Kalamazoo Company Announces New Drug Target For Diabetes

KALAMAZOO -- Metabolic Solutions Development Co. LLC announced Wednesday the publication of data in the latest issue of the scientific journal PLOS ONE on a new drug target for treating type 2 diabetes by boosting the body's sensitivity to insulin.

For the full study, visit http://dx.plos.org/10.1371/journal.pone.0061551.

The new target is located in the inner mitochondrial membrane, which includes recently identified proteins that control mitochondrial pyruvate import.

MTOT (mitochondrial target of thiazolidinediones) is a mitochondrial protein complex through which new anti-diabetic drugs exert their insulin sensitizing effects.

Data suggest mTOT functions as a molecular sensor switch that coordinates carbohydrate, lipid, and amino acid metabolism with cell function.

Recently published Phase 2b clinical data from a study in 258 type 2 diabetic patients further demonstrate modulating mTOT could constitute a new approach for the discovery and development of potentially more useful and novel insulin sensitizers. This new drug target may also play a role in other diseases of aging such as Alzheimer's disease and Parkinson's disease.

Diabetes is an undertreated global epidemic affecting an estimated 340 million people world-wide, with a rapidly increasing incidence throughout the developed and developing world. In the United States alone, nearly 26 million adults and children live with the disease. An additional 79 million have pre-diabetes, placing them at increased risk for developing type 2 diabetes.

Recently released research by the American Diabetes Association estimates the total costs of diagnosed diabetes have risen to $245 billion in 2012 from $174 billion in 2007, when the cost was last examined. This figure represents a 41 percent increase over a five-year period.

"The only drug that attacks both insulin resistance and beta cell dysfunction, the root causes of type 2 diabetes, is an insulin sensitizer," said Ralph A. DeFronzo, M.D., professor of medicine and chief of the diabetes division at the University of Texas Health Science Center and the Audie L. Murphy Memorial VA Hospital in San Antonio, Texas. "There is a growing interest in a new generation of insulin sensitizers that appear to bind to proteins in the mTOT complex, but not activate the PPAR receptor at therapeutic doses. As such, these new therapeutic agents likely will not elicit the side effects associated with currently approved insulin sensitizers."

Previously, it was believed that both the activity and the side-effects of the only approved class of drugs used to treat insulin resistance, thiazolidinedione insulin sensitizers, were mediated through PPAR. It is now generally accepted that activating PPAR drives the side effects of this class of therapeutic agents (e.g., increased adiposity, volume expansion, bone loss and congestive heart failure), which has limited the use of current drugs and prevented the development of new insulin sensitizing agents. With the discovery of the mTOT complex, researchers now have a clear path forward to create new, more useful insulin sensitizers.

The mTOT discovery team is led by MSDC's co-founders, Jerry Colca and Rolf Kletzien, who were among the original researchers in the field of insulin sensitizers, and who selected and led the early development of Actos (pioglitazone), a PPAR agonist. MSDC scientists are utilizing their unique insight into the potential key role of the mTOT complex in the regulation of metabolic function to develop several classes of novel insulin sensitizers, which do not have the side effects that have prevented the development of new therapeutic treatments for type 2 diabetes.

Phase 2b clinical data published in the Jan. 18, 2013 issue of Clinical Pharmacology & Therapeutics on the company's prototype compound, MSDC-0160, a novel once-a-day oral insulin sensitizer and the first in a new class of therapeutic agents called mTOT Modulators, showed this new generation of insulin sensitizer met the study's primary endpoint of significantly reducing fasting plasma glucose and significantly reduced hemoglobin A1c.

The study was a 90-day, randomized, double-blind, comparator- and placebo-controlled, multi-dose study completed in 258 patients with type 2 diabetes. The study compared three doses of MSDC-0160 (50 mg, 100 mg and 150 mg) to maximum dose Actos(pioglitazone 45 mg) or placebo taken orally once daily for 12 weeks. All treatments were well tolerated. There were no serious adverse events attributed by investigators to the MSDC drug.