Nature Publication Reports on Key Role of Bile Acids in Glucose Metabolism and Insulin Signaling

  Intercept Pharmaceuticals is Advancing Bile Acid-Derived Small Molecules

         with Potential Applications in Treating Metabolic Diseases



    NEW YORK, Aug. 7 /EMWNews/ -- Historically, bile acids have been

recognized primarily as natural detergents that regulate the absorption of

dietary lipids and cholesterol homeostasis. However, recent research

advances provide evidence that bile acids have broader systemic endocrine

functions, acting as important mediators of glucose metabolism and insulin

signaling. The featured article in the current issue of Nature Reviews Drug

Discovery (Vol. 7, Number 8, August 2008) describes why bile acid receptors

are promising targets for drug development in obesity, type 2 diabetes,

atherosclerosis and other chronic metabolic disorders such as nonalcoholic

steatohepatitis.



    Highlights of the article, "Targeting bile acid signaling for metabolic

diseases," authored by Drs. Charles Thomas, Roberto Pellicciari, Mark

Pruzanski, Johan Auwerx and Kristina Schoonjans, include:



    -- Bile acids serve as metabolic integrators, activating major

signaling pathways regulated by nuclear hormone receptors including the

farnesoid X receptor (FXR) and G protein-coupled receptors (GPCRs) such as

TGR5.



    -- Bile acids play a major role in lipid metabolism and homeostasis.

For example, bile acid activation of FXR results in a decrease in serum

triglyceride levels.



    -- The activation of TGR5 by bile acids increases energy expenditure

and reduces diet-induced obesity. Conversely, "knockout" animal models

engineered to lack TGR5 show a tendency towards weight gain.



    -- Bile acids have broad effects on glucose homeostasis, including a

decrease in gluconeogenesis (glucose synthesis by the liver). These effects

have been attributed primarily to activation of FXR. Additionally, mice

that lack FXR have impaired glucose tolerance and are insulin-resistant.



    Dr. Schoonjans, Ph.D., a group leader at the Ecole Polytechnique

Federale de Lausanne commented, "Our research efforts have uncovered a

number of endocrine effects mediated by bile acids acting on receptors such

as FXR and TGR5. This review is one of the first to provide a comprehensive

summary of what is now known about bile acid signaling and its relevance

for metabolic function. From this broad viewpoint, we can see the potential

for identifying important new therapeutics that can address a number of

important disorders."



    Dr. Pruzanski, founder, President and CEO of Intercept Pharmaceuticals,

commented, "At Intercept, we have proprietary insight into the rational

design of potent FXR and TGR5 agonists derived from bile acid scaffolds. To

date, we have advanced our lead compound, INT-747, a first-in-class FXR

agonist, into three ongoing Phase II trials. The innovative research being

reported in the current issue of Nature Reviews provides additional support

for our programs, and we look forward to reporting the progress of our

discovery and development efforts in the appropriate forums."

    About Intercept Pharmaceuticals



    Intercept is a clinical stage biopharmaceutical company focused on

discovering and developing small molecule drugs for the treatment of

chronic fibrotic and metabolic diseases. The company's scientists and

affiliated researchers have published extensively on the role of bile acid

signaling via the nuclear hormone receptor FXR and the G protein-coupled

receptor TGR5. These receptors are key mediators of energy homeostasis and

are involved in maintaining integral functions of the liver, intestine and

kidney, organs exposed to bile acid flux. The company's chemocentric

discovery programs are based on proprietary expertise in the rational

design and synthesis of natural and synthetic small molecule derivatives

targeting FXR, TGR5 and other related targets. For more information on

Intercept, please visit the company's website at http://www.interceptpharma.com.