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Oral presentation

The increasing prevalence of obesity has led the World Health Organization (WHO) to declare this condition as a global epidemic. Around the world, over half a billion people are overweight, defined as having a body mass index (BMI) of 30 or greater. Obesity is now so widespread that, for the first time in the history of humanity, its prevalence exceeds that of malnutrition and infectious diseases. This situation implies grave consequences, including a higher risk of developing certain conditions such as diabetes and cardiovascular disease, but also certain forms of cancer.

The market for products aiming to tackle obesity is enormous, nonsaturated and represents a tremendous opportunity for the advancement of Research and Development. Over the past two decades, research into obesity has led to many discoveries. The most talked-about is probably leptin, a hormone produced by fat cells which sends signals to the brain about the amount of fat stored in the body. However, new neuropeptides, uncoupling mitochondrial proteins or proteins synthesized by peripheral tissues involved in obesity, have also been identified. And, while the hypothetical "obesity gene" is yet to be discovered, research has also revealed a certain number of genetic factors leading to predisposition to the disease.

In the past, antiobesity drugs sought to reduce appetite and often led to extremely severe side effects. In 1997, KnollPharmaceutical's sibutramine, a noradrenaline/serotonin reuptake inhibitor, was the first drug introduced onto the obesity market made practically barren by the fen-phen disaster. The cardiovascular adverse effects observed, i.e., tachycardia and hypertension, are frequent, often leading to treatment discontinuation. Orlistat, a lipase inhibitor, was the latest drug to enter the obesity market, in 1999. Because of its different mechanism of action, its cardiovascular safety profile is better, but its gastrointestinal effects also frequently prompt patients to stop treatment.

Early drug development in obesity may be broadly divided into two types of studies: i) safety and tolerability studies, and ii) proof-of-concept studies.

Safety and tolerability studies are generally conducted in a homogeneous population of obese patients, i.e., males with a BMI falling between 30 and 40, the latter figure corresponding to so-called "morbid" obesity. This is a special population, and the inclusion/exclusion criteria must be adapted to enable successful enrollment, particularly in terms of blood pressure range and laboratory values (transaminases and gamma-GT, along with lipid profile). Studying the pharmacokinetic profile is essential, as it often differs from that of the classic healthy young male population, a difference explained by the specific characteristics of the compound (in particular, lipophilia) and by the physiological changes associated with obesity. A classic design (versus placebo), a large number of subjects and a clearly-identified primary endpoint (tolerability study, primarily) are the keys to success. Of course, a variety of pharmacodynamic parameters, whether laboratory or clinical, may also be incorporated. The duration of this type of study is interesting as many pharmaceutical companies are deciding more and more frequently to move directly from phase I development to a robust phase IIb program (large number of patients over longer periods of time). These phase I studies would thus allow making this "link" if the duration of administration, i.e., at least 3 weeks, were sufficient. Moreover, this type of study, requiring long hospitalization periods and a considerable number of subjects for phase I, must be managed by an experienced investigator to enable the proper assessment of the product's safety, while taking into account the "psychological" aspects of this population, particularly when a clear difference in weight loss is demonstrated between two populations within a given study group.

Proof-of-concept studies are also very interesting, enabling rapid initial assessment of a treatment's efficacy. A placebo group is indispensable to these studies as well, which should preferably be performed using a crossover design with active substance, and, most importantly, be carried out at a single center. In such studies, the differences between primary and secondary endpoints are extremely artificial, often only aiming at determining the appropriate sample size. One of the more promising designs is that combining "standardized" meals with "different choices" meals during hospitalization. Studying satiety and hunger with visual analog scales, food consumption and change in body weight are then suitable assessment parameters. These studies require the participation of a CRO for recruitment and logistics, and a well-experienced team specialized in dietetics and nutrition.

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