Takeda Resubmits New Drug Applications in the U.S. for their Alogliptin and Alogliptin/Pioglitazone Combo

The FDA will review the New Drug Applications (NDA) resubmissions within the next six months. Pioglitazone was approved in 1999 for the treatment of type 2 diabetes as an adjunct to diet and exercise. Alogliptin is a selective dipeptidyl peptidase IV inhibitor (DPP-4i) under investigation in the U.S. for the treatment of type 2 diabetes as an adjunct to diet and exercise.Discovered by Takeda San Diego, Inc., alogliptin is designed to slow the inactivation of incretin hormones GLP-1 (glucagon-like peptide-1) and GIP (glucose-dependent insulinotropic peptide), which play a role in regulating blood glucose levels.

David Recker, M.D., senior vice president, clinical science, Takeda Global Research & Development Center, stated that, "We believe interim results from a cardiovascular outcomes trial satisfy the FDA's cardiovascular safety requirements to allow the Agency to complete its review of our NDA, and further support the product profile of alogliptin." "If approved, alogliptin/pioglitazone will be the first type 2 diabetes treatment option in the U.S. to include both a DPP-4 inhibitor and a thiazolidinedione in a single tablet."

The NDA resubmissions include interim results from the EXAMINE (EXamination of CArdiovascular OutcoMes: AlogliptIN vs. Standard of CarE in Patients with Type 2 Diabetes Mellitus and Acute Coronary Syndrome) study, a cardiovascular outcomes trial requested by the FDA to satisfy the criteria outlined in the December 2008 "Guidance for Industry: Diabetes Mellitus -- Evaluating Cardiovascular Risk in New Antidiabetic Therapies to Treat Type 2 Diabetes." The EXAMINE study was designed to comply with the Guidance. This randomized, double-blind, placebo-controlled outcomes study continues to evaluate cardiovascular endpoints following treatment with alogliptin in addition to standard of care, versus standard of care alone, in patients with type 2 diabetes and a recent acute coronary syndrome (ACS). Final study results are expected in 2014.

Twelve phase 3 clinical trials of alogliptin involving more than 8,000 patients were conducted in over 1,000 centers worldwide. The safety and efficacy of alogliptin was studied as a once-daily monotherapy adjunct to diet and exercise and as an add-on therapy to several other classes of antidiabetic medications, including metformin, thiazolidinediones (TZDs), insulin and sulfonylureas. In these studies, alogliptin 25 mg, taken once daily, demonstrated statistically significant reductions in hemoglobin A1c, which reflects average blood glucose concentration over the previous two to three months. The common adverse events (greater than or equal to 5% and greater than placebo) identified in this phase 3 program include headache, urinary tract infection, nasopharyngitis, and upper respiratory tract infection.

Of the 8,000 patients, the alogliptin/pioglitazone studies included more than 3,000 patients. Study results indicated that alogliptin/pioglitazone produced significant improvements in glycemic control. The common adverse events (greater than or equal to 5% and greater than placebo) identified in this phase 3 program include nasopharyngitis, back pain, urinary tract infection, and influenza.

Alogliptin is a DPP-4i being investigated, as an adjunct to diet and exercise, for the treatment of type 2 diabetes. DPP-4 inhibitors address insulin deficiency by slowing the inactivation of incretin hormones GLP-1 (glucagon-like peptide-1) and GIP (glucose-dependent insulinotropic peptide). As a result, an increased amount of active incretins enables the pancreas to secrete insulin, in a glucose-dependent manner, thereby assisting in the management of blood glucose levels. An NDA for alogliptin was approved in April 2010 by the Japanese Ministry of Health, Labour and Welfare for the treatment of type 2 diabetes.  

Alogliptin/pioglitazone is a fixed-dose combination therapy in development for the treatment of type 2 diabetes, which combines alogliptin and pioglitazone in a single tablet. Pioglitazone is a TZD that directly targets insulin resistance, a condition in which the body does not efficiently use the insulin it produces to control blood glucose levels, and is approved in adults for the treatment of type 2 diabetes as an adjunct to diet and exercise. An NDA for the alogliptin/pioglitazone fixed-dose combination was approved in July 2011 by the Japanese Ministry of Health, Labour and Welfare for the treatment of type 2 diabetes.

News release: Takeda Global Research & Development 7-25-2011