Aiming at a target

Intercept, Servier in deal to develop diabetes drug

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NEW YORK —Intercept Pharmaceuticals has reached a $163million deal with Les Laboratoires Servier to collaborate on new TGR5 agonistsfor diabetes and other metabolic ailments.
Under the terms of the agreement, Intercept will receive upto $163 million in total upfront, research support and milestone payments, aswell as royalties on sales, based on the successful outcome of thecollaboration. Intercept and Servier will jointly support the discovery effort,while Servier alone will be responsible for all costs associated with theglobal development, regulatory approval and commercialization of any compoundselected as a lead candidate by the parties. Intercept retains all rights inthe United States and Japan.
It's the first time the companies have worked together, andthe collaboration will leverage Intercept's drug discovery platform based onits proprietary bile acid analog chemistry and expertise targeting TGR5 andother bile receptors.
Dr. Mark Pruzanski, Intercept's president and CEO, says theagreement provides important validation of the company's approach to targetingTGR5.
"Type 2 diabetes and associated metabolic disorders havereached epidemic proportions globally, and there is a critical need for noveleffective and safe drugs," he says. "Intercept is uniquely positioned toexploit the therapeutic potential of rationally modified bile acids, which playa central role in the maintenance of metabolic homeostasis."
Over the past decade, new roles for bile acids in paracrineand endocrine regulation of cholesterol homeostasis, lipid and carbohydratemetabolism and immunomodulatory functions have been discovered. Pruzanskipoints out that most of the early discoveries focused on the genomic actions ofbile acids through the activation of families of nuclear receptors, such as thefarnesoid X receptor (FXR), until a new chapter in the bile acid biology unfoldedwith the discovery of TGR5, a novel G-protein coupled receptor regulatingvarious non-genomic functions via bile acid signaling.
TGR5 (also known as GPR131 and Gpbar1) was identifiedthrough the exploration of GPCRs in the GenBank database with human spleencDNAs and finding a genomic DNA sequence coding for a novel GPCR, designatedTGR5.
Moreover, Pruzanski explains that TGR5 is an attractivecandidate because its activation in enteroendocrine L cells potently inducessecretion of the incretin GLP-1 in the intestine with resulting insulin-sensitizingeffects.
"GLP-1 is a validated target in the treatment of type 2diabetes given the DPP4 inhibitor and GLP-1 analog classes of drugs, and a TGR5agonist might be used in combination with such drugs and/or other diabetesdrugs to drive further insulin sensitizing effects," he says. "TGR5 has alsobeen shown to induce energy expenditure through enhanced mitochondrial functionin brown adipose tissue and skeletal muscle with resulting resistance to weightgain."
Pruzanski also points out that TGR5 is involved in themodulation of cytokine production by immune cells, potentially playing a rolein the control of chronic inflammation that is a feature in diabetes and otherassociated metabolic disorders. Thus, the activation of TGR5 signaling pathwaysis expected to counteract the metabolic dysfunction associated with type 2diabetes. 
As the new partners move forward, Pruzanski notes thatduring the research phase of the collaboration, "we are working towards furthercharacterizing TGR5 agonists we have been working on, while also working onnovel discovery to generate additional compounds that have differentcharacteristics we will select for. If, together with Servier, we identify aTGR5 agonist we wish to advance to an IND and into the clinic, we will considerthe collaboration a success."
Pruzanski explains that Intercept's science is based on therecent discovery that bile acids act as complex signaling molecules involved inthe maintenance of lipid, glucose and overall energy homeostasis, while alsopreserving the functional integrity of the liver and other organs. 
"Intercept has a pipeline of lead compounds invented byProf. Roberto Pellicciari, a leader in bile acid chemistry at the University ofPerugia in Italy and head of Intercept's drug discovery programs," he says."Working in collaboration with his group, the company has built a proprietarydrug discovery capability." 
Pascal Touchon, director of scientific cooperation andbusiness development at Servier, says the collaboration with Intercept willallow the French company to further expand its diabetes and metabolic diseasefranchise. He adds the French company has a specific discovery team working ondiabetes and metabolism, with various programs on new innovative targets.
"The TGR5 target is one that we know very well, and thatcomplements our internal work on other targets," he says.
The Servier pipeline currently has other drugs for thetreatment of diabetes.
In clinical development, Touchon notes that Servier hasfixed-dose combinations based mainly on gliclazide, as well as an anti-IL1 betaMAb in collaboration with its partner, Xoma of Berkeley, Calif.
"In the preclinical stage, we have several compounds actingon undisclosed targets," he adds.

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