Forest licenses TransTech’s glucokinase activators

Interest in glucokinase activators, a class of diabetes compounds with a rocky past, appears to be reviving. Forest Laboratories agreed today to pay $50 million upfront and up to $1.1 billion in milestones for access to TransTech Pharma’s glucokinase activator program. The deal includes the rights to TTP399, which is poised to start Phase II trials, and several other compounds in pre-clinical and Phase I studies. TransTech’s glucokinase activator (GKA) program was developed during a six-year research pact with Novo Nordisk. The Danish firm licensed the program back to TransTech in 2007, when it decided to divest its small molecule drug discovery programs. So what makes glucokinase an interesting diabetes target? A few words on GKAs from our earlier coverage: Glucokinase belongs to a family of enzymes called hexokinases, which catalyze the phosphorylation of glucose to glucose-6-phosphate, a critical first step in metabolizing sugar. Hexokinases are generally marked by their ubiquity—several serve housekeeping functions and are thus found in nearly every tissue in the body—and their tight bond to glucose. But glucokinase is something of a black sheep among hexokinase kin. It is found in relatively fewer tissues, and its affinity for glucose is delicate. In the pancreas it is believed to "sense" just the right concentration of glucose in β cells to signal the release of insulin. And in the liver glucokinase initiates the first step of glucose metabolism, kicking into action after a meal and later sensing when the body is in a fasting state and needs to store glucose. Back when we wrote about GKAs in 2008, several of the companies publicly working on this target talked up the dual roles of glucokinase in the liver and pancreas. While newer diabetes drugs like Merck’s Januvia and Amylin’s Byetta only affect the pancreas, GKAs were expected to have an effect on both organs, improving their control over blood glucose. TransTech, however, is touting the fact that its GKA compounds are “liver selective.” The biggest safety concern with GKAs in development has been hypoglycemia, or low blood sugar. TransTech says that “by activating glucokinase selectively in the liver but not in the pancreas, it may increase glucose utilization and lower blood glucose levels without inducing excessive insulin secretion thus reducing the risk of hypoglycemia.” Interest in glucokinase as a target has waxed and waned. Roche was actively pursuing GKAs not long ago, but a perusal of their public pipeline, which includes multiple diabetes programs,  shows no mention of the target. And a quick look at clinicaltrials.gov shows that Lilly suspended work on its program—licensed from OSI Pharmaceuticals for $25 million upfront in 2007--pending further toxicology testing. Still, late last year, Amgen paid $60 million upfront for access to Array BioPharma’s portfolio of glucokinase activators. The deal included ARRY-403, now called AMG-151, in Phase I trials to treat type-2 diabetes. We'll have to wait for Phase II results to see if the target is worth the effort. Stay tuned!

Author: Lisa Jarvis

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