Obesity is a common, serious and growing problem. Current epidemiological estimates suggest that 1.1 billion people worldwide are above their ideal weight. In the US, 65% of adults (
127 million people) are overweight or obese (Fig. 1). Obesity is blamed as a contributing factor in over 300,000 deaths in the US annually, with economic costs of the epidemic reaching more than US$100 billion1. Although obesity has long been associated with serious health issues, it has only recently been regarded as a disease in the sense of being a specific target for medical therapy. Consequently, developing obesity treatments that target novel pathways is a growing focus for both biopharmaceutical and the medical device industries.
Figure 1 | Obesity prevalence in US adults (20–74 years).
![Figure 1 : Obesity prevalence in US adults (20|[ndash]|74 years). Unfortunately we are unable to provide accessible alternative text for this. If you require assistance to access this image, or to obtain a text description, please contact npg@nature.com](/nrd/journal/v5/n5/thumbs/nrd2037-f1.jpg)
Obesity is described on the basis of the normalizing measure called the body mass index (BMI). BMI is calculated by dividing a person's weight (in kilograms) by the square of that person's height (in metres). A normal BMI is below 24.9 kg m-2. An individual who has a BMI of 25–29.9 kg m-2 is considered 'overweight,' and a BMI of greater than 30 kg m-2 is considered to be 'obese.' Source: National Health and Nutrition Examination Survey
Current therapies
Other than the over-the-counter (OTC) market, current therapies for obesity are based on diet and exercise, a select number of drugs for a fraction of patients, and stomach (bariatric) surgery for extremely obese individuals. Although surgery and implantable devices could offer a solution for significantly obese patients, traditional drug-based approaches are necessary to address the needs of a broader market. Although older drugs, such as generic amphetamine-like agents, are reasonably effective in the short term they carry the risks of addiction and serious cardiovascular complications2.
Only two weight-loss medications have been approved by the FDA for long-term use, but they have failed to gain a large market share. Sibutramine (Meridia; Abbott Laboratories), a serotonin- and noradrenaline-reuptake inhibitor, controls appetite by producing a feeling of satiety. But because its prominent side effect is hypertension, it is not widely prescribed, limiting sales to US$230 million in 2005. Orlistat (Xenical; Roche) reduces weight by limiting caloric intake through inhibition of the lipase-mediated breakdown of fat in the gastrointestinal tract. Unfortunately, approximately 20% of patients develop unacceptable side effects, such as faecal incontinence and urgency, limiting its broader use. In 2005, orlistat made US$450 million in worldwide sales, only 20% of which was in the US. GlaxoSmithKline has rights to a lower-dose OTC version of orlistat. Though GSK received an approvable letter for the drug from the FDA last month, the company says it still expects to introduce what would be the first FDA-approved OTC weight-loss drug by the end of the year.
Controlling appetite
Appetite control can be achieved through the use of agonists for appetite suppressing pathways or antagonists for appetite-stimulating pathways. Much anticipation has surrounded rimonabant (Acomplia; Sanofi-Aventis), a first-in-class selective cannabinoid type 1 (CB1) receptor antagonist for obesity/metabolic syndrome and smoking cessation. Over-stimulation of the CB1 receptor is associated with excessive food intake, fat accumulation and nicotine dependence. In clinical studies, rimonabant produced moderate weight loss (5% body mass). However, rimonabant use was associated with a high dropout rate (40–50%) partly due to psychiatric side effects, such as depression, anxiety and aggression3. This is of concern, especially for a drug intended for broad and chronic use and with high potential for recreational abuse.
In February 2006, the FDA issued an approvable letter for rimonabant for weight loss and a non-approvable one for smoking cessation. Sanofi-Aventis says it will launch this drug for weight loss by the second half of 2006, but experts suggest that approval could be delayed by a safety-conscious FDA, which might require additional studies. Even if approved, rimonabant is likely to have a rather narrow label, potentially limiting its prospects for third-party reimbursement.
Activation of certain seretonin (5-HT) receptors is also known to inhibit appetite. A 5-HT agonist, fenfluramine and dexfenfluramine (Fen-Phen; Wyeth), was a highly effective weight-loss drug, but was withdrawn from the market in the 1990s due to severe cardiac toxicity. Arena Pharmaceuticals is developing a highly specific 5-HT2C receptor agonist, APD356, designed to avoid Fen-Phen safety issues. In clinical trials conducted to date, ADP356 produced meaningful weight loss without serious adverse events, including cardiovascular toxicity. Pivotal Phase III studies could begin later this year and, if successful, Arena anticipates filing for regulatory approval in 2009.
Inhibiting fat uptake
Can blocking fat absorption through inhibition of lipases be achieved without the unpleasant side effects of orlistat? Some companies believe this is possible. Alizyme's cetilistat (ATL-962) has a different structure than orlistat, but blocks the same pancreatic and gastric lipases. So far in Phase I/II clinical trials, cetilistat showed similar efficacy to orlistat and much better tolerability (2.5% versus 11.6% dropout rate).
Peptimmune's GT 389-255 is a conjugate of a pancreatic lipase inhibitor and a fat-binding hydrogel polymer. The addition of the fat-binding polymer should prevent formation of oil pools that could lead to the aforementioned side effects. Indeed, GT 389-255 was well tolerated in healthy volunteers. Peptimmune now has to conduct efficacy trials of GT 389-255 in obese individuals to demonstrate that the compound is actually better tolerated and perhaps more efficacious than orlistat.
Outlook
Obesity therapies will be an increasingly important part of future healthcare growth, as obesity is being recognized as a serious health condition that should be treated. Due to the complexity of this disease it is unlikely that any single drug will be effective at producing meaningful and sustainable weight loss. Therefore, the future of obesity therapy will probably involve several different approaches that act independently, and ideally, are combined with a defined diet and exercise regimen.
Market indicators
Obesity is gradually being regarded as a specific, distinct medical problem rather than just a consequence of overeating. In the past, the costs of medical intervention for obesity might have outweighed the benefit in health expenditures. For instance, the US healthcare system is currently geared to treating the individual obesity-related diseases rather than the underlying cause — anti-obesity therapies receive very limited insurance coverage. In the US, the direct expenditures for surgery and prescription drugs to control obesity are thought to be $4 billion annually (Fig. 2), whereas the OTC market for weight-loss remedies and diets is estimated to be as much as $50 billion. However, the increase of obesity to epidemic status significantly alters this calculation. Because even minor reductions in weight causes health improvement, a powerful economic case can be made for coverage of weight loss drugs that meet regulatory standards for long-term weight reduction. There are numerous companies pursuing drug therapies for weight management (Table 1). Experts believe that over the next 5–10 years a variety of drug products will transform obesity into a therapeutic area much like the $15-billion markets for cardiovascular disease or hypertension.
