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ADA: New DPP-4 Inhibitor Demonstrated Efficacy in Reducing Glucose Levels

The first ever human data for Alogliptin, Takeda’s investigational compound for Type 2 diabetes, Alogliptin, a highly selective dipeptidyl peptidase-IV (DPP-4) inhibitor under investigation for the treatment of type 2 diabetes, demonstrated efficacy in reducing glucose levels throughout the day, in an early phase clinical study. Alogliptin, a highly selective dipeptidyl peptidase-IV (DPP-4) inhibitor under investigation for the treatment of type 2 diabetes, demonstrated efficacy in reducing glucose levels throughout the day, in an early phase clinical study. Safety results for this multi-dose study showed that alogliptin was well tolerated in patients with type 2 diabetes, with an incidence of hypoglycemia similar to placebo. No serious adverse event was reported, and no dose-limiting toxicity was observed over the entire dose range of 25 to 400 mg

"These are encouraging early results for alogliptin as a potential new type 2 diabetes treatment to help manage glucose levels throughout the day,” said Qais A. Mekki, MD, PhD, vice president, Clinical Science at Takeda Global Research & Development, Inc. “Alogliptin is a reflection of Takeda’s commitment to finding innovative options to help patients manage their type 2 diabetes.”

This was a randomized, double-blind, placebo-controlled, parallel-group, multi-dose study conducted in multiple centers. Subjects were patients with type 2 diabetes who were either newly diagnosed or treated with diet and exercise alone for the previous three months and were between the ages of 18 and 75 years. The objectives of the study were to assess the uptake, utilization and metabolism, as well as the tolerability, of alogliptin after multiple-dose administration to patients with type 2 diabetes. The primary efficacy endpoint was change in mean 4-hour postprandial plasma glucose levels from Baseline (Day -1) to Day 14. Secondary efficacy endpoints included change in mean 4-hour postprandial insulin levels; fasting plasma levels of C-peptide, fructosamine, and glycosylated hemoglobin (A1C); and incidence of hyperglycemia (blood glucose ≥200 mg/dL).

Alogliptin demonstrated rapid and sustained inhibition of plasma DPP-4 activity, across all doses:  On Days 1 and 14, mean peak inhibition of plasma DPP-4 activity ranged from 93.8% to 98.9% across all alogliptin doses; median time to peak inhibition ranged from 1.0 to 2.5 hours.

o At 24 hours and 72 hours after Day 14, mean inhibition ranged from 81.8% to 96.7% and from 66.3% to 81.6%, respectively, across all alogliptin doses.

Alogliptin, initially referred to as SYR-322, is a highly selective and potent DPP-4 inhibitor and is under investigation for the treatment of type 2 diabetes. Alogliptin was designed by Takeda to selectively inhibit DPP-4 and not other closely related proteins that are associated with other biologic activity. In in vitro studies, alogliptin has been shown to be 10,000-fold more selective for DPP-4 over other closely related proteins.

DPP-4 inhibitors are a new class of oral agents for the treatment of type 2 diabetes that block the degradation of GLP-1 (glucagon-like peptide-1) and GIP (glucose-dependent insulinotropic peptide), known as incretins, which are normally released in the digestive tract in response to food, and mediate glucose-dependent insulin secretion. GLP-1 also suppresses pancreatic glucagon secretion and subsequent liver glucose production, slows gastric motility and elicits satiety, a feeling of fullness. In type 2 diabetes, GLP-1 levels are decreased and the insulinotropic response to GIP is reduced, contributing to high blood sugar. DPP-4 inhibitors have displayed a weight-neutral profile along with a risk of low blood sugar similar to placebo due to their glucose-dependent mechanism of action.

Aogliptin is being developed by Takeda Global Research & Development and is currently in Phase 3 clinical studies.
American Diabetes Association 2007 Scientific Sessions

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FACT:
ADA: Diabetes a Risk Factor for Cardiovascular Morbidity and Mortality in 3.3 Million Subjects:  A new study concludes that patients with type 2 diabetes 30 years of age and older who are receiving glucose-reducing treatment should also receive prompt intensive prophylactic treatment for cardiovascular disease. See this week’s Item #6

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