Compliance Column

What is obesity?

Obesity arises from the accumulation of excess fat in the body. In recent years, body mass index (BMI) has become the medical standard used to determine whether someone is overweight or obese. BMI uses a mathematical formula based on a person's height and weight and is calculated by weight in kilograms divided by height in meters squared (BMI = kg/m2). A BMI of 25 to 29.9 indicates a person is overweight, whereas a BMI of 30 or higher is considered obese.

While obesity is now recognized as a disease in its own right, it is also one of the key risk factors for other chronic diseases. Non-fatal, health problems include respiratory difficulties, chronic musculoskeletal problems, skin problems and infertility. The more life-threatening problems fall into four main areas: cardiovascular disease; conditions associated with insulin resistance such as type 2 diabetes; certain types of cancers, especially the hormonally related and large-bowel cancers; and gallbladder disease.

Heavy on cost

While obesity clearly has negative effects on the nation’s health there are also important consequences to the budget. According to a study of national costs attributed to being overweight or obese, medical expenses accounted for 9.1 percent of total U.S. medical expenditures in 1998 and may have reached as high as $78.5 billion ($92.6 billion in 2002 dollars).

Obesity has no single cause and there will be no single solution, rather it will be brought under control only as a result of coordinated, complementary efforts from a variety of sectors of society. The pharmaceutical industry hopes to play a major role in reducing obesity levels and has launched a massive drive to develop anti-obesity drugs.

The return on investment could be huge. The global obesity market has been described as a potential gold mine for the pharmaceutical industry with estimates of a market potential of $3.7 billion by 2008. This has led many pharmaceutical companies to prioritize the identification of novel anti-obesity products. A look at product pipelines shows that there are plenty of promising obesity products and some may be potentially in the blockbuster category. By some estimates, 180 drugs are currently being tested by more than 70 companies.

To date, researchers have explored various therapeutic strategies including:

Serotonin and noradrenaline reuptake inhibitors (anorectic agents) – e.g. sibutramine sold under the brand name Meridia® by Abbott Laboratories, which diminishes appetite by affecting brain neurotransmitters.
Lipase inhibitors – e.g. orlistat marketed as Xenical® by Roche and the investigational ATL-962 from Alizyme
ß 3-adrenoreceptor agonists
Leptin agonists/Ghrelin antagonists
Melanocortin-3 agonists

Mission Acomplia

The one product touted as being closest to pharmacy shelves is rimonabant (Acomplia®) from Sanofi-Aventis and it doesn’t fall in to one of the traditional obesity treatment categories listed above. Rimonabant was developed from the knowledge that cannabis smokers often experience extreme hunger pangs, known as "the munchies". Researchers at Sanofi-Aventis worked on the premise that if cannabinoids stimulate appetite, blocking cannabinoid receptors in the brain might reduce appetite. Known as a cannabinoid type I (CB1) blocker, Acomplia® is the first of an entirely new class of drugs, which works by blocking a pleasure center in the brain. As a result of successful clinical trials, the company plans to file an NDA with the FDA during the first half of this year and, if successful, hopes to bring Acomplia® to market in early 2006.

Spray away fat

Nastech Pharmaceutical has taken an innovative approach to controlling obesity through use of a nasal spray. The company is investigating PYY, a naturally occurring human hormone produced by specialized endocrine cells (L-cells) in the gut in proportion to the calorie content of a meal. In September, 2004, they entered into a multimillion-dollar deal with Merck to co-develop a nasal spray that sends the appetite-suppressing hormone into the bloodstream. So far the trial results are impressive. If successful, the PYY nasal spray would provide a new treatment option for obesity that would be non-invasive and easy to administer.

Prickly solution

UK-based Phytopharm have also taken an innovative approach to solving the problem of obesity. Their researchers are looking at a plant that has been used for thousands of years by the Sans bushmen of the Kalahari desert to stave off hunger. The plant, a widespread and unprepossessing tentacled, spiky cactus-like succulent called Hoodia gordonii was licensed exclusively by Phytopharm from the South African Council for Scientific and Industrial Research (CSIR) in 1997. The company had initially hoped to market a slimming drug from Hoodia with Pfizer but the research collaboration came to an end in 2003. However, they have just entered a deal with Anglo-Dutch food giant Unilever to develop snacks containing the extract of Hoodia gordonii. Unilever hope to have products containing the Phytopharm extract, called p57, available within the next 3 years.

A checkered past

The campaign for new weight-loss drugs is shadowed by a checkered history of spurious cure-alls and addictive amphetamines. More recent efforts to develop safe and effective drugs were marred by the discovery that the popular "fen-phen" drug combination caused life-threatening heart-valve problems. Fen-phen refers to the use in combination of fenfluramine and phentermine. Fenfluramine acts through serotonergic mechanisms resulting in a feeling of increased satiety and phentermine has a stimulant effect acting more through noradrenergic and dopaminergic mechanism resulting in decreased appetite and less frequent eating.

Fenfluramine and phentermine were approved by the FDA as individual agents for short-term use in the medical management of obesity. The use of the products concomitantly as fen-phen was never approved in the United States but the combination of the two products was used "off label" by many American health care practitioners for the management of obesity, often for extended periods of time. Wyeth (formerly known as American Home Products) made Pondimin, the fenfluramine half of fen-phen, and a chemical cousin, Redux. The company voluntarily pulled Pondimin and Redux from the market in September 1997 at the request of the FDA amid safety concerns linking the products to cardiac valvular disease.

Sibutramine – the next "fen-phen"

Sibutramine (Meridia®) was approved by the FDA in 1997, by Health Canada in 2002, and by several European regulatory agencies. However the drug has recently come under considerable scrutiny due to concerns over its safety profile. Sibutramine was the first diet drug approved following the FDA’s ban on fen-phen but some consumer safety groups feel that the approval was a major mistake. According to the watchdog group, Public Citizen, sibutramine has been associated with 29 deaths and 397 serious adverse events, including arrhythmias, heart attacks, high blood pressure, dilated cardiomyopathy, seizures, and stroke.

Internationally, Italian regulatory authorities temporarily suspended market authorization of all drugs containing sibutramine in 2002, and have referred the matter to the European Medicines Evaluation Agency Secretariat for a comprehensive assessment of the risk/benefit profile of sibutramine. France, Germany, England, the Netherlands, Denmark, Portugal, Sweden, Finland and Spain have issued statements informing the public of the market suspension of sibutramine in Italy. France, Germany and England have announced that they are conducting reviews of sibutramine but have not withdrawn the Abbott drug (known as Reductil in Europe) from the market.

Presently, the FDA is evaluating the reported deaths and injuries in the United States and abroad and Health Canada is also conducting a safety review of the product.

A quick fix?

While obesity represents a huge and growing problem, available treatment options remain limited. The FDA are therefore under considerable pressure by some obesity experts to consider approving obesity drugs based on shorter safety studies with less demanding criteria. The American Obesity Association argue that obesity is a risky disease, and with assessing obesity drugs the FDA need to balance the risks of the versus the benefits. However, the agency has to strike a balance between encouraging obesity drug development while avoiding another fen-phen debacle. The FDA also knows that drugs approved for the obese will often be taken by individuals who are only overweight and for these individuals the risk-benefit profile is less clear.

For some who are overweight or obese, lifestyle changes can work but it is a slow process and much harder than popping a pill, for others medical intervention is needed. But for all of us when the issue is weight loss, we are always hungry for the next quick fix.