Forest licenses TransTech’s glucokinase activators
Jun08

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...

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Array, Novartis Team for Mek-inhibitor
Apr19

Array, Novartis Team for Mek-inhibitor

Boulder, Colo.- based Array BioPharma is again cashing in on its discovery platform for small molecules that block the protein kinase Mek. Novartis has agreed to pay $45 million out of the gate for ARRY-162, a MEK-inhibitor in Phase I cancer trials, and other back-up MEK-blocking compounds. As part of the Novartis deal, Array could earn up to $422 million in additional milestones as the compound moves through the pipeline. Array is keeping a hand in the project, agreeing to pay for part of the development costs for the compound in exchange for what it calls “a significantly higher royalty rate” for U.S. sales of ARRY-162. ARRY-162 blocks MEK, one of several protein kinases in a cell signaling pathway associated with cancer cell proliferation and survival. The compound is currently in an early-phase study in advanced cancer patients with solid tumors to determine the right dose and assess its safety. ARRY-162 isn’t the first MEK inhibitor Array has married off. AstraZeneca licensed what is now known as AZD6224 as part of a long-standing collaboration around the protein target. Though AstraZeneca continues to develop AZD6224, most notably testing the drug in combination with Merck’s Akt inhibitor MK-2206, Array was freed from the exclusivity of the partnership last year. But in the six years of the pact, the biotech not only earned research funding, but pocketed some $96 million in milestone payments. From the looks of the Novartis deal structure, it looks like the Swiss drug major will pick up where AstraZeneca left off. Array appears to be on a bit of a roll in scoring deals that wed reasonable upfront payments with research funding, while also keeping a healthy slice of future product sales. The biotech scored a $60 million upfront payment in December, when Amgen signed on to jointly develop ARRY-403, a second-generation glucokinase activator in Phase I. Glucokinase “senses” glucose in the pancreas by catalyzing the phosphorylation of glucose to glucose-6-phosphate, a critical first step in metabolizing sugar. Drugs like ARRY-403 enable the pancreas to better sense glucose, leading to increased insulin production. Amgen also agreed to provide funding over the course of a two-year research collaboration around glucokinase...

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