Inhibitor Report for: Trelagliptin

Chondrocyte dysregulation plays a critical role in the development of osteoarthritis (OA). The pro-inflammatory cytokine interleukin-1beta (IL-1beta) activates chondrocytes and degrades the structural extracellular matrix (ECM). These events are the important mechanism of OA. Trelagliptin, a selective inhibitor of dipeptidyl Peptidase 4 (DPP-4) used for the treatment of type 2 diabetes mellitus (T2DM), has displayed a wide range of anti-inflammatory capacities. The effects of Trelagliptin in OA and chondrocytes have not been tested before. Here, we show that Trelagliptin mitigates IL-1beta-induced production of inflammatory cytokines such as interleukin 6 (IL-6), interleukin 8 (IL-8), and tumor necrosis factor-alpha (TNF-alpha) in human chondrocytes. Trelagliptin ameliorates IL-1beta-induced oxidative stress by reducing the generation of reactive oxygen species (ROS). Particularly, the presence of Trelagliptin prevents IL-1beta-induced reduction of Acan genes and the protein Aggrecan. Moreover, we show that Trelagliptin restores IL-1beta-induced reduction of SOX-9 and that the knockdown of SOX-9 abolishes the protective effects of Trelagliptin. Mechanistically, we demonstrate that AMPK is required for the amelioration of Trelagliptin on SOX-9- reduction by IL-1beta. Collectively, our study demonstrates that the DPP-4 inhibitor Trelagliptin has a protective effect on chondrocyte function. Trelagliptin may have the potential role to antagonize chondrocyte-derived inflammation in OA.

Trelagliptin (SYR-472), a novel dipeptidyl peptidase-4 inhibitor, shows sustained efficacy by once-weekly dosing in type 2 diabetes patients. In this study, we characterized in vitro properties of trelagliptin, which exhibited approximately 4- and 12-fold more potent inhibition against human dipeptidyl peptidase-4 than alogliptin and sitagliptin, respectively, and >10,000-fold selectivity over related proteases including dipeptidyl peptidase-8 and dipeptidyl peptidase-9. Kinetic analysis revealed reversible, competitive and slow-binding inhibition of dipeptidyl peptidase-4 by trelagliptin (t1/2 for dissociation approximately 30 minutes). X-ray diffraction data indicated a non-covalent interaction between dipeptidyl peptidase and trelagliptin. Taken together, potent dipeptidyl peptidase inhibition may partially contribute to sustained efficacy of trelagliptin.

BACKGROUND: In patients with type 2 diabetes, improving adherence to medication is important in order to maintain favourable glycaemic control during long-term treatment and, thus, prevent the onset or aggravation of complications. SYR-472 is a novel once-weekly oral DPP-4 inhibitor for type 2 diabetes, which could be a treatment option when clinicians seek to improve medication adherence by reducing the number of required administrations. In this study, we assessed the efficacy and safety of SYR-472 in patients with type 2 diabetes. METHODS: In this phase 2, multicentre, randomised, double-blind, parallel-group, placebo-controlled, dose-ranging study, we included Japanese patients with inadequately controlled type 2 diabetes despite diet and exercise treatment. Patients were randomly assigned (allocation ratio 1:1:1:1:1:1) to receive either placebo or SYR-472 at five different doses (12.5 mg, 25 mg, 50 mg, 100 mg, or 200 mg). Randomisation was done with a permuted block schedule. All investigators and patients were unaware of the treatment assignment. Treatment drug was given orally once weekly for 12 weeks. The primary efficacy variable was the change in HbA1c concentration from baseline to the end of treatment. This study has been registered at the Japan Pharmaceutical Information Center (JAPIC) Clinical Trials Information: Japic CTI-090899. FINDINGS: 322 patients were randomly assigned to receive placebo (55 patients) or SYR-472 at 12.5 mg (54 patients), 25 mg (52 patients), 50 mg (51 patients), 100 mg (55 patients) or 200 mg (55 patients). The least square (LS) mean change in HbA1c concentration from baseline was 0.35% (SE 0.068; -20 mmol/mol) for the placebo group, -0.37% (0.068; -28 mmol/mol) for the 12.5 mg group, -0.32% (0.070; -27 mmol/mol) for the 25 mg group, -0.42% (0.070; -28 mmol/mol) for the 50 mg group, -0.54% (0.068; -29 mmol/mol) for the 100 mg group, and -0.55% (0.069; -30 mmol/mol) for the 200 mg group. In general, HbA1c concentration decreased in a dose-dependent manner (trend test using contrast coefficients p<0.0001) and the reduction was significantly greater for all SYR-472 doses (p<0.0001 for each group) than for placebo. The incidence of treatment-emergent adverse events in each SYR-472 group was similar to that in the placebo group. The most common adverse event was nasopharyngitis in all groups. No episodes of hypoglycaemia defined by investigator occurred with any treatment during the study. INTERPRETATION: Once-weekly SYR-472 treatment produced clinically and statistically significant improvements in glycaemic control in patients with type 2 diabetes. It was well tolerated and might be a new treatment option for patients with this disease. FUNDING: Takeda Pharmaceutical Company Limited.

Chondrocyte dysregulation plays a critical role in the development of osteoarthritis (OA). The pro-inflammatory cytokine interleukin-1beta (IL-1beta) activates chondrocytes and degrades the structural extracellular matrix (ECM). These events are the important mechanism of OA. Trelagliptin, a selective inhibitor of dipeptidyl Peptidase 4 (DPP-4) used for the treatment of type 2 diabetes mellitus (T2DM), has displayed a wide range of anti-inflammatory capacities. The effects of Trelagliptin in OA and chondrocytes have not been tested before. Here, we show that Trelagliptin mitigates IL-1beta-induced production of inflammatory cytokines such as interleukin 6 (IL-6), interleukin 8 (IL-8), and tumor necrosis factor-alpha (TNF-alpha) in human chondrocytes. Trelagliptin ameliorates IL-1beta-induced oxidative stress by reducing the generation of reactive oxygen species (ROS). Particularly, the presence of Trelagliptin prevents IL-1beta-induced reduction of Acan genes and the protein Aggrecan. Moreover, we show that Trelagliptin restores IL-1beta-induced reduction of SOX-9 and that the knockdown of SOX-9 abolishes the protective effects of Trelagliptin. Mechanistically, we demonstrate that AMPK is required for the amelioration of Trelagliptin on SOX-9- reduction by IL-1beta. Collectively, our study demonstrates that the DPP-4 inhibitor Trelagliptin has a protective effect on chondrocyte function. Trelagliptin may have the potential role to antagonize chondrocyte-derived inflammation in OA.

INTRODUCTION: Trelagliptin is a novel, long-acting dipeptidyl peptidase-4 (DPP-4) inhibitor approved for the treatment of type 2 diabetes mellitus (T2DM) in japan. The safety and efficacy of trelagliptin has been evaluated in three published clinical trials to date: one phase II and two phase III studies. As trelagliptin only requires dosing once per week, this new agent has the potential to improve compliance and subsequently, glycaemic control, in patients with T2DM. Areas covered: This article reviews the available safety data for trelagliptin from published clinical trials, and evaluates the published safety profile relative to competitor once-daily and once-weekly DPP-4 inhibitors. Expert opinion: Clinical trial data to date suggest that trelagliptin is a safe and efficacious medication with a similar safety profile to once-daily DPP-4 inhibitors, and to the once-weekly DPP-4 inhibitor, omarigliptin. Trelagliptin is well tolerated when given alone, and in combination with other anti-diabetic medications. An advantage of trelagliptin over existing once-daily DPP-4 inhibitors is the decrease of dosing frequency, rather than once-daily. No specific, serious adverse events have been reported for trelagliptin in published clinical trials, making it an attractive alternative to other DPP-4 inhibitors.

Trelagliptin (SYR-472), a novel dipeptidyl peptidase-4 inhibitor, shows sustained efficacy by once-weekly dosing in type 2 diabetes patients. In this study, we characterized in vitro properties of trelagliptin, which exhibited approximately 4- and 12-fold more potent inhibition against human dipeptidyl peptidase-4 than alogliptin and sitagliptin, respectively, and >10,000-fold selectivity over related proteases including dipeptidyl peptidase-8 and dipeptidyl peptidase-9. Kinetic analysis revealed reversible, competitive and slow-binding inhibition of dipeptidyl peptidase-4 by trelagliptin (t1/2 for dissociation approximately 30 minutes). X-ray diffraction data indicated a non-covalent interaction between dipeptidyl peptidase and trelagliptin. Taken together, potent dipeptidyl peptidase inhibition may partially contribute to sustained efficacy of trelagliptin.

BACKGROUND: Trelagliptin, an oral DPP-4 inhibitor, which is administered once per week and characterized by a long half-life in blood. The effects of trelagliptin on vascular endothelial functions have not been clarified to date. The objective of the present study was to examine the effects of trelagliptin on vascular endothelial functions in patients with type 2 diabetes mellitus (DM) using flow-mediated dilatation (FMD), adiponectin, and asymmetric dimethylarginine (ADMA) as evaluation indicators. METHODS: This study was a preliminary single-arm prospective pilot study. The subjects of this study were type 2 DM patients aged 20-74 years, who visited our outpatient department. The patients were treated with trelagliptin, and their FMD, adiponectin, and ADMA levels were measured at baseline and at 12 weeks after initial treatment to determine the changes during the study period. RESULTS: A total of 27 patients, excluding three dropouts, were included in the population for analysis. Trelagliptin treatment showed no significant changes in FMD (2.42 +/- 2.7% at baseline vs. 2.66 +/- 3.8% post-treatment, P = 0.785) and ADMA (0.41 +/- 0.0 microg/mL at baseline vs. 0.40 +/- 0.0 microg/mL post-treatment, P = 0.402). Trelagliptin treatment resulted in a significant increase of serum adiponectin level (7.72 +/- 6.9 microg/mL at baseline vs. 8.82 +/- 8.3 microg/mL post-treatment, P < 0.002). CONCLUSIONS: In this pilot study, trelagliptin treatment showed no significant changes in FMD. On the other hand, it was believed that trelagliptin treatment may increase serum adiponectin level. Trial Registration http://www.umin.ac.jp (Trial ID UMIN000018311).

INTRODUCTION: Dipeptidyl peptidase-4 (DPP-4) inhibitors are weight neutral and well tolerated, and provide better glycaemic control for a longer period compared to conventional therapies. Despite the fact that various drugs are available, glycaemic control remains suboptimal in approximately half of patients with type 2 diabetes mellitus; one of the major reasons for low medication adherence. AREAS COVERED: A novel DPP-4 inhibitor, trelagliptin, was approved in Japan in March 2015, and is the first once-weekly oral antidiabetic agent in the world. In this review, current issues concerning medication adherence for the treatment of diabetes are discussed followed by a summary of the characteristics and future expectations of trelagliptin, by reviewing the recent phase I, II, and III clinical studies of trelagliptin. EXPERT OPINION: Trelagliptin has demonstrated superiority to placebo and non-inferiority to alogliptin, indicating its efficacy and tolerance in Japanese patients. Trelagliptin is expected to improve adherence and prevent complications. Due to the convenient dosing regimen, it is expected to be widely used in the clinical setting. A large-scale long-term study will help further confirm its long-term efficacy and safety, patients' satisfaction, and medication adherence.

Trelagliptin (Zafatek((R))) is an orally active dipeptidyl peptidase (DPP)-4 inhibitor developed by Takeda and approved in Japan for the treatment of type 2 diabetes mellitus (T2DM). Unlike other approved agents of its class, which are usually administered once daily, trelagliptin can be administered once weekly. Phase II development of trelagliptin was discontinued in the USA and EU, as Takeda considered that the costs associated with obtaining approval in these markets were prohibitive. This article summarizes the milestones in the development of trelagliptin leading to this first approval for T2DM.

BACKGROUND: In patients with type 2 diabetes, improving adherence to medication is important in order to maintain favourable glycaemic control during long-term treatment and, thus, prevent the onset or aggravation of complications. SYR-472 is a novel once-weekly oral DPP-4 inhibitor for type 2 diabetes, which could be a treatment option when clinicians seek to improve medication adherence by reducing the number of required administrations. In this study, we assessed the efficacy and safety of SYR-472 in patients with type 2 diabetes. METHODS: In this phase 2, multicentre, randomised, double-blind, parallel-group, placebo-controlled, dose-ranging study, we included Japanese patients with inadequately controlled type 2 diabetes despite diet and exercise treatment. Patients were randomly assigned (allocation ratio 1:1:1:1:1:1) to receive either placebo or SYR-472 at five different doses (12.5 mg, 25 mg, 50 mg, 100 mg, or 200 mg). Randomisation was done with a permuted block schedule. All investigators and patients were unaware of the treatment assignment. Treatment drug was given orally once weekly for 12 weeks. The primary efficacy variable was the change in HbA1c concentration from baseline to the end of treatment. This study has been registered at the Japan Pharmaceutical Information Center (JAPIC) Clinical Trials Information: Japic CTI-090899. FINDINGS: 322 patients were randomly assigned to receive placebo (55 patients) or SYR-472 at 12.5 mg (54 patients), 25 mg (52 patients), 50 mg (51 patients), 100 mg (55 patients) or 200 mg (55 patients). The least square (LS) mean change in HbA1c concentration from baseline was 0.35% (SE 0.068; -20 mmol/mol) for the placebo group, -0.37% (0.068; -28 mmol/mol) for the 12.5 mg group, -0.32% (0.070; -27 mmol/mol) for the 25 mg group, -0.42% (0.070; -28 mmol/mol) for the 50 mg group, -0.54% (0.068; -29 mmol/mol) for the 100 mg group, and -0.55% (0.069; -30 mmol/mol) for the 200 mg group. In general, HbA1c concentration decreased in a dose-dependent manner (trend test using contrast coefficients p<0.0001) and the reduction was significantly greater for all SYR-472 doses (p<0.0001 for each group) than for placebo. The incidence of treatment-emergent adverse events in each SYR-472 group was similar to that in the placebo group. The most common adverse event was nasopharyngitis in all groups. No episodes of hypoglycaemia defined by investigator occurred with any treatment during the study. INTERPRETATION: Once-weekly SYR-472 treatment produced clinically and statistically significant improvements in glycaemic control in patients with type 2 diabetes. It was well tolerated and might be a new treatment option for patients with this disease. FUNDING: Takeda Pharmaceutical Company Limited.