Results

Demographics

In the single-dose arm, a total of 61 subjects were enrolled, and 60 subjects completed the study. The mean (± standard deviation) age, body weight and BMI of the randomized subjects were 30.75 ± 6.89 years, 71.06 ± 7.48 kg, and 23.43 ± 2.06 kg/m2, respectively.
In the multiple-dose arm, 62 subjects were enrolled, and 60 subjects completed the study. The mean (± standard deviation) age, body weight and BMI of the randomized subjects were 30.84 ± 5.43 years, 70.72 ± 7.15 kg, and 23.47 ± 2.07 kg/m2, respectively. The demographic characteristics were comparable among the dose groups for both single and multiple arms.

Pharmacodynamics

In the single dose arm, UGE0-24h and UGElast increased in a dose-dependent manner in the range of 0.2 to 1.0 mg. UGE0-24h tended to be saturated in the range of 1.0 mg to 5.0 mg of DWP16001, which was similar to that of dapagliflozin 10 mg. Meanwhile, UGElast was higher over 1.0 mg of DWP16001 than that of dapagliflozin (Figure 1,2 Table 1).
In the multiple dose arm, daily UGE reached a plateau at 50 - 60 g/day at the steady state. The UGE was higher with all doses of DWP16001 and dapagliflozin 10 mg compared with placebo (Table S1). The mean UGE over 24 hours at steady state of 0.1 mg, 0.3 mg, 0.5 mg, 1.0 mg, and 2.0 mg DWP16001 were 36.1 g, 48.3 g, 55.1 g, 56.8 g, and 53.4 g, respectively, and the corresponding value of dapagliflozin 10 mg was 40.5 g (Figure 1,2, Table 1).
In the OGTT after dosing for 14 consecutive days of DWP16001, the Emax of the plasma glucose was lower than that of baseline. The mean Emax changed from baseline of 0.1 mg, 0.3 mg, 0.5 mg, 1.0 mg and 2.0 mg DWP16001 were -27.5, -32.8, -7.8, -23.9 and -17.4 mg/dL, respectively. These values were different from -2.2 mg/dL of placebo, but similar to -21.6 mg/dL of dapagliflozin 10 mg. A similar pattern was observed for AUEC0-4h after OGTT. The mean AUEC0-4h changed from baseline was positive in placebo (4.3 mg*h/dL) , whereas 0.1 mg, 0.3 mg, 0.5 mg, 1.0 mg, 2.0 mg DWP16001 were -46.8, -55.6, -40.1, -54.0 and -21.9 mg*h/dL, respectively. Postprandial insulin showed a decreasing tendency after multiple doses, but it was not statistically significant (Figure S1, Table S2).

Pharmacokinetics

DWP16001 was rapidly absorbed after a single dose with Tmax between 1 and 3 h post-dose. After reached a Tmax, plasma concentration of DWP16001 fell in a biphasic manner with the elimination half-life of 11 to 28 hours (Figure 3). The t1/2 was tended to decrease as the dose of DWP16001 increased (Table 2).
After multiple doses, the time-plasma concentration was similar to that of the single-dose arm. The mean Tmax and t1/2 at steady state were within a range of 1 to 2 hours and 17 to 23 hours, respectively. After multiple administrations, the 95% CIs of the slope of the log-transformed Cmax,ss and AUCtau,ss included 1.0 (0.98–1.10 and 0.98–1.09, respectively), thus considered dose-proportional. The mean accumulation index was approximately 1.6 to 1.9 over the range of 0.1 mg to 2.0 mg of DWP16001. Less than 3 % of DWP16001 was excreted unchanged in the urine at all doses (Table 2). The metabolic ratio of M1 ranged from 0.20 to 0.25. M2 was detected in very low amounts compared to the parent molecules in all dose groups (Table S3).

PK-PD relationship

Drug exposure and UGE showed a clear exposure-response relationship. The AUCtau and UGE over 24 h after the last dose were correlated, with a Spearman correlation coefficient of 0.4061 (p=0.0002). The PK-PD relationship was well-explained by a sigmoid Emax model, and the E0, Emax, EC50, EC90, and γ were calculated to be 0.1 g, 58.8 g, 31.8 μg·h/L, 58.4 μg·h/L, and 3.6, respectively (Figure 4).

Effect of Food

After a high-fat meal was provided, the median Tmax was prolonged from 1.3 to 2.5 hours, and the Cmax was decreased approximately 43 % (GMR [90% CIs]: 0.57 [0.45–0.72]), compared to that of fasting state (Figure 5). However, the AUCinf was similar between fed and fasting state (GMR [90% CIs]: 0.97 [0.82–1.16]). The UGE was comparable between fed and fasting state; GMR [90% CIs] of UGE0-24h and UGElast were 0.80 [0.66–0.97] and 0.90 [0.68–1.19], respectively.

Safety and Tolerability

DWP16001 was found to be safe and tolerable in all dose groups, both in single- and multiple-dose administration. In the single-dose arm, treatment-emergent adverse events (TEAEs) were reported in 12 cases by 5 subjects who received DWP16001. In the multiple-dose arm, 27 cases were reported in 13 subjects who received DWP16001, and four cases were reported in three subjects who received placebo. Adverse drug reactions (ADRs) that were determined to have a causal relationship with the investigational product were reported in two cases from one subject in the single-dose group and 22 cases from 12 subjects in the multiple-dose group (Table 3). The most frequently reported ADRs were abdominal pain, headache, and rhinorrhea. Abdominal pain was reported by three subjects (1 in the 0.1 mg group and 2 in the 1.0 mg group). All TEAEs were mild and spontaneously resolved. There were no serious adverse events, and no subject withdrew from the study owing to adverse events. No other clinically significant changes were observed in the clinical laboratory tests, vital signs, ECGs, or physical examinations.
Renal tubular marker [N-acetyl-β-D-glucosaminidase (NAG) and β2-microglobulin (B2M)] tests were conducted in the multiple-dose arm. Only one subject (DWP16001 2.0 mg group) had an increased B2M by more than 0.5 µg/mL compared to the baseline, but it was found to be closer to the baseline level in a post-study visit. The mean change in NAG and B2M concentrations showed no significant increase across the different dose groups (Table S4).