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Feature Articles : Jul 1, 2012 (Vol. 32, No. 13)

Obesity Proving Complicated and Personal

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

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.

Unsurprisingly, gene variants don’t tell the whole story. For example, the obesity-related genes we have identified to date are estimated to predict only 5% of obesity risk. This is where the role of environment, behavior, epigenetics, and other factors will likely come into play from individual to individual.

In fact, we already have clear signs that obesity is a heterogeneous disease. Lorcaserin, a 5HT2c agonist, produces a more than 3% weight loss when considering all randomized patients, but one-third respond well, losing more than 10% of body weight with accompanying substantial and clinically meaningful improvements in diabetes and CV risk.

Why do some respond and others don’t? We at the Translational Research Institute for Metabolism and Diabetes (TRI) believe that the tipping point in obesity pharmacotherapy will lie in the answer to that question and should be the focus of both academic and industry research.

Another route to accelerate obesity R&D will involve leveraging the known links between obesity and type 2 diabetes. While obesity and type 2 diabetes are distinct diseases, we are beginning to learn more about shared common pathways and underlying defects.

Obviously, we have had far more success in treating diabetes from a pharmacological perspective and in securing FDA approval for novel diabetes therapies. Some of today’s most effective diabetes therapies, such as GLP-1 agonists, also carry weight loss benefits. This presents an opportunity from a development and regulatory perspective to identify type 2 diabetes therapies with weight-loss potential and expand to an indication in obesity.

Examples of Early Progress

For extreme obesity, surgery is currently the preferred and only effective treatment modality. Exciting new data suggests that in addition to substantial weight loss, bariatric surgery is highly effective in controlling, and in some patients, completely eliminating, type 2 diabetes symptoms. It appears that bariatric surgery triggers massive changes in metabolic—specifically gut—hormones, which leads to a decrease in appetite and improved diabetes.

Preclinical and some early clinical efforts to replicate these hormonal changes without surgery are quite promising. While surgery is certainly an important option right now for people with extreme obesity, we need to focus in the long term on producing the same hormonal changes without surgery, eliciting the same substantial weight loss, and improving or resolving type 2 diabetes.

In fact, gut hormones present a plethora of opportunities for obesity drug development. And because they represent peripheral targets, they likely will have significantly fewer side effects than drugs targeting CNS pathways.

Another exciting area of research we are focused on at TRI employs a novel strategy to increase energy expenditure at the cellular level. Our partners at Sanford Burnham Medical Research Institute found that orexin, an appetite-producing hormone that is produced in the brain, activates brown adipose tissue, or brown fat.

Brown fat is a kind of “good fat” that burns high quantities of sugar and fat in a process that is designed by nature to moderate body temperature in babies, who have a large number of brown fat cells. By activating brown fat in adults, calories that otherwise would be stored as unwanted white fat can be burned.

Low levels of orexin are associated with obesity, while high levels are associated with leanness. At TRI, we have now advanced orexin research into the clinical phase, and are undertaking proof of concept experiments to validate this new drug target and evaluate its safety and efficacy.

The augmented focus on obesity has sparked heightened clinical research to better understand the complex pathophysiology of this disease. Exploring and beginning to define the heterogeneity of obesity will put us on a path toward more targeted, effective, and safe treatment strategies and, hopefully someday, prevention.

While we have made some progress, we have a long way to go. But dispelling the myth that the obesity problem can be resolved if people would simply just eat less and exercise more is a critical first step.

Predictors of Obesity in Children

The prevalence of childhood obesity in the U.S. has increased over the past several decades, putting the nation’s youth at risk of developing serious disorders such as type 2 diabetes and cardiovascular disease. Though obesity is such a complex disease, likely involving genetic and environmental factors, behavioral factors do play a significant role.

Scientists from the University of California, San Diego wanted to examine children’s physical activity and dietary behaviors as they related to BMI and body fat. They studied 271 six- to nine-year-olds for 24 months, and published their results in a recent issue of Childhood Obesity, a Mary Ann Liebert, Inc., journal.

At baseline, obese children were less active than normal-weight children. Over the two-year observational period, the researchers noted that increased physical activity and number of breakfasts with the family were associated with lower BMI and body fat. Additionally, decreased sedentary behavior and sugary drink consumption were also associated with lower body fat.

Many factors are involved in the causes of obesity, and there is a dire need for new therapeutics and increased R&D. However, as this study demonstrates, the starting point to prevent and tackle this disease is still the classic approach: lead an active lifestyle and maintain a healthy diet.