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Striking a balance

Healthy eating, exercise and drugs combined will provide the answer to obesity issues

Obesity is a complex condition with serious social and psychological dimensions affecting virtually all ages and socioeconomic groups around the world.

It has reached epidemic proportions with more than 1 billion overweight adults; at least 300 million of them are clinically obese, while an estimated 22 million children aged under five worldwide are overweight.

The condition is a major contributor to the global burden of chronic disease and disability, and obesity is now on the verge of surpassing smoking-related illness as the primary cause of preventable death.

In several developed countries, obesity accounts for up to 7 per cent of total healthcare costs - around $100bn; however, the true costs are undoubtedly much greater once obesity-related conditions are factored into the equation.

Being obese, or even overweight, has detrimental metabolic effects on blood pressure, cholesterol, triglycerides and insulin resistance. Health consequences range from increased risk of premature death to serious chronic conditions that reduce overall quality of life, including coronary heart disease, dyslipidaemia, hypertension, stroke, Type II diabetes, osteoarthritis, respiratory problems, and certain cancers (eg, endometrial, breast, and colon cancer).

Key forces driving the obesity epidemic are linked to societal changes, arising from global urbanisation leading to an alarming shift in increased consumption of energy-dense, nutrient-poor foods high in saturated fats and sugars, combined with reduced physical activity.

In light of the soaring costs and human toll attributed to obesity-related disorders, pharmaceutical companies are increasingly exploring therapeutic intervention strategies to supplement healthy diet and exercise as part of a weight loss regimen in an attempt to combat this modern-day health crisis. Weight loss should not just be considered as a cosmetic issue, but as a medical benefit.

Bulging pipeline
The market for weight loss drugs has been plagued by a shadowy and controversial past, as highlighted by major product withdrawals due to serious adverse events for popular drugs such as fenfluramine and dexfenfluramine combined separately with phentermine (fen-phen and dexfen-phen, respectively).

These drug combinations caused life-threatening heart valve problems in 'healthy obese` subjects which prompted the Food and Drug Administration (FDA) to pull them from the US market in 1997.

Since then, a number of therapeutic approaches have been explored, including lipase inhibitors, noradrenaline/serotonin reuptake inhibitors (anorectic agents), b3-adrenoreceptor agonists, leptin agonists, and melanocortin-3 agonists. Only two drugs are currently approved for long-term treatment of obesity, namely Roche's orlistat (Xenical, a lipase inhibitor) and Abbott's sibutramine (Meridia, an anorectic agent). However, the use of both drugs has been limited by undesirable side effects. There exists a vacuum for an effective and well-tolerated drug to satisfy this area of high medical need.

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Better profile
A potentially safer drug could be sanofi-aventis' rimonabant (Acomplia), the first in a class of agents that selectively blocks cannabinoid type-1 (CB1) receptors of the endocannabinoid (EC) signalling system in the brain.

The identification of the EC system in the 1990s arose largely from the agonistic action of tetrahydrocannabinol, the psycho-active component of marijuana (Cannabis sativa), on stimulating appetite and food intake.

Activation of CB1 receptors by endogenous cannabinoid ligands, such as anadamide, is believed to affect central and peripheral action on fat, as well as glucose metabolism in adipose tissue, and regulate feeding behaviour; thus, blocking of such receptors might have opposite effects. Preclinical studies subsequently revealed that the CB1 receptor antagonist could reduce the consumption of fats and sugars in animals.

Sanofi-aventis submitted rimonabant for regulatory approval with European and US authorities in April 2005, based on positive findings from the Rimonabant In Obesity (RIO) series of pivotal phase III trials, involving over 6,000 subjects.

Data from the RIO studies confirmed that the drug maintained weight loss safely and effectively for periods of at least two years in overweight and obese patients. Rimonabant recipients achieved significant reductions in body weight, waist circumference and showed improved lipid as well as blood glucose profiles versus placebo. The agent also had a significant impact on metabolic cardiovascular risk factors that was greater than that expected by weight loss alone.

The European Medicines Agency (EMEA) approved the drug in June 2006 as an adjunct to diet and exercise for obese or overweight patients with associated risk factors; rimonabant is already available in the UK with further European launches expected in the second half of 2006.

Meanwhile, the drug received an approvable letter from the US FDA for obesity in February 2006. However, the FDA declined to issue final approval, pending satisfactory resolution of a number of unspecified issues.

Rimonabant is the most advanced CB1 receptor antagonist in clinical development with an ongoing phase IIIb trial programme encompassing studies in patients with diabetes (SERENADE), cardiovascular disease (STRADIVARIUS, AUDITOR and CRESCENDO) and dyslipidaemia (ADAGIO).

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Potential rivals
Additional CB1 receptor antagonists are being designed to curb appetite, prevent weight gain and burn fat and many companies are evaluating such experimental compounds. Although the majority are in the earliest stages, some have advanced into clinical testing. Surinabant and AVE 1625 are in phase II with sanofi-aventis as back-up compounds to rimonabant. Pfizer's CP 945598 and Merck's MK 0364 are in phase II, while Solvay/Bristol-Myers Squibb's SLV 319 is in phase I.

Xsira Pharmaceuticals, 7TM Pharma, Acadia Pharmaceuticals, Glenmark Pharmaceuticals, Esteve, Vernalis, OSI Pharmaceuticals, EPIX Pharmaceuticals, Bayer and Novasite Pharmaceuticals are all undertaking separate research projects to develop CB1 receptor antagonists. In addition, Ortho-McNeil is investigating CB1 receptor inverse agonists. Overall, compounds that act on the EC signalling system via modulation of the CB1 receptor may offer a safer and convenient alternative to existing drugs.

It could take a few years, but many experts believe that it is the start of a new era in the management of obesity; at least a handful of safe and effective drugs are expected to emerge that will transform obesity therapy.

However, it remains unlikely that a single agent cure for obesity will be found, given the existence of multiple metabolic signals to prevent starvation. An assorted combination of drugs plus a healthy diet and exercise will be necessary (perhaps for life) to overcome the body's survival instinct to stockpile fat. This could create a market emulating those for other major chronic diseases, such as AIDS and cancer.

The author of Pharmaceutical Marketing's November Pipeline contribution is Darrell Ng of Adis International, using information derived from Adis Clinical Trials Insight and R&D Insight.

2nd September 2008

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