Dutogliptin

Dutogliptin, a dipeptidyl peptidase-4 inhibitor for the treatment of type 2 diabetes mellitus

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.

Dutogliptin in Combination with Filgrastim in Early Recovery Post-Myocardial Infarction-The REC-DUT-002 Trial

Patients with acute myocardial infarction are at high risk for developing heart failure due to scar development. Although regenerative approaches are evolving, consistent clinical benefits have not yet been reported. Treatment with dutogliptin, a second-generation DPP-4 inhibitor, in co-administration with filgrastim (G-CSF) has been shown to enhance endogenous repair mechanisms in experimental models. The REC-DUT-002 trial was a phase 2, multicenter, double-blind placebo-controlled trial which explored the safety, tolerability, and efficacy of dutogliptin and filgrastim in patients with ST-elevation Myocardial Infarction (STEMI). Patients (n = 47, 56.1 ㊣ 10.7 years, 29% female) with STEMI, reduced left ventricular ejection fraction (EF ≒ 45%) and successful revascularization following primary PCI were randomized to receive either study treatment or matching placebo. Cardiac magnetic resonance imaging (cMRI) was performed within 72 h post-PCI and repeated after 3 months. The study was closed out early due to the SARS-CoV-2 pandemic. There was no statistically significant difference between the groups with respect to serious adverse events (SAE). Predefined mean changes within cMRI-derived functional and structural parameters from baseline to 90 days did not differ between placebo and treatment (left ventricular end-diastolic volume: +13.7 mL vs. +15.7 mL; LV-EF: +5.7% vs. +5.9%). Improvement in cardiac tissue health over time was noted in both groups: full-width at half-maximum late gadolinium enhancement (FWHM LGE) mass (placebo: -12.7 g, treatment: -19.9 g; p = 0.23). Concomitant treatment was well tolerated, and no safety issues were detected. Based on the results, the FDA and EMA have already approved an adequately powered large outcome trial.

Safety, tolerability, pharmacokinetics and pharmacodynamics of parenterally administered dutogliptin: A prospective dose-escalating trial

Aims: Animal studies suggest that inhibition of dipeptidyl peptidase 4 (DPP-IV) may improve heart function and survival after myocardial infarction by increasing cardiac myocytes' regenerative capacity. Parenterally administered dutogliptin may provide continuous strong DPP-IV inhibition to translate these results into humans. This trial investigated the safety and tolerability, as well as pharmacokinetics and pharmacodynamics, of parenterally administered dutogliptin after single and repeated doses.
Methods: In an open-label trial, volunteers received dutogliptin at increasing doses of 30-120 mg subcutaneously or 30 mg intravenously in the single-dose cohorts. Subjects in the multiple-dose cohort received 60, 90 or 120 mg dutogliptin subcutaneously once daily on 7 consecutive days.
Results: Forty healthy males were included in the trial. No related serious adverse events occurred. Mild local injection site reactions with no requirement for intervention comprised 147 of 153 (96%) related adverse events. Subcutaneous bioavailability was approximately 100%. Multiple injections at daily intervals did not lead to the accumulation of the study drug. The accumulation ratios based on AUC_0-24h range from 0.90 to 1.03, supporting this argument. All subjects receiving ≡60 mg dutogliptin yielded a maximum DPP-IV inhibition >90%. The duration of DPP-IV inhibition over time increased in a dose-dependent manner and was highest in the 120-mg multiple-dosing cohort with a maximum AUEC_0-24h of 342 h % (standard deviation: 73), translating into 86% DPP-IV inhibition 24 hours after dosing.
Conclusion: Parenteral injection of dutogliptin was safe and subcutaneous bioavailability is excellent. DPP-IV inhibition increased dose dependently to >86% over 24 hours after multiple doses of 120 mg dutogliptin.

Dutogliptin, a selective DPP4 inhibitor, improves glycaemic control in patients with type 2 diabetes: a 12-week, double-blind, randomized, placebo-controlled, multicentre trial

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.

Evaluation of the potential for pharmacokinetic and pharmacodynamic interactions between dutogliptin, a novel DPP4 inhibitor, and metformin, in type 2 diabetic patients

Objective: Dutogliptin is a novel, orally available, potent, and selective DPP4 inhibitor that improves glycemic control in type 2 diabetic patients. The objective of this study was to evaluate the potential pharmacokinetic and pharmacodynamic interactions, as well as the tolerability, of dutogliptin and metformin alone and in combination in type 2 diabetic patients.
Methods: This was a single-center, randomized, open-label, 3-way, crossover study in type 2 diabetic patients. All patients received three treatment regimens, each of 5 days duration in order to reach steady state: 400 mg once daily of dutogliptin (the anticipated clinical dose); 1000 mg metformin twice daily (maximum effective clinical dose); and concomitant administration of 400 mg dutogliptin once daily and 1000 mg metformin twice daily.
Results: Co-administration of dutogliptin and metformin did not alter the pharmacokinetics of either agent. The geometric mean ratio, GMR (dutogliptin + metformin/dutogliptin) of the area under the plasma concentration-time curve (AUC(0-24h)) at steady state was 0.91 (90% CI: 0.79-1.06; p = 0.29); the GMR of the maximum plasma concentrations (C(max)) was 0.95 (90% CI: 0.76-1.19; p = 0.70); the time to maximum plasma concentrations (T(max)) was essentially the same for dutogliptin with or without metformin. The GMR (dutogliptin + metformin/metformin) of AUC(0-12h) at steady state was 0.99 (90% CI: 0.84-1.17; p = 0.93); the GMR of C(max) was 0.91 (90% CI: 0.79-1.04; p = 0.18); T(max) was comparable for metformin with or without dutogliptin. Metformin added to dutogliptin had no effect on plasma DPP4 inhibition. All three treatment regimens were well tolerated.
Conclusions: In this small, multiple dose study, the steady state pharmacokinetics of either dutogliptin or metformin were not altered by co-administration of the two agents. Dutogliptin and metformin were well tolerated either alone or in combination and co-administered metformin did not alter the ex vivo DPP4 inhibition by dutogliptin. There is no need to consider pharmacokinetic and pharmacodynamic interactions when determining the dosage of either agent for co-administration. A phase 3 clinical trial is underway to provide more definitive data on the safety and efficacy of dutogliptin administered on a background of metformin treatment.