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In December 2009, Array granted Amgen exclusive worldwide rights to Array's small-molecule glucokinase activator program, including ARRY-403, currently being tested in a Phase 1 clinical trial in patients with Type 2 diabetes. Array received an upfront payment of $60 million and additional contingent payments for certain clinical and commercial milestones. Array is responsible for completing the Phase 1 trial for ARRY-403. Amgen is responsible for future clinical development and commercialization for ARRY-403 and any resulting back-up compounds, with Array having an option to co-promote in the United States. Array will receive double digit royalties on sales of ARRY-403. In addition, Amgen will fund an agreed upon number of full-time Array employees as part of a two-year research collaboration intended to identify and advance second-generation glucokinase activators.
About ARRY-403 / Glucokinase activation
Glucokinase activators (GKAs) reduce glucose levels via a dual mechanism of action - working in both the pancreas and the liver. Glucokinase (GK) is the Enzyme that senses glucose in the pancreatic beta cells, stimulating insulin release in a glucose-dependent manner. GK also regulates glucose uptake and glucose production in the liver. In diabetic patients, there is a reduction of glucokinase (GK) activity in the pancreas and the liver. The activation of glucokinase lowers glucose levels by enhancing the ability of pancreatic beta cells to sense glucose, in turn increasing the level of insulin that is produced by the pancreas. Simultaneously, GKAs also increase the uptake of glucose in the liver, while reducing the amount of glucose produced by the liver. These combined actions of GKAs result in improved beta cell function and increased insulin sensitivity in the liver.
Preclinical Results
ARRY-403 demonstrated potent, highly glucose-blood-level dependent, control of both fasting and non-fasting glucose concentrations. The data showed that in multiple well-established in vivo models of Type 2 diabetes, ARRY-403 was highly efficacious in controlling both fasting and non-fasting glucose, with rapid onset of effect and maximal efficacy within five to eight days. In combination with existing standard-of-care drugs (metformin, DPP4 inhibitor, or PPAR(gamma) agonist), ARRY-403 provided additional glucose-control, which reached maximal efficacy after five to seven days of once-daily dosing. ARRY-403 showed no adverse increases of body weight, plasma triglycerides or total cholesterol, whether used as monotherapy or in combination.
Phase 1 Single Ascending Dose Top-Line Results
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ARRY-403 met its primary and secondary endpoints of safety, pharmacokinetics and glucose control in a Phase 1 single ascending dose study. The study included seven dose cohorts, with a total of 41 patients with Type 2 diabetes receiving either placebo or single doses of ARRY-403 ranging from 25 mg to 400 mg. ARRY-403 was well tolerated at all doses. ARRY-403 was rapidly absorbed, and exposure was dose-dependent. The pharmacokinetic profile is consistent with once daily therapeutic dosing. ARRY-403 provided dose-dependent reduction in glucose excursions in response to a standardized meal as well as reduction in 24-hour fasting blood glucose.
Future Milestones
Based on Phase 1 SAD and other results, Array is initiating a Phase 1 multiple ascending dose study in patients with Type 2 diabetes.
About Diabetes
According to the Centers for Disease Control, approximately 24 million (8 percent) Americans have diabetes. Current therapies for this progressive disease are insufficient or inconvenient, creating a need for the development of novel therapeutic approaches. GKAs, such as ARRY-403, represent a promising new class of drugs for the treatment of Type 2 diabetes.
Scientific Posters
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