(Laurie Barclay, MD, November 2002)

Obesity is a chronic, metabolic disease that is caused by inherited as well as acquired factors including excessive food intake, sedentary lifestyle, and unhealthy eating habits. It is a burgeoning epidemic worldwide, especially in the U.S. and other developed countries, with rapidly increasing prevalence over the past 10 to 15 years.

In the U.S. alone, approximately 70 million people are obese, which directly or indirectly contributes to about $100 billion in healthcare costs and 300,000 deaths annually. In the U.S., obesity as a leading cause of preventable death is exceeded only by cigarette smoking. Because it increases the risk of other chronic diseases including atherosclerosis, coronary artery disease, diabetes, sleep apnea, respiratory problems, osteoarthritis, hypercholesterolemia, and some cancers, obesity demands a continued search for effective treatment.

Currently approved anti-obesity drugs include lipase inhibitors which reduce fat absorption, such as Xenical (orlistat), anorectics or appetite suppressants, such as phentermine, and Meridia (silbutramine), a serotonin and noradrenaline re-uptake inhibitor. Other medications approved for other indications used off-label for obesity include Wellbutrin (bupropion), Procyglem (diazoxide), Tenuate (diethylpropion), Glucophage (metformin), Revia (naltrexone), Bontril (phendimetrazine), and Zoloft (sertraline).

Side effects of anorectics include mood elevation, wakefulness and high blood pressure, and Meridia also has the potential to raise blood pressure and cause heart problems. Clinical success with available drugs has been modest at best, due in part to the complex pathophysiology of diet-induced obesity, for which fundamental protein targets are both poorly understood and entwined in multiple metabolic and physiologic pathways. Modifying these targets may lead to serious adverse effects, as was the case with fen-phen, which was recalled in 1997 after it was linked to heart valve damage, adverse cardiovascular effects, and other serious conditions.

The discovery that patients taking Topamax (topiramate) as an anti-epileptic drug often lost weight led Johnson & Johnson to reformulate this sulfamate-substituted monosaccharide for obese patients. Despite significant efficacy for weight loss, Phase III trials were halted in February because of adverse effects including memory problems, fatigue, sleepiness, difficulty in concentration, and tingling in the fingers and toes. Instead of continuing current trials, Johnson & Johnson is attempting to improve the adverse effect profile, and plans to develop a controlled-release formulation using technology developed by the recently acquired Alza Corp.

Axokine, in Phase III development by Regeneron Pharmaceuticals, is a genetically engineered version of the naturally occurring human protein known as ciliary neurotrophic factor (CNTF). It binds to specific CNTF receptors in the hypothalamus, stimulating signalling pathways that suppress appetite.

After 12 weeks of treatment in a multicenter study, obese subjects who took the optimal dose of Axokine lost 3.6% percent of their body weight and maintained weight loss 24 weeks after stopping therapy, while those in the placebo group gained 0.5%. Side effects included cough and nausea.

Unfortunately, the injectable formulation and requirement for frequent dosing is a major disadvantage of Axokine. Regeneron is also in Phase I testing of PegAxokine, a second-generation, pegylated version of Axokine made by attaching polyethylene glycol polymer chains to Axokine molecules.

Rimonabant (SR 141716), a selective CB1-cannabinoid receptor antagonist, is another appetite suppressant in Phase III development by Sanofi-Synthelabo Pharmaceuticals. Because cannabinoids naturally produced by the body may trigger hunger much as smoking marijuana brings on "the munchies," the rationale behind this drug is to reduce appetite by blocking cannabinoid receptors in the hypothalamus.

In a seven-day study, this drug decreased hunger, caloric intake and body weight in overweight and obese men. A 16-week Phase IIb trial showed a dose-response relationship with mean weight loss of 4 kg at the highest dose tested. Except for some gastrointestinal side effects at the highest dose, the drug was generally well-tolerated, but long-term efficacy and safety are still unknown.

Ongoing phase III trials of 6,180 patients include a North American trial of 2,800 patients and a European trial of 1,400 patients, both comparing 5 mg and 20 mg doses of Rimonabant to placebo over a two-year period.

Pfizer is in Phase II development of P57, a novel oral appetite suppressant derived from an African plant. Native African healers and desert nomads first used this plant to quench their thirst and suppress hunger on long hunting trips. In a double-blind, randomized, study of 19 overweight males, there was a significant reduction in the average daily caloric intake of the P57 group compared with the placebo group (P=.014), as well as in body fat content (P=.035). There were no serious adverse effects.

Lipase inhibitors such as ATL-962, in phase IIb testing by Alizyme, reduce caloric absorption from ingested fat. Results from Phase Ib clinical trials suggest that ATL-962 is safe, well-tolerated, and effective. Compared with placebo, 55% of subjects who received ATL-962 had at least a threefold greater increase in fat excretion and 27% of subjects had at least a sevenfold increase. Adverse events were comparable to placebo, with oily stool reported most commonly.

Amgen is in Phase II development of leptin, a genetically engineered hormone involved in several neuroendocrine pathways regulating appetite, energy intake and expenditure, including neuropeptide Y, glucagon-like peptide-1, melanocortins, corticotropin-releasing hormone, and other hypothalamic systems. One mechanism of preventing excess weight gain is through its role in a feedback loop that affects the appetite and satiety centers of the brain, thereby regulating body-fat mass.

Unfortunately, many obese people seem to be somewhat resistant to leptin, in part due to low cerebrospinal fluid to blood level ratio. Both genetic and environmental factors also appear to influence sensitivity to this hormone. To overcome these drawbacks, second-generation versions of leptin are designed to cross the blood-brain barrier more easily. In early Phase I clinical trials, eight patients treated with subcutaneous injections of leptin for six months have shown weight loss of 5 kg more than in untreated patients.

Another hormonal intervention is the Advanced Obesity Drug 9604 (AOD9604), which mimics the fat metabolic properties of human growth hormone (hGH). Metabolic Pharmaceuticals has completed phase IIa testing of this orally administered drug. Like growth hormone, AOD9604 is thought to reduce body fat reduction through lipolysis, or breakdown of fat into basic chemical components; anti-lipogenesis, or reduction of the rate of synthesis of fat from its chemical components; and an increase in resting energy expenditure, while avoiding other systemic effects of growth hormone such as insulin resistance or effects on bone, muscle and organ growth.

AOD9604 is a peptide variant of hGH 177-191, a small region of the growth hormone molecule which appears to be responsible for its specific effect on fat without any effect on growth or on insulin resistance. In Phase I trials of intravenously administered AOD9604 in obese subjects, there were signs of acute fat metabolism without adverse effects.

Although adverse events and limited understanding of the pathophysiology of obesity have hindered development of safe, effective antiobesity drugs, ongoing research may eventually yield promising agents by targeting neuroendocrine and metabolic pathways as well as fat absorption and appetite suppression. Intravenous administration of hormone analogues is a major drawback of agents developed to date.