Takeda Pharmaceutical received a complete response letter from the FDA regarding alogliptin and fixed-dose combination (FDC) alogliptin and pioglitazone in type 2 diabetes. The company believes that it can address the agency’s concerns by supplying postmarketing data from outside the U.S. as well as data from its ongoing clinical trial program.
“We will immediately request a meeting with the FDA to determine the appropriate next steps and are committed to addressing outstanding issues,” says Thomas Harris, vp, regulatory affairs, Takeda Global Research & Development Center. “We remain confident in the benefit that alogliptin will bring to patients with type 2 diabetes in the U.S. if approved.
The most common adverse events (≥5% and greater than placebo) reported in the alogliptin Phase III program included headache, urinary tract infection, nasopharyngitis, and upper respiratory tract infection. With regard to the co-administration of alogliptin and pioglitazone, common adverse events (≥5%) reported include nasopharyngitis, back pain, urinary tract infection, and influenza.
While details about what FDA requires from Takeda were not provided, the company faced complete response letters in 2009 that raised concern over cardiovascular risks. At the time FDA informed Takeda that, although the NDAs were filed prior to the release of the December 2008 FDA guidance on evaluating cardiovascular risk in antidiabetic therapies, the agency did not believe that the amount of existing clinical data was sufficient to meet certain statistical requirements outlined in that guidance.
Takeda says that it has supplied FDA with more information from post-marketing evaluations. In Europe, the company pulled its MAA in 2009 to conduct a long-term clinical study for alogliptin. 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, and the therapy is currently available under the brand name Nesina® in this market. The alogliptin-pioglitazone combo was approved in Japan in July 2011, and the therapy is currently available under the brand name Liovel® in this market. Furiex receives royalty payments from Takeda for the sale of these products in Japan.
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. Alogliptin is designed to slow the inactivation of incretin hormones GLP-1 (glucagon-like peptide-1) and GIP (glucose-dependent insulinotropic peptide), which play roles in regulating blood glucose levels.
The FDC alogliptin and pioglitazone combines two complementary agents with distinct mechanisms of action. If approved it will be the first type 2 diabetes treatment option in the U.S. to include both a DPP-4i and the thiazolidinedione (TZD) pioglitazone in a single tablet. Pioglitazone-containing medicines have been available in the U.S. since 1999 for the treatment of type 2 diabetes as an adjunct to diet and exercise.
“Takeda has built a strong foundation in and maintained a robust focus on diabetes over the past 20 years, and we will continue to invest in developing a diverse range of innovative products for the growing type 2 diabetes population,” Harris remarks.