Obesity is recognised as a growing problem. It is defined as having a BMI (body mass index) of more than 30. A person's BMI is a measure of body fat based on height and weight. The American Obesity Association describes it as “a global epidemic”, which is increasing at “an alarming rate”. According to the World Health Organisation, there are now more than one billion overweight adults world-wide, at least 300 million of them obese. It notes that this epidemic is not restricted to industrialised societies: the increase is often faster in developing countries as they switch to Western diets and habits. Obesity poses a major risk for chronic diseases, including Type II diabetes, cardiovascular disease, hypertension and stroke, and certain forms of cancer.
Various things can be done to reduce weight, such as regular exercise, combined with eating a healthy, well-balanced diet, but these tactics are often unsuccessful long-term. A number of drug treatments are therefore also available. In the past, many of these were amphetamine-based and had a number of side-effects.
New pharmacological approaches
Newer drugs for obesity have begun to emerge and research is looking at different approaches, which lead to weight loss with fewer side-effects. Recently, R&D has been ongoing in the area of cannabinoid antagonists and one of these, sanofi-aventis' Acomplia (rimonabant) should reach the market soon. Scientists have also been studying the interaction between fat and hunger. Fat produces a hormone called leptin, which turns off the feeling of hunger in the brain, so if we have high fat levels, our appetite is low. But when they drop we become hungry. Although the link between leptin levels and hunger is not simple, it may be possible to develop drugs that interfere with this cycle. Amgen is currently studying metreleptin, a leptin analogue in clinical trials for obesity and diabetes.
There is low regulatory tolerance for side-effects with obesity drugs, as they are given to otherwise healthy individuals; this sector has been a problematic one for pharmaceutical companies in the past, with all drugs apart from one (Roche's Xenical) having been withdrawn at some point.
What drug treatments are available?
Two products, Roche’s Xenical (orlistat) and Abbott’s Reductil/Meridia (sibutramine), dominate the anti-obesity class. Together, they accounted for 68.8% of the global market for ‘Anti-obesity Preparations, Excluding Dietetics’ (ATC A8A class) in 2005. This class was valued by IMS at $1.2 billion globally in 2005. Xenical, first launched in 1997, led the class, with a 42% market share and 2% fixed-rate dollar growth. Reductil, marketed as Meridia in the US, was number two, with a 26.8% market share, but saw a 4% drop in sales in fixed-rate dollar terms, according to IMS.
Xenical is a lipase inhibitor and blocks the absorption of dietary fat in the intestines. When taken with a mildly hypocaloric diet, orlistat inhibits absorption of about 30% of ingested fat. In 2002, Roche completed a Type II diabetes prevention trial (XENDOS) in more than 3,000 obese patients. In 2004, the European label was amended to state that orlistat can reduce the risk of developing Type II diabetes. This data has also been added in other markets, including the USA. Xenical is also the only weight-loss treatment in the USA and Europe approved for use in adolescents (12 years plus). It has some benign but unpleasant gastric side-effects, however, notably oily stools and urgency, which often prompt patients to discontinue treatment.
GlaxoSmithKline has a deal with Roche to sell a low-dose version of Xenical over-the-counter in the USA as Alli. This would be the first OTC-switch obesity drug. Alli would be targeted at the overweight (not just obese people) and analysts think that it could be a blockbuster. The FDA issued GSK an ‘approvable’ letter for Alli in April 2006, even as some critics said that its results were modest and side-effects still considerable. Separately in April, the US consumer group Public Citizen sent a petition to the FDA demanding the withdrawal of Xenical, after animal studies suggested that it could be linked to the development of precancerous colon lesions.
Meridia was first launched in the USA in 1998. In Europe, however, Reductil’s approval was delayed, following efficacy and safety concerns. European approval came in 2001, although doubts about the centrally-acting drug persisted. In 2002, it was withdrawn in Italy, but later in that year, the EU’s advisory committee issued a positive opinion that reaffirmed its favourable risk:benefit profile. Sibutramine was re-introduced in Italy, though only certain specialists were allowed to prescribe it (prescribing and dispensing restrictions were also introduced in France). Side-effects include dry mouth, headache, insomnia, constipation and increased blood pressure. In the USA, litigation is ongoing regarding 49 cardiovascular deaths and the FDA has come under fire for not banning sibutramine, concluding that its overall risk:benefit profile supports its use in appropriately selected obese patients. Sibutramine, a 5-HT reuptake inhibitor, acts on the central nervous system and reduces food intake by enhancing satiety and increasing metabolic rate.
The rest of the market is highly fragmented, mainly made up of sanofi-aventis' Dinintel (clobenzorex), an anorectic drug metabolised by the body to amphetamine, with a 4.3% market share and 22% dollar growth, sibutramine sold by other companies, and branded and generic versions of the old appetite suppressant phentermine.
All eyes on Acomplia
The next new drug in this area will be Acomplia, an orally-active cannabinoid receptor antagonist from sanofi-aventis. It has been developed for both obesity and as a smoking cessation aid, and analysts have predicted blockbuster sales in the former indication. The FDA deemed Acomplia ‘approvable’ in February 2006, but rejected it as a smoking cessation aid; the EU’s advisory body issued a similar opinion in April 2006. sanofi-aventis hopes to begin launches of Acomplia in the second half of 2006. Rimonabant is also in trials for the prevention of diabetes, the treatment of dyslipidaemia, the prevention of atherosclerosis, and the prevention of coronary heart disease. It is not without its own side-effect issues, however: Acomplia users in clinical trials discontinued treatment more often than those given placebo owing to adverse events, and it appears to increase depression and anxiety.
A number of other obesity drugs are currently in Phase II trials. Some are also being studied for other indications, often related to the concept of ‘metabolic syndrome’ (e.g. diabetes, hyperlipidaemia and obesity).
Selected Phase II R&D compounds for obesity*
| Drug | Developers | Mechanism of action |
| CP 945598 | Pfizer | cannabinoid antagonist |
| surinabant | sanofi-aventis | cannabinoid antagonist |
| AVE 1625 | sanofi-aventis | cannabinoid antagonist |
| cetilistat | Alizyme/Takeda | lipase inhibitor |
| GT 389-255 | Peptimmune/Genzyme | lipase inhibitor |
| PYY3-36 | Nastech | neuropeptide Y2 agonist |
| TM 30338 | 7TM Pharma | neuropeptide Y2/Y4 agonist |
| lorcaserin (APD-356) | Arena | 5-HT2C agonist |
| metreleptin | Amgen/INSERM | leptin analogue |
| CYT009-GhrQb | Cytos | ghrelin vaccine |
| 181771 | GSK | cholecystokinin 1 agonist |
| AOD 9604 | Metabolic | analogue of hGH fragment |
| P 57 | Phytopharm/Unilever | Hoodia gordonii extract (appetite suppressant) |
| S 2367 | Shionogi | CNS antagonist |
Source: IMS LifeCycle R&Dfocus
*Note: no compounds were in Phase III trials for obesity as of May 2006, according to R&Dfocus, and only rimonabant was pending approval
Analysts view Alizyme's cetilistat and Pfizer's cannabinoid antagonist CP 945598 as the most promising R&D compounds for obesity. CP 945598 in particular, aided by Pfizer’s marketing muscle, is thought to be a serious threat to Acomplia, especially the metabolic syndrome/diabetes treatment arena; it could reach the market in 2009.
Cetilistat is viewed as having serious potential: it is not centrally-acting, and therefore very safe. It has a similar mechanism of action to Xenical, but is more easily tolerated. Cetilistat could be launched in 2008. Alizyme, a small UK biotech, has licensed Japanese rights to Takeda and is reportedly seeking commercialisation partners for cetilistat in other markets.
Analysts note that sanofi-aventis' major aim is to position Acomplia as a cardiovascular/diabetes prevention drug. They therefore welcomed the wording of the EU’s positive opinion, which recommended the approval of Acomplia as an adjunct to diet and exercise for obese or overweight (BMI of at least 27kg/m2) patients with associated risk factors, such as Type II diabetes or dyslipidaemia. Highlighting the link with serious risk factors would help sanofi-aventis position the drug as more than a simple weight-loss aid. Much of its success will depend on the outcome of the CRESCENDO trial, which is viewed as the most important of a number of ongoing major clinical studies. The success of CRESCENDO is viewed as key to Acomplia getting, and staying, ahead of new rival products.
This article was written by Susan Murray, Senior Editor of IMS Company Profiles. Covering 100 of the top pharmaceutical and biotechnology companies, the profiles offer authoritative insight into company strategy, finances, portfolio management, R&D and history and also contain top-line IMS sales data. For more information, please contact Stephanie Earle, or call +44 207 393 5757.