Inhibitor Report for: Dutogliptin

Dutogliptin (PHX-1149T), being developed by Phenomix Corp, Forest Laboratories Inc and Chiesi Farmaceutici SpA, is a small-molecule dipeptidyl peptidase-4 (DPP-4) inhibitor for the potential oral treatment of type 2 diabetes mellitus (T2DM). DPP-4 quickly degrades the insulin secretory hormones, glucose-dependent insulinotropic peptide and glucagon-like peptide-1; thus inhibiting the degradation of these hormones is a viable treatment option for patients with T2DM. In preclinical studies, dutogliptin potently inhibited DPP-4 and, in a model of T2DM, treatment with dutogliptin improved glucose homeostasis. Pharmacokinetic analyses in animals, healthy individuals and patients with T2DM demonstrated that drug exposure increased in a dose-dependent manner. Results from phase II clinical trials indicated that once-daily dutogliptin, in combination with other oral diabetes therapies, reduces postprandial blood glucose and HbA1c levels, both indicators of successful diabetes management. In phase I and II trials, dutogliptin was safe, well tolerated and associated with extremely low rates of hypoglycemia. At the time of publication, phase III trials were underway and the results of these will be imperative to determine the efficacy of dutogliptin compared with other small molecule DPP-4 inhibitors, such as sitagliptin and vildagliptin.

AIM: To determine efficacy and tolerability of dutogliptin, a dipeptidyl peptidase 4 (DPP4) inhibitor, in patients with type 2 diabetes mellitus. METHODS: This was a 12-week, multicentre, randomized, double-blind, placebo-controlled trial in 423 patients with type 2 diabetes with suboptimal metabolic control. Following a 2-week single-blind placebo run-in, patients aged 18-75 years with a body mass index of 25-48 kg/m(2) and baseline HbA1c of 7.3-11.0% were randomized 2:2:1 to receive once-daily oral therapy with either dutogliptin (400 or 200 mg) or placebo on a background medication of either metformin alone, a thiazolidinedione (TZD) alone or a combination of metformin plus a TZD. RESULTS: Average HbA1c at baseline was 8.4%. Administration of dutogliptin 400 and 200 mg for 12 weeks decreased HbA1c by -0.52% (p < 0.001) and -0.35% (p = 0.006), respectively (placebo-corrected values), with absolute changes in HbA1c for the 400 mg, 200 mg and placebo groups of -0.82, -0.64 and -0.3%, respectively. The proportion of patients achieving an HbA1c < 7% was 27, 21 and 12% at dutogliptin doses of 400 and 200 mg or placebo, respectively (p = 0.008 for comparison of 400 mg vs. placebo). Fasting plasma glucose (FPG) levels were significantly reduced in both active treatment groups compared to placebo: the placebo-corrected difference was -1.00 mmol/l (p < 0.001) for the 400 mg group and -0.88 mmol/l (p = 0.003) for the 200 mg group. Dutogliptin caused significantly greater reductions in postprandial glucose AUC (0-2h) in both the 400 and 200 mg groups (placebo corrected values -2.58 mmol/l/h, p < 0.001 and -1.63 mmol/l/h, p = 0.032, respectively). In general, patients tolerated the study drug well. There were minor, not clinically meaningful differences in adverse events (AEs) between dutogliptin-treated patients and placebo controls, and 60% of all reported AEs were mild. Vital signs and body weight were stable, and routine safety laboratory parameters did not change compared with placebo. Trough ex vivo DPP4 inhibition at the end of the 12-week treatment period was 80 and 70%, at the 400 and 200 mg doses of dutogliptin, respectively. CONCLUSIONS: Dutogliptin treatment for 12 weeks improved glycaemic control in patients with type 2 diabetes who were on a background medication of metformin, a TZD or metformin plus a TZD. Tolerability was favourable for both doses tested. The 400 mg dose of dutogliptin resulted in larger changes of HbA1c and FPG and more subjects reached an HbA1c target of < 7% than the 200 mg dose.