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Aiming at a target
NEW YORK —Intercept Pharmaceuticals has reached a $163 million deal with Les Laboratoires Servier to collaborate on new TGR5 agonists for diabetes and other metabolic ailments.
Under the terms of the agreement, Intercept will receive up to $163 million in total upfront, research support and milestone payments, as well as royalties on sales, based on the successful outcome of the collaboration. Intercept and Servier will jointly support the discovery effort, while Servier alone will be responsible for all costs associated with the global development, regulatory approval and commercialization of any compound selected as a lead candidate by the parties. Intercept retains all rights in the United States and Japan.
It's the first time the companies have worked together, and the collaboration will leverage Intercept's drug discovery platform based on its proprietary bile acid analog chemistry and expertise targeting TGR5 and other bile receptors.
Dr. Mark Pruzanski, Intercept's president and CEO, says the agreement provides important validation of the company's approach to targeting TGR5.
"Type 2 diabetes and associated metabolic disorders have reached epidemic proportions globally, and there is a critical need for novel effective and safe drugs," he says. "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."
Over the past decade, new roles for bile acids in paracrine and endocrine regulation of cholesterol homeostasis, lipid and carbohydrate metabolism and immunomodulatory functions have been discovered. Pruzanski points out that most of the early discoveries focused on the genomic actions of bile acids through the activation of families of nuclear receptors, such as the farnesoid X receptor (FXR), until a new chapter in the bile acid biology unfolded with the discovery of TGR5, a novel G-protein coupled receptor regulating various non-genomic functions via bile acid signaling.
TGR5 (also known as GPR131 and Gpbar1) was identified through the exploration of GPCRs in the GenBank database with human spleen cDNAs and finding a genomic DNA sequence coding for a novel GPCR, designated TGR5.
Moreover, Pruzanski explains that TGR5 is an attractive candidate because its activation in enteroendocrine L cells potently induces secretion of the incretin GLP-1 in the intestine with resulting insulin-sensitizing effects.
"GLP-1 is a validated target in the treatment of type 2 diabetes given the DPP4 inhibitor and GLP-1 analog classes of drugs, and a TGR5 agonist might be used in combination with such drugs and/or other diabetes drugs to drive further insulin sensitizing effects," he says. "TGR5 has also been shown to induce energy expenditure through enhanced mitochondrial function in brown adipose tissue and skeletal muscle with resulting resistance to weight gain."
Pruzanski also points out that TGR5 is involved in the modulation of cytokine production by immune cells, potentially playing a role in the control of chronic inflammation that is a feature in diabetes and other associated metabolic disorders. Thus, the activation of TGR5 signaling pathways is expected to counteract the metabolic dysfunction associated with type 2 diabetes.
As the new partners move forward, Pruzanski notes that during the research phase of the collaboration, "we are working towards further characterizing TGR5 agonists we have been working on, while also working on novel discovery to generate additional compounds that have different characteristics we will select for. If, together with Servier, we identify a TGR5 agonist we wish to advance to an IND and into the clinic, we will consider the collaboration a success."
Pruzanski explains that Intercept's science is based on the recent 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.
"Intercept has a pipeline of lead compounds invented by Prof. Roberto Pellicciari, a leader in bile acid chemistry at the University of Perugia in Italy and head of Intercept's drug discovery programs," he says. "Working in collaboration with his group, the company has built a proprietary drug discovery capability."
Pascal Touchon, director of scientific cooperation and business development at Servier, says the collaboration with Intercept will allow the French company to further expand its diabetes and metabolic disease franchise. He adds the French company has a specific discovery team working on diabetes and metabolism, with various programs on new innovative targets.
"The TGR5 target is one that we know very well, and that complements our internal work on other targets," he says.
The Servier pipeline currently has other drugs for the treatment of diabetes.
In clinical development, Touchon notes that Servier has fixed-dose combinations based mainly on gliclazide, as well as an anti-IL1 beta MAb in collaboration with its partner, Xoma of Berkeley, Calif.
"In the preclinical stage, we have several compounds acting on undisclosed targets," he adds.