine in obese patients, dose-related reductions in body weight, body fat, and waist circumference, as well as improvements in other obesity-related measures, were observed. Minor adverse events included elevations in heart rate and significant increases in blood pressure only at the highest tested dose. The drug is soon to be tested in phase 3 clinical trials.
Cetilistat is a new lipase-inhibitor with a similar mode of action to orlistat, inhibiting pancreatic lipase and blocking digestion and absorption of dietary fat, so that it can be eliminated unchanged with the stool. Cetilistat has completed a 12-week phase 2b trial in obese patients, demonstrating weight loss consistent with other obesity medications and significant improvements in other obesity-related parameters. Unpleasant adverse effects, including flatus with discharge and oily spotting, were reported by fewer than 3% of patients using cetilistat.
It is probable that, like orlistat, cetilistat will also block the absorption of fat-soluble vitamins, and this possibility was raised by the FDA in 2009, cautioning that cetilistat could "lead to malabsorption of nutrients and vitamin deficiency." Cetilistat has now been cleared to conduct phase 3 trials in patients with obesity.
The combination of these 2 agents represents a novel integrated neurohormonal approach to obesity. Pramlintide is an analogue of amylin, a hormone secreted by pancreatic beta cells along with insulin. Exogenous amylin can increase the absorption of glucose, slow gastric emptying, and by binding to hypothalamic receptors, promote satiety, reduce food intake and elicit weight loss. Metreleptin is recombinant methionine human leptin. Leptin is a neurohormone secreted by adipocytes that also binds to receptors in the hypothalamus to promote satiety. When someone reduces dietary intake to lose weight, leptin levels drop, and this triggers a host of counter-regulatory responses aimed at maintaining body weight. Administration of metreleptin restores leptin concentrations and attenuates the effects of counter-regulation.
Pramlintide is already an approved drug in the treatment of diabetes. Metreleptin has been tested as monotherapy for obesity/weight loss, but failed because of the development of leptin resistance. However, these 2 hormones are believed to act synergistically to reduce food intake and body weight.
Mildly and moderately obese patients (without diabetes) who took this combination lost about 13% of baseline body weight in 24 weeks with no weight-loss plateau, significantly more than was seen with either drug administered as a single agent. Patients who continued treatment with pramlintide/metreleptin for a total of 52 weeks exhibited sustained weight loss, whereas those who received placebo during the extension study regained almost all of their lost weight. The combination therapy appeared to be generally well tolerated. The most common adverse effect was nausea.
Pramlintide/metreleptin combination is an injectable therapy, which may limit its application in the general obese population.
Medscape Diabetes © 2010
Cite this: Laura A. Stokowski. Weight Loss Drugs: What Works? - Medscape - Dec 13, 2010.