GSK and Vanderbilt Invest in Severe Obesity Treatment

Continuing a trend of renewed investment in obesity treatment research, Vanderbilt University yesterday announced a research agreement with GlaxoSmithKline on new treatments for severe obesity.

This investment in targeting severe obesity is noteworthy. It marks a departure from failed strategies of pursuing weight loss for broad populations that some have characterized as a search for miracle diet pills. In 2012, The George Washington University published an expert report of obesity research and patient advocates. They called for a shift of focus to the medical management of obesity and away from a narrow preoccupation with weight loss outcomes.

The research target is the melanocortin-4 receptor (MC4-R), which is involved in energy homeostasis — the balance of food intake and energy expenditure — and the regulation of body weight. Defective melanocortin signaling is the most common cause of severe, early-onset obesity.With major support from the National Institutes of Health (NIH), Roger Cone, Ph.D., and colleagues at Vanderbilt have identified a series of drug-like compounds, called positive allosteric modulators or PAMs, that “gently increase” MC4-R activity.

Under the collaboration agreement, Vanderbilt will do the pharmacology and pre-clinical testing, while GSK scientists will try to develop chemically similar compounds with improved activity and efficacy. The goal is to begin Phase I testing in humans within three years — in 2016. “It’s a very aggressive timeline,” said Cone, chair of the Department of Molecular Physiology and Biophysics, who discovered MC4-R and demonstrated its potential for treating obesity in the late 1990s.

Up to 5 percent of cases of severe, early-onset obesity have been linked to heterozygous mutations in MC4-R that reduce melanocortin signaling by less than 50 percent of normal levels. Clinical trials of drugs that directly activated every MC4 receptor throughout the brain were not successful, however, because some individuals experienced a rise in blood pressure.

In comparison, PAMs act indirectly to “boost” only those receptors that are already being turned on by a native hormone. “Rather than activating all the receptors everywhere all the time, we just want to gently increase receptor activity twofold,” Cone said. This approach should avoid raising blood pressure in patients with partially defective melanocortin signaling, and may be effective in treating common obesity as well.

Under the terms of the agreement, GSK will provide research support to Vanderbilt for three years, additional payments for meeting project milestones, and a share of royalties. Cone’s lab will continue research on the receptor supported by NIH grant DK070332.

Click here to read more in MedCity News.

Keratinocytes and Melanocytes imaged using the GE Healthcare IN Cell Anayzer by Emeline Ratineau © General Electric Company