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Background: Janagliflozin is a novel sodium–glucose cotransport-2 inhibitor. Despite its remarkable effect in glycemic control, no systematic research has evaluated the effect of renal impairment (RI) on its pharmacokinetics and pharmacodynamics. Methods: Here, patients with T2DM (n = 30) were divided into normal renal function (eGFR ≥ 90 mL/min/1.73 m2), mild RI (eGFR between 60 and 89 mL/min/1.73 m2), moderate RI-I (eGFR between 45 and 59 mL/min/1.73 m2), and moderate RI-II (eGFR between 30 and 44 mL/min/1.73 m2) groups. They were administered 50 mg janagliflozin orally, and plasma and urine samples were collected for the determination of janagliflozin concentration. Results: Following oral administration, janagliflozin was rapidly absorbed, with the time to Cmax of 2–6 h for janagliflozin and 3–6 h for its metabolite XZP-5185. Plasma exposure levels were similar for janagliflozin in T2DM patients with or without RI but decreased for the metabolite XZP-5185 in T2DM patients with eGFR between 45 and 89 mL/min/1.73 m2. Janagliflozin significantly promoted the excretion of urinary glucose, even in patients with reduced eGFR. Janagliflozin was well tolerated in patients with T2DM with or without RI, and no serious adverse events (SAEs) occurred during this trial. Conclusions: The exposure levels of janagliflozin in T2DM patients were slightly increased with worsening of RI (i.e., 11% increase in the AUC in patients with moderate RI compared with the normal renal function group). Despite worsening of renal function, janagliflozin exerted a significant pharmacologic effect and was well tolerated, even in patients with moderate RI, implying a promising role in the treatment of patients with in T2DM. Registration: China Drug Trial register (http://www.chinadrugtrials.org.cn/I) identifier no.: CTR20192721. [ABSTRACT FROM AUTHOR]

Aims: To evaluate the efficacy and safety of janagliflozin, a selective renal sodium‐glucose cotransporter‐2 inhibitor, as monotherapy in drug‐naive Chinese patients with type 2 diabetes mellitus (T2DM). Materials and methods: This Phase 3 trial included a 24‐week, multicentre, randomized, double‐blind, placebo‐controlled period, followed by a 28‐week extension period. A total of 432 patients with glycated haemoglobin (HbA1c) levels ≥7.0% (53 mmol/mol) and ≤10.5% (91 mmol/mol) were randomized (1:1:1) to receive once‐daily placebo, 25 mg or 50 mg janagliflozin. After 24 weeks, patients on placebo were switched and re‐randomized (1:1) to 25 mg or 50 mg janagliflozin, whereas patients on janagliflozin maintained the initial therapy. The primary endpoint was change from baseline in HbA1c after 24 weeks. Results: At Week 24, the placebo‐adjusted least squares mean changes in HbA1c were −0.80% (95% confidence interval [CI] −0.98% to −0.62%)/−8.7 mmol/mol (95% CI −10.7 mmol/mol to −6.8 mmol/mol) and −0.88% (95% CI −1.06% to −0.70%)/−9.6 mmol/mol (95% CI −11.6 mmol/mol to −7.7 mmol/mol), respectively (P < 0.001 for both). A higher proportion of patients achieved HbA1c <7.0% (53 mmol/mol) with janagliflozin 25 mg and janagliflozin 50 mg compared with placebo (47.2%, 49.3%, and 23.5%, respectively). Both janagliflozin doses significantly decreased fasting plasma glucose, 2‐hour postprandial glucose, body weight and systolic blood pressure, as well as increased high‐density lipoprotein (HDL) cholesterol and insulin sensitivity compared with placebo (P < 0.05 for all). The trends in improvement of these variables were sustained during the 28‐week extension period. Overall incidences of adverse events were 67.8%, 71.5% and 60.7% with janagliflozin 25 mg, janagliflozin 50 mg and placebo, respectively. The incidence of urinary tract infections and genital fungal infections was low. No severe hypoglycaemia or ketoacidosis occurred. Conclusions: Janagliflozin 25 mg and 50 mg monotherapy once‐daily effectively improved glycaemic control, reduced body weight and blood pressure, improved HDL cholesterol and insulin sensitivity, and was generally well tolerated. [ABSTRACT FROM AUTHOR]

Aim: To apply model-informed drug development (MIDD) approach to support the decision making in drug development and accelerate the clinical development of janagliflozin, an orally selective SGLT2 inhibitor. Method: We previously developed a mechanistic pharmacokinetic/pharmacodynamic (PK/PD) model of janagliflozin based on preclinical data to optimize dose design in the first-in-human (FIH) study. In the current study, we used clinical PK/PD data of the FIH study to validate the model and then simulate the PK/PD profiles of multiple ascending dosing (MAD) study in healthy subjects. Besides, we developed a population PK/PD model of janagliflozin to predict steady-state urinary glucose excretion (UGE [UGE,ss]) in healthy subjects in the Phase 1 stage. This model was subsequently used to simulate the UGE, ss in patients with type 2 diabetes mellitus (T2DM) based on a unified PD target (ΔUGEc) across healthy subjects and patients with T2DM. This unified PD target was estimated from our previous work of model-based meta-analysis (MBMA) for the same class of drugs. The model-simulated UGE,ss in patients with T2DM was validated by data from the clinical Phase 1e study. Finally, at the end of the Phase 1 study, we simulated the 24-week hemoglobin A1c (HbA1c) level in patients with T2DM of janagliflozin based on the quantitative UGE/FPG/HbA1c relationship informed by our previous MBMA study for the same class of drugs. Results: The pharmacologically active dose (PAD) levels of multiple ascending dosing (MAD) study were estimated to be 25, 50,100 mg once daily (QD) for 14 days based on the effective PD target of approximately 50 g daily UGE in healthy subjects. Besides, our previous MBMA analysis for the same class of drugs has provided a unified effective PD target of ΔUGEc approximately 0.5–0.6 g/(mg/dL) in both healthy subjects and patients with T2DM. In this study, the model-simulated steady-state ΔUGEc (ΔUGEc,ss) of janagliflozin in patients with T2DM were 0.52, 0.61 and 0.66 g/(mg/dL) for 25, 50, 100 mg QD dose levels. Finally, we estimated that HbA1c at 24 weeks would decrease 0.78 and 0.93 from baseline for the 25 and 50 mg QD dose groups. Conclusions: The application of MIDD strategy adequately supported the decision making at each stage of janagliflozin development process. A waiver of Phase 2 study was successfully approved for janagliflozin based on these model-informed results and suggestions. This MIDD strategy of janagliflozin could be further utilized to support the clinical development of other SGLT2 inhibitors. [ABSTRACT FROM AUTHOR]

Aim: To evaluate the efficacy and safety of janagliflozin in Chinese patients with type 2 diabetes (T2D) inadequately controlled with metformin monotherapy. Materials and methods: This multicentre phase 3 trial included a 24‐week, randomized, double‐blind, placebo‐controlled period, followed by a 28‐week extension period. Patients (N = 421) with HbA1c of 7.0% or higher and 10.5% or less were randomized (1:1:1) to receive once‐daily placebo, janagliflozin 25 or 50 mg. After the 24‐week treatment period, patients on placebo were re‐randomized (1:1) to janagliflozin 25 or 50 mg for the additional 28‐week treatment, whereas patients on janagliflozin maintained the same therapy. The primary endpoint was the change from baseline in HbA1c to week 24. Results: At week 24, the placebo‐adjusted least squares mean changes of HbA1c were –0.58% and –0.58% with janagliflozin 25 and 50 mg, respectively (P <.0001 for both). The proportion of patients achieving HbA1c less than 7.0% was higher with janagliflozin 25 and 50 mg compared with placebo (41.8%, 41.7% and 28.0%, respectively). Both janagliflozin doses provided significant reductions in fasting plasma glucose, 2‐hour postprandial glucose, body weight and systolic blood pressure, and improvements in high‐density lipoprotein cholesterol and insulin sensitivity compared with placebo (P <.05 for all). The trends in improvement of these variables were retained during the 28‐week extension period. No severe hypoglycaemia occurred throughout the whole 52‐week treatment. Conclusions: Janagliflozin 25 or 50 mg once‐daily added to metformin therapy significantly improved glycaemic control, reduced body weight and systolic blood pressure, improved high‐density lipoprotein cholesterol and insulin sensitivity, and was generally well‐tolerated by Chinese T2D patients who had poor glycaemic control with metformin monotherapy. [ABSTRACT FROM AUTHOR]