Alogliptin is a potent highly selective DPP-4 inhibitor originally discovered by Syrrx (Takeda San Diego) that has completed Phase 3 clinical trials for the treatment of T2DM. Discovery of alogliptin: a potent, selective, bioavailable, and efficacious inhibitor of dipeptidyl peptidase IV J Med Chem. 2007 May 17;50(10):2297-300.
Although the NDA for Alogliptin was filed with the FDA in December 2007, the FDA required additional information from Takeda in regard to assessment of the cardiovascular risk profile of the drug as outlined in a March 6 2009 Press Release. Alogliptin was approved for use in Japan in 2011.
Takeda Receives New Information on Alogliptin (SYR-322) NDA
OSAKA, Japan, March 6, 2009 - Takeda Pharmaceutical Company Limited today announced that Takeda Global Research and Development Center, Inc., a wholly owned United States (U.S.) subsidiary, was informed as part of regular discussions about the alogliptin New Drug Application (NDA) with the United States Food and Drug Administration (FDA), that although the alogliptin NDA was filed prior to issuance of FDA’s December 2008 guidance on new Type 2 diabetes treatments, the FDA will apply these guidelines when reviewing the alogliptin NDA.
Additionally, the FDA does not believe that the amount of existing alogliptin clinical data is sufficient to meet certain statistical requirements in the new guidance. The agency is open to discussions regarding the design of additional CV studies with alogliptin. Alogliptin’s Prescription Drug User Fee Act (PDUFA) date – June 26, 2009 - remains unchanged.
In December, 2008 the FDA issued “Guidance for Industry: Diabetes Mellitus — Evaluating Cardiovascular Risk in New Antidiabetic Therapies to Treat Type 2 Diabetes”.
In October 2008, Takeda received notification from the FDA that it was unable to complete its review of the alogliptin NDA by the original PDUFA date — October 27, 2008 — due to internal resource constraints. The FDA did not raise any issues with the data in the alogliptin NDA at that time. In December 2007, Takeda submitted its NDA for alogliptin to the FDA.
The PK/PD profile of various alogliptin doses (25, 100 or 400 mg) was studied in human subjects with T2DM over 14 days. All of these doses produced effective potent suppression of plasma DPP-4 activity ranging from 82-97% at trough 24 hrs after administration of the last dose. The majority of alogliptin is excreted unchanged in the urine. Pharmacokinetic, pharmacodynamic, and tolerability profiles of the dipeptidyl peptidase-4 inhibitor alogliptin: a randomized, double-blind, placebo-controlled, multiple-dose study in adult patients with type 2 diabetes Clin Ther. 2008 Mar;30(3):499-512
Analysis of the efficacy of 12.5 or 25 mg of a single daily dose of alogliptin was assessed over 26 weeks in subjects with T2DM not previously receiving therapy. Alogliptin produced a mean reduction in HbA1c of .56-.59%, starting from a baseline A1c of 7.9%, with no significant change in body weight. Minor skin-related AEs were more common with alogliptin and two patients discontinued therapy due to skin-related AEs. Alogliptin was well tolerated and not associated with an increased risk of hypopglycemia. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor alogliptin in patients with type 2 diabetes and inadequate glycemic control: a randomized, double-blind, placebo-controlled study Diabetes Care. 2008 Dec;31(12):2315-7.
Alogliptin was also assessed in patients previously treated with a sulphonylurea. All patients were treated with alogliptin or placebo in addition to glyburide for 26 weeks. The mean baseline A1c was 8.1%, with a mean duration of diabetes of ~ 8 years. Alogliptin produced a further reduction in A1c of 0.38 and 0.52% for patients treatewd with 12.5 and 25 mg, respectively. Twentyfive % of patients randomized to alogliptin therapy did not complete the 26 week course of treatment, with failure to achieve hyperglycemic targets the most common reason for discontinuing therapy. No significant improvements were seen in parameters of beta cell function and no clear trend was reported for AEs in patients treated with alogliptin. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor alogliptin in patients with type 2 diabetes inadequately controlled by glyburide monotherapy Diabetes Obes Metab. 2009 Feb;11(2):167-76
Nauck and colleagues examined the efficacy of alogliptin added to metformin therapy in subjects with T2DM over 26 weeks. Baseline A1c was ~ 8.%, mean duration of diabetes was 6 years, and about 80% of the randomized subjects completed the study. Alogliptin therapy (12.5 or 25 mg daily) reduced A1c by ~ 0.6% and no worrisome signal was reported in regard to AEs, however minor skin AEs were slightly more common with alogliptin. Efficacy and safety of adding the dipeptidyl peptidase-4 inhibitor alogliptin to metformin therapy in patients with type 2 diabetes inadequately controlled with metformin monotherapy: a multicentre, randomised, double-blind, placebo-controlled study. Int J Clin Pract. 2009 Jan;63(1):46-55