Intercept Pharmaceuticals could receive up to $163 million from Servier as part of a worldwide (excluding the U.S. and Japan) agreement centered on the discovery and development of TGR5 (GPR131) agonists for the treatment of type 2 diabetes and other metabolic indications. The partnership will exploit Intercept’s drug discovery platform, which is based on bile acid analog chemistry, and expertise in targeting TGR5 and other bile receptors.
The firms will jointly support the discovery phase, with Servier shouldering responsibility for all costs associated with global development, regulatory approval, and commercialization of any products selected for development. Intercept retains all rights to products in the U.S. and Japan.
TGR5 is a cell surface GPCR that is regulated by bile acids. It has been shown to represent a key regulatory of energy homeostasis, the firm explains. “This agreement provides important validation of our approach to targeting TGR5,” remarks mark Pruzanski, M.D., Intercept president and CEO. “Intercept is uniquely positioned to exploit the therapeutic potential of rationally modified bile acids, which play a central role in the maintenance of metabolic homeostasis.”
Intercept's science is based on the discovery that bile acids act as complex signaling molecules involved in the maintenance of lipid, glucose, and overall energy homeostasis while also preserving the functional integrity of the liver and other organs. The company's drug development programs are currently focused on modified human bile acids and other synthetic small molecules that selectively target the bile acid-regulated nuclear receptor FXR and TGR5.
Lead FXR agonist, obeticholic acid (OCA, designated INT47), is a first-in-class FXR agonist derived from the primary human bile acid chenodeoxycholic acid (CDCA), which is the natural endogenous FXR agonist, Intercept states. The oral candidate has completed Phase II trials as a potential treatment for primary biliary cirrhosis (both as monotherapy and as part of combination therapy with ursodeoxycholic acid ) and in the treatment of type 2 diabetics with co-morbid fatty liver disease. Intercept says it is now preparing for Phase III trials in Europe and the U.S.
The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) is in addition sponsoring a clinical trial evaluating OCA in patients with nonalcoholic steatohepatitis under a CRADA. The 72-week Flint Study was initiated in March and will enrol 280 patients at the eight U.S. centers comprising the NIDDK-sponsored NASH Clinical Research Network.
Positive results from Intercept’s own 59-patient, placebo-controlled Phase II trial evaluating OCA as monotherapy against PBC were reported just a couple of days after the NIDDK NASH study was initiated. The day before the data was released, Dainippon Sumitomo Pharma confirmed negotiating an exclusive licensing agreement for the development and commercialization OCA in Japan and China for the treatment of chronic liver diseases, with an initial focus on primary biliary cirrhosis (PBC) and nonalcoholic steatohepatitis (NASH).
Lead TGR5 agonist, INT-777, is an orally bioavailable compound that has completed studies required for IND filing. Intercept has also developed a dual FXR/TGR5 agonist, INT-767, which has been characterized in a range of animal models. Intercept says the CDCA derivative is a significantly more potent FXR agonist than OCA and is highly selective for these two receptors.