The slim pill

Obesity pervades society at large due to changing lifestyles. Nonetheless, there are too few remedies which are available for it. The quest is still on for the magic pill that can offer releif to a number of obese people in the world. Katya Naidu looks at the obesity treatments under development

Obesity is the modern day plague which is making its presence felt all over the world. Over the past few years, obesity is becoming a growing concern, owing to the sedentary lifestyles of the urban population. A Nutrition Foundation of India sample study of the urban population of Delhi shows that more than 35 percent males and 50 percent females of the higher income classes were overweight compared to one percent male and four percent females in the poor class, confirming the socio-economic angle to the disease.

Obesity can be broadly defined as excess of body fat cells, which accumulate to form adipose tissues. Though obesity is regarded as an eating disorder, there are numerous factors that are related to obesity, like genetic syndromes, neuro-endocrine disorders like thyroid deficiency, Cushing's syndrome, hyper-secretion of insulin and injury to hypothalamus. Certain drugs like cortecosteroids and tricyclic antidepressants too can result in obesity.

Obesity is a disorder, which restricts the physical activity of a person and causes various complications. Some studies have also linked obesity to premature death. “There are many diseases associated with obesity, especially morbid or severe obesity. The prevalence increases as patients gain more weight over their ideal weight,” says Dr Shrihari Dhorepatil, Consultant Obesity Surgeon at PD Hinduja National Hospital & Research Centre and Breach Candy Hospital & Research Centre. Some diseases that result due to obesity are Type II diabetes, hypertension, dyslipidemia (hypercholesteremia), cardio-vascular diseases, asthma, arthritis, infertility, gallstones, sleep apnoea and venous stasis (thromboembolism).

Remedies

The awareness of the disease is increasing rapidly but unfortunately it is not reflected in the number of drugs in this space. Currently, USFDA has recommended very few drugs for obesity like Orlistat (Xenical) and Sibutramine (Laptos/Obestat). Obesity drugs also have serious drawbacks. “The shortcomings in obesity drugs are that the weight loss is not significant and consistent. The drugs are not effective for long-term use due to developing tolerance,” informs Dhorepatil.

Drugs like Phenteramine and Ephedrine have been recalled decreasing the freedom of choice. “Some drugs had deleterious effects on heart valves and central nervous system and were withdrawn from the market. Among the existing drugs, side-effects like diarrhoea, headache, nausea and rise in blood pressure are observed,” he adds.

Research under way

Considering the limited options and the increasing prevalence of obesity, the quest is on for a magic pill, which can work wonders. A few companies have embarked on drug discovery in this front and there are quite a few promising molecules under trial.

Several therapeutic categories of drugs including anorectic agents, lipase inhibitors, and ß3 [beta 3] receptor agonists have been evaluated for their utility in the treatment of obesity. Lipase inhibitors work by preventing the absorption of fats. “However, these treatment options have not produced satisfactory results, with most drugs producing a maximum of five to ten percent decrease in body weight with minimal effect, if any, on the associated co-morbidities and with unacceptable side-effect profiles,” says Dr Swaroop Kumar, President, Drug Discovery and Clinical Research, Glenmark Pharmaceuticals.

Mission Acomplia

Cannabinoid [CB1] receptor antagonists act by blocking the action of endogenous cannabinoid ligands [responsible for stimulating abnormal levels of hunger] by binding to both the central and peripheral CB1 receptors. “Due to the highly selective nature of CB1 receptor antagonists, they have emerged as a possible therapeutic option in the treatment of obesity and related co-morbidities,” says Kumar. However, there are very few clinical candidates in this therapeutic category and no approved molecule on the market so far.

One prominent product in the CB1 receptor antagonists category is Acomplia (rimonabant) under development by Sanofi-Aventis. It is a selective CB1 endocannabinoid receptor antagonist and is currently undergoing Phase III clinical trials. It works by blocking endogenous cannabinoid binding to neuronal CB1 receptors.

The central cannabinoid (CB1) receptors are believed to play a role in controlling food consumption and the phenomena of dependence and habituation. To develop suitable drugs against this target, the human cannabinoid receptor was first cloned and then expressed in cells. Compounds with potential inhibitory activity against this receptor were then screened. Rimonabant emerged from this screening process as a potent CB1 receptor antagonist. Pre-clinical animal studies subsequently showed that it could reduce consumption of fats and sugars, which contribute to weight gain. It is also interesting to note that this class of drugs may decrease the tendency to abuse substances such as alcohol and tobacco.

Glenmark's NCE

Glenmark has announced its new chemical entity in this segment, the molecule GRC 10389.

While work is still in the early stages for GRC 10389, in-vitro studies have revealed it to be highly specific to the target with an IC50 of 14 nM and Ki (humans). “In the in-vivo food intake studies, GRC 10389 produced a significant reduction of food and nutrient intake in animal models. The compound was also well absorbed showing good bio-availability in rats and dogs consistent with pharmacodynamic activity observed,” says Swaroop. Presently, GRC 10389 is in the pre-clinical trial stage for obesity.

“The drug raises more expectations in terms of its action in handling associated disorders. While we have not commenced working with GRC 10389 for its associated disorders, the possible ones are diabetes, hypertension, stroke, myocardial ischemia, congestive heart failure and osteoarthritis,” he observes.

Research in surgery section

While drugs are a good option to counter obesity, surgery is emerging as a popular method in obesity treatment. The most commonly performed cosmetic surgery procedure is liposuction. Liposuction, also called suction-assisted lipectomy, is a surgical technique designed to remove pockets of localised fat from a specific area of the body, such as the waist, abdomen, arms, thighs, ankles or small areas of the face. A technique called tunulescent liposuction is in use today. It is a process where the fat cells are infiltrated with saline solution so that they swell and can be easily aspirated. The unique procedures under research are the use of ultrasonic energy or laser energy.

Yet another novel idea under trial is the effect of gastric (stomach) stimulation. This is a process, where electrodes are placed in the stomach laparoscopically, with a rechargeable battery under the skin. The stimulator is activated remotely at the mealtimes so that the person feels satiated and will consume less without being hungry. “This technique is in the clinical trial stage in US and Europe and may be available in the market in the near future,” says Dhorepatil.

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