Next Generation Obesity Treatments: Creating Beige Fat (Part 3 of 3)
In recent posts, we’ve taken a look at the impact that obesity is having on the U.S. – both on the population in general and on healthcare facilities – and how traditional treatments have failed. Surgical options and medications produce limited results, dangerous side effects, and patients often regain lost weight within two or three years.
Breakthroughs are likely just a few years away, however, and the ability to attack and reduce fat cells directly shows great promise for a new approach. It has long been known that there is a kind of adipose tissue named “brown fat” that looks and functions differently than ordinary “white fat.” White fat stores energy, but brown fat is engineered to burn fat, generating heat. Recently, Dana Faber’s Bruce Spiegelman has made the case that there is a third variety of adipose tissue that functionally falls somewhat between brown and white fat. He aptly nicknamed it “beige fat.” A key difference from brown fat is that beige fat cells can be “revved-up,” i.e. their rate of fat burning can be increased almost to the level of brown fat in response to certain stimuli such as a cold temperatures or exposure to the newly discovered muscle hormone irisin. Moreover, in a new paper in Cell, Spiegelman reports that irisin can also stimulate white fat to produce more of the beige fat cell type.
For these unique properties, “beige fat” may be likely at the center of the next wave of obesity treatments. Researchers have succeeded in isolating irisin and using it to stimulate white fat, forcing it to produce more of the beige fat variety which then starts burning off fat, ultimately also depleting the excess fat stored in white adipose tissue.
DHK Pharma is currently pursuing a “beige fat” approach with its lead compound, TatdMt, that seems to closely mimic the activity of irisin. In preclinical studies, TatdMt has shown the ability to dramatically increase the production of a protein named UCP-1 (uncoupling protein) that is essential for beige and brown fat cells to burn off fat safely. These changes on the molecular level are associated with rapid weight-loss, higher body temperature, higher oxygen consumption and increased physical activity.
TatdMt is especially intriguing as a drug candidate, as the same molecule also acts as an appetite suppressing agent by stimulating hypothalamic melanocortin-4 receptors. In this aspect, it mimics the activity of the well-known peptide hormone a-MSH (melanocyte stimulating hormone). The hope is that this dual MOA – eat less and burn more fat – may lead to superior clinical efficacy.
In normal rabbits, significant weight effects have been observed even if TatdMt was administered only once every two weeks. And so far, preliminary safety studies in rats and dogs are promising, avoiding the negative side effects that have marred earlier market entrants. However, more comprehensive toxicological studies still need to be completed before the program can be advanced to clinical trials.
The current version of TatdMt is formulated for a weekly (or possibly bi-weekly) subcutaneous injection as a treatment for severe obesity (BMI>35), thus providing a pharmacological alternative for bariatric surgery. Eventually, DHK Pharma may also advance second generation compounds aimed for broader indications and test alternative routes of administration.
We’ve seen a great deal of interest from the Venture Capital community in these novel mechanisms of action that focus on local fat metabolism. MedCap Advisors believes strongly that DHK Pharma can be an important innovator in the fight against obesity, and we will stay close to the progress of the treatment as TatdMt makes its way through clinical trials.