Phase 3 Results for Alogliptin Demonstrated Significant Blood Sugar Reductions in Monotherapy and Four Add-On Therapy Studies

Market Wire, June, 2008

Results from five pivotal phase 3 studies of alogliptin were announced today at the American Diabetes Association (ADA) 68th Scientific Sessions by Takeda Global Research & Development Center, Inc. Alogliptin, which has been shown to be a highly selective inhibitor of dipeptidyl peptidase-4 (DPP-4), is currently under investigation as an oral treatment for type 2 diabetes. Alogliptin administered once daily demonstrated statistically significant reductions in hemoglobin A1c (HbA1c) versus placebo as a monotherapy and as an add-on therapy with the major classes of type 2 diabetes medications: metformin, thiazolidinediones, insulin and sulfonylureas.

"Almost half the patients with type 2 diabetes are not at the American Diabetes Association recommended HbA1c goal of less than 7 percent, so it's important to have new treatment options that are both effective and well tolerated to potentially address the large number of patients who aren't adequately controlled," said Richard Pratley, MD, director of the Diabetes & Metabolism Translational Medicine Unit at the University of Vermont College of Medicine. "These clinical data show that alogliptin effectively reduces blood sugar in patients, alone or when used in combination with existing oral anti-diabetic treatments as well as insulin, increasing the range of treatment options for patients."

In the alogliptin monotherapy study, a significantly greater percentage of patients achieved HbA1c levels of less than or equal to 7 percent. Similar results were seen in the add-on to metformin, thiazolidinedione and sulfonylurea studies. Across all studies, patients achieved significant reductions in HbA1c, up to 0.80 percent, depending on the alogliptin dose and their treatment regimen. Greater HbA1c reductions were seen in patients with higher baseline HbA1c. Safety results showed that alogliptin was weight neutral and well tolerated in patients with type 2 diabetes, with an incidence of hypoglycemia similar to placebo.

"Alogliptin is another example of Takeda's commitment to advance the science of diabetes," said David Recker, M.D., senior vice president, Clinical Sciences, at Takeda. "The addition of alogliptin to the Takeda diabetes franchise would potentially enable us to address two of the core defects associated with type 2 diabetes, insulin deficiency and insulin resistance, ultimately helping patients improve their overall blood glucose control."

Alogliptin Phase 3 Study Results

In all five studies, at study end (week 26), mean change from baseline HbA1c levels were significantly greater, (P < .001), for both 12.5 mg and 25 mg alogliptin doses versus placebo, respectively:

--  alogliptin monotherapy: -0.56 percent, -0.59 percent, -0.02 percent
--  metformin add-on: -0.60 percent, -0.60 percent, -0.1 percent
--  thiazolidinediones add-on: -0.66 percent, -0.80 percent, -0.19 percent
--  insulin add-on: -0.63 percent, -0.71 percent, -0.13 percent
--  sulfonylurea add-on: -0.38 percent, -0.52 percent,  0.01 percent
    

A greater percentage of patients achieved HbA1c levels of less than or equal to 7 percent at both 12.5 mg and 25 mg alogliptin doses versus placebo, respectively, in the following studies:

--  alogliptin monotherapy: 47 percent (P=.001), 44 percent (P=.008), 23
    percent
--  metformin add-on: 52 percent (P < .001), 44 percent (P < .001), 18
    percent
--  sulfonylurea add-on: 30 percent (P=.057), 35 percent (P=.002), 18
    percent
    

In all five studies, at study end, mean changes from baseline HbA1c levels were similar regardless of age, BMI or ethnicity.

Alogliptin was well-tolerated at all doses and in combination with other type 2 diabetes medications. Common adverse events were similar across groups in each study.

Alogliptin Phase 3 Study Design

Phase 3 studies were conducted in over 2,000 patients in 220 centers worldwide. All five phase 3 studies were randomized, double blind, placebo-controlled studies, designed to assess the efficacy and safety of alogliptin, alone or when added to another type 2 diabetes medication: metformin, pioglitazone, insulin or glyburide. The primary end point was change from baseline in HbA1c at week 26 (or last observation) in the intent-to-treat population. Alogliptin was studied at 12.5 mg and 25 mg, once daily, in all studies.

In all studies, except for the insulin add-on, mean baseline HbA1c was between 7.9 percent and 8.1 percent, and mean duration of type 2 diabetes was between six to eight years. In the insulin add-on, mean baseline HbA1c was 9.3 percent and mean duration of type 2 diabetes was 13 years. Mean age, in all studies, was between 53 and 57 years.

About Hemoglobin A1c (HbA1c)

HbA1c is a measure of an individual's average blood sugar over a three-month period. The ADA has recommended a target HbA1c level of < 7 percent. ADA guidelines recommend clinical intervention for HbA1c > 8 percent and to be considered for HbA1c between 7 and 8 percent.

About Alogliptin

Alogliptin, previously known by the development code SYR-322, is a selective 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.