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Jul 1, 2012 (Vol. 32, No. 13)

Obesity Proving Complicated and Personal

Rethinking Obesity R&D Essential to Drive Therapeutic Advancement and Innovation

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    Steven R. Smith, M.D.

    The pursuit of effective therapies for weight loss has been under way for decades—long before obesity was even recognized as a public health crisis. Yet, compared with other areas of drug development, R&D for weight loss therapies has seen remarkably little advancement—and innovation. Rather, the space has been riddled with drama and plagued by disappointing failures.

    Billions of R&D dollars later, there remain shockingly limited treatment options for what is now an exploding epidemic. It is estimated that more than two-thirds of U.S. adults and nearly one-third of U.S. children are either overweight or obese. Medical-related expenses attributable to obesity are projected to top $344 billion by the year 2018.

    We must crack the code on obesity drug development. But to accomplish this we need to radically rethink our understanding of obesity and redirect our R&D efforts accordingly.

    By and large our approach to understanding and hence treating obesity has been driven, and simultaneously hampered by, a gross oversimplification of what in reality is a highly complex disease. In fact, even acknowledging that obesity is a disease rather than merely a consequence of poor lifestyle choices is a relatively nascent and still-debated concept.

    The prevailing notion by the general public and many within the medical community as well is that obesity is caused by a simple equation: too high caloric intake + too low energy expenditure. The solution, then, would be seemingly straightforward: eat less and exercise more. However, this mantra is not working, and it also perpetuates an unconstructive “blame game”. The cause of obesity is not that simple—and neither is the remedy.

    Promoting a lifestyle grounded in healthy eating and regular physical activity undoubtedly should be the foundation of our efforts to combat obesity. While prevention needs to remain a priority, we have to help the millions of people with obesity today, who are at substantial risk for developing myriad co-morbidities like cardiovascular disease (CV), stroke, cancer, and type 2 diabetes, to name a few.

    Millions of people struggle to lose weight and to keep off the pounds. Why is that? Are some of us predisposed biologically to weight gain—and to an inability to lose weight? What happens to the body with repeated cycles of (even incremental) weight gain and weight loss? Do these cycles sabotage future weight loss efforts? What is the role and interplay of a person’s environment, food intake, and habits on metabolism?

    In order to effectively address the obesity epidemic, we need to tackle these and other pressing questions head on, expand our understanding of the pathophysiology of this disease, and then rapidly translate that understanding into strategies for safe and effective treatment and, ultimately, prevention.

  • Targeted Approaches to Development

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    The solution to the obesity epidemic is not as simple as eating less and exercising more. The pathophysiology of the disease is complex, and augmented research is necessary for the ultimate development of safe and effective treatments. [Karen Roach/Fotolia.com]

    Historically, there has been a bias toward central nervous system (CNS) targets, which as we know have been associated with serious adverse events while demonstrating low rates of response. In general, our pharmacologic approach to obesity has been serendipitous in nature, rather than driven by rational drug design. Faced with an extremely risk-adverse regulatory environment, it is imperative that we pursue therapies that deliver high benefit with low associated risk.

    To that end, I believe that we need to move beyond exploring medications that modulate brain signals associated with food craving and appetite. Rather, we need to harness our expanding body of knowledge of the complex pathophysiology of obesity and employ a more thoughtful approach, targeting peripheral pathways that will yield greater efficacy with a much more favorable safety profile.

    Numerous examples, such as glucagon-like peptide-1 (GLP-1) peptides, demonstrate that these peripheral targets can produce meaningful weight loss by mimicking and amplifying normal endocrinology and satiety. Other pathways to safer and more effective obesity therapies include increasing fat metabolism or increased calorie burning, also known as thermogenesis. These peripheral approaches have been proven in preclinical models and should be rapidly pushed into the clinic.

    Medicine, in general, is slowly modulating from a one-size-fits-all approach characterized by trial-and-error drug development and prescribing to a more personalized approach. Obesity R&D needs to similarly evolve. Accomplishing this will require the identification of molecular subtypes of obesity and disease-segmenting biomarkers in order to design targeted therapies for those subtypes, as well as to predict treatment response and risk for weight gain in addition to certain co-morbidities.

    Genomic sequencing has led to the identification, thus far, of many genes associated with obesity. Obesity gene variants appear to be involved in what we now believe to be multiple central and peripheral molecular pathways that impact energy homeostasis.

    Like many diseases, we should begin considering obesity as a disease caused by a disturbance in homeostasis, and devote significant energy and resources on eliciting a more solid understanding of what causes these disturbances.

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