The data showed that ARRY-403 demonstrated potent, highly glucose-blood-level dependent, control of both fasting and non-fasting glucose concentrations. Based on these and other results, Array plans to advance ARRY-403 into human clinical studies in the first half of 2009. The data were presented today at an annual metabolic diseases conference in London.
"There is a significant need for new, more effective oral diabetes treatments - and glucokinase activation represents a promising new mechanism," said Kevin Koch, Ph.D., President and Chief Scientific Officer. "GKAs hold the potential to bring a significant benefit to Type 2 diabetes patients and we believe ARRY-403 is a highly potent and safe glucokinase activator."
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 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.
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.
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Previous studies in animals and humans showed that two aspects of gastroparesis were: 1) loss of Kit, a marker for interstitial cells of Cajal (ICC), and 2) loss of expression of neuronal nitric oxide synthase (nNOS). ICC cells produce electrical signals that regulate muscle contraction in the digestive tract. nNOS generates nitric oxide, which transmits nerve impulses in the digestive tract. Both are important for normal functioning but can be depleted by oxidative stress (an imbalance in ionic charges at the molecular level), a problem common in diabetes that also can lead to heart and kidney damage.
The research team decided to test a molecule known to protect cells against oxidative injury -- heme oxygenase-1 (HO1). The team measured gastric emptying in a set of diabetic mice and then looked at expression of HO1. Results showed that production of HO1 was lost in all mice with gastroparesis and nNOS expression was decreased. When the team induced HO1 production by introducing hemin, a red blood derivative, gastric emptying returned to normal and Kit and nNOS expression were restored, despite the diabetes. The team says that future research should target the HO1 pathway as a means of reversing the affects of diabetic gastroparesis.
Others researchers were Kyoung Moo Choi, Ph.D.; Simon Gibbons, Ph.D.; Tien Nguyen; Gary Stoltz; Matthew Lurken; Tamas Ordog, M.D.; and Joseph Szurszewski, Ph.D., all of Mayo Clinic. The research was funded by the National Institutes of Health.
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