The FDA issued a complete response letter to Takeda Pharmaceutical Co. Ltd. regarding new drug applications for alogliptin and fixed-dose combinations of alogliptin and pioglitazone for Type II diabetes, products partnered with Furiex Pharmaceuticals Inc.

Takeda's submission included extensive Phase III data, interim findings from a cardiovascular outcomes trial and postmarketing data from outside the U.S. The FDA has requested additional information, which Takeda, of Osaka, Japan, believes it can supply from the postmarketing data.

Alogliptin, a highly selective dipeptidyl peptidase IV (DPP-4i) inhibitor, was approved in Japan in 2010. It is designed to modify blood glucose levels through inactivation of glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP).

The alogliptin/pioglitazone combination, if approved, would be the first diabetes therapy in the U.S. that includes a DPP-4i and pioglitazone, a thiazolidinedione, in a single tablet. Pioglitazone was approved in 1999 for Type II diabetes.

Takeda pays royalties to Furiex, of Morrisville, N.C., for sales of the drug in Japan under the trade names Nesina and Liovel. Takeda encountered hurdles in the U.S., however, receiving a complete response letter in 2009, in which the FDA requested a cardiovascular outcomes study.

In 2008, Takeda reported results from five Phase III studies of alogliptin that enrolled 2,000 patients in 220 centers worldwide. All studies were randomized, double-blind and placebo-controlled. Administered once daily, at 12.5 mg or 25 mg, the drug showed statistically significant reductions in hemoglobin A1c(HbA1c) compared to placebo as a monotherapy and as an add-on to other diabetes medications: metformin, thiazolidinediones, insulin and sulfonylureas.

In the monotherapy study, a significantly larger percentage of patients achieved HbA1c levels less than or equal to 7 percent. Across all studies, HbA1c decreased by up to 0.80 percent, with greater reductions seen in patients with higher baseline HbA1c.

Safety data showed alogliptin was weight neutral and well tolerated in patients with Type II diabetes, and the incidence of hypoglycemia was similar to placebo. In spite of the comprehensive and nearly bullet-proof nature of Takeda's Phase III trials, alogliptin appears to have been derailed by new FDA policies on cardiovascular outcomes.

It issued a publication titled "Guidance for Industry: Diabetes Mellitus – Evaluating Cardiovascular Risk in New Antidiabetic Therapies to Treat Type II Diabetes," in December 2008 while reviewing Takeda's NDA for alogliptin.

The FDA's complete response letter in 2009 requested a cardiovascular outcomes study. The agency also rejected the investigational fixed-dose combination of alogliptin and pioglitazone in 2009 for the same reason.

The cardiovascular outcomes trial, EXAMINE, began in August 2009, and enrolled approximately 5,400 patients at 1 ,000 sites in the U.S., Europe and Asia with a primary outcome measuring time from randomization to the occurrence of the primary major adverse cardiac events, a composite of cardiovascular death, nonfatal myocardial infarction and nonfatal stroke.

Takeda's resubmission for alogliptin in July 2011 included interim data from its cardiovascular outcome study that it believed would satisfy the agency's concerns.

Alogliptin has now been studied in 12 Phase III trials including more than 8,000 patients at more than 1,000 centers worldwide.

Takeda requested a meeting with the FDA to determine appropriate next steps. It intends to try a third time for U.S. approval.