Safety, tolerability, pharmacokinetics, and pharmacodynamics of novel glucokinase activator HMS5552: results from a first-in-human single ascending dose study

Figures & data

Table 1 Demographic and baseline characteristics

Category	HMS5552						Placebo (n=12)	Total (N=60)
	5 mg (n=8)	10 mg (n=8)	15 mg (n=8)	25 mg (n=8)	35 mg (n=8)	50 mg (n=8)
Age, years
Mean (SD)	22.9 (3.0)	23.3 (2.4)	24.3 (2.0)	26.6 (3.6)	22.0 (2.4)	24.0 (2.4)	25.8 (3.5)	24.2 (3.1)
Sex, n (%)
Male	4 (50)	4 (50)	4 (50)	4 (50)	4 (50)	5 (62.5)	6 (50)	31 (51.7)
Female	4 (50)	4 (50)	4 (50)	4 (50)	4 (50)	3 (37.5)	6 (50)	29 (48.3)
BMI, kg/m^2
Mean (SD)	21.0 (1.9)	22.7 (1.3)	21.1 (1.1)	22.5 (0.8)	22.0 (1.0)	21.8 (1.7)	20.7 (1.4)	21.6 (1.5)
FPG, mmol/L
Mean (SD)a	4.8 (0.4)	5.2 (0.2)	4.9 (0.3)	4.9 (0.4)	4.8 (0.2)	5.0 (0.2)	4.9 (0.3)	4.9 (0.3)
OGTT, mmol/L
Mean (SD)b	5.5 (1.2)	6.0 (0.9)	5.4 (0.6)	5.2 (0.7)	5.4 (1.2)	5.9 (1.2)	6.1 (0.8)	5.7 (1.0)
HbA1c, %
Mean (SD)	5.3 (0.2)	5.3 (0.3)	5.0 (0.2)	5.1 (0.5)	5.2 (0.3)	5.2 (0.2)	5.0 (0.4)	5.2 (0.3)

Notes: N, number of subjects;

a mean glucose level at baseline = (C_−0.5 + C_−0.25+ C₀)/3; C_−0.5, glucose score at 0.5 h pre-dose; C_−0.25, glucose score at 0.25 h pre-dose; C₀, glucose score before dosing on day 1.

b Mean glucose level was detected 2 hours after supplement with 75 g glucose dissolved in 300 mL water at screening.

Abbreviations: BMI, body mass index; SD, standard deviation; FPG, fasting plasma glucose; OGTT, oral glucose tolerance test; h, hour(s); HbA_1c, glycated hemoglobin.

Table 2 Adverse events following a single oral dose of HMS5552 in healthy subjects

Adverse events	HMS5552**								Total
	5 mg		15 mg		25 mg		35 mg		HMS5552		Placebo
	N (%)	n	N (%)	n	N (%)	n	N (%)	n	N (%)	n	N (%)	n
Number of subjects with any AE	1		3		2		1		7		2
Adverse events	1 (12.5)	2	3 (37.5)	3	2 (25.0)	3	1 (12.5)	2	7 (14.6)	10	2 (16.7)	5
Dizziness			1 (12.5)	1			1 (12.5)*	1	2 (4.2)	2	1 (8.3)	2
Palpitation	1 (12.5)	1			1 (12.5)*	1			2 (4.2)	2
Cold sweat							1 (12.5)*	1	1 (2.1)	1
Nausea	1 (12.5)	1							1 (2.1)	1
Dry mouth			1 (12.5)	1					1 (2.1)	1
Vomiting											1 (8.3)*	1
Belching											1 (8.3)*	1
Bulbar hyperemia											1 (8.3)	1
Urinary WBC			1 (12.5)	1	1 (12.5)	1			2 (4.2)	2
Proteinuria					1 (12.5)*	1			1 (2.1)	1

Notes: N, number of subjects; n, number of adverse events (AEs).

* Adverse event was considered to be related to HMS5552 by the blinded investigator.

** No adverse events in the 10 or 50 mg HMS5552 group.

Abbreviation: WBC, white blood cells.

Table 3 Summary of geometric mean (SD) pharmacokinetic parameters of HMS5552

Parameters	HMS5552 (N=48)a
	5 mg (n=8)	10 mg (n=8)	15 mg (n=8)	25 mg (n=8)	35 mg (n=8)	50 mg (n=8)
Cmax (ng/mL)	62.6 (11.4)	119.0 (26.9)	204.0 (41.5)	350.0 (65.2)	418.0 (68.1)	582.0 (202)
Tmax (h)b	1.75 (0.46)	2.25 (0.99)	1.50 (1.24)	2.50 (1.58)	2.00 (1.07)	1.25 (1.77)
AUC0–t (ng⋅h/mL)	405 (84.5)	857 (140)	1,261 (4,349)	2,124 (644)	2,653 (193)	3,969 (1,314)
AUC0–∞ (ng⋅h/mL)	413 (86.6)	867 (141)	1,268 (351)	2,135 (646)	2,665 (192)	3,979 (1,316)
t1/2 (h)	4.48 (1.05)	6.37 (3.08)	5.41 (1.07)	6.94 (1.16)	7.51 (3.15)	6.34 (2.11)
V/f (L)	78.3 (15.9)	106 (51.7)	92.4 (36.8)	117 (44.5)	142 (53.3)	115 (41.0)
CL/f (L/h)	12.1 (2.79)	11.5 (1.96)	11.8 (3.59)	11.7 (3.65)	13.1 (0.98)	12.6 (5.87)
Ae0–72 (mg)	0.44 (0.06)	0.79 (0.24)	1.29 (0.44)	2.07 (0.97)	3.24 (0.37)	5.24 (0.97)
fe0–72 (%)	8.85 (1.28)	7.90 (2.40)	8.57 (2.91)	8.29 (3.89)	9.25 (1.05)	10.48 (1.94)

Notes: N, total number of subjects; n, number of subjects in each group.

a Four males and four females per group except the 50 mg group (five males and three females).

b Median (SD).

Abbreviations: SD, standard deviation; C_max, maximum plasma concentration; T_max, time to reach maximum plasma concentration; AUC_0–t, area under the curve 0 to the last quantifiable concentration; AUC_0–∞, area under the curve from 0 to infinity; t_1/2, terminal elimination half-life; V/f, volume of apparent distribution during the terminal phase; CL/f, apparent total plasma clearance; Ae_0–72, amount of drug excreted in urine from 0 to 72 hours; fe_0–72, fraction of unchanged dose excreted in urine from 0 to 72 hours.

Figure 1 Mean HMS5552 plasma concentration (ng/mL) versus time after a single oral administration in healthy subjects at six different doses (n=8 per dose group).

Figure 2 HMS5552 and its major metabolites in human plasma and urine.

Notes: HMS5552 and its major metabolites in human plasma (A) and urine (B) at different time points. Time point 0~24 hours in plasma is the area under the curve pooling sample.

Figure 3 Effect of HMS5552 on mean glucose and insulin concentrations during fasting and after a standardized meal.

Notes: Effect of HMS5552 on mean glucose (A) and insulin (B) concentrations at specified times (-0.5, -0.25, 0, 0.25, 0.5, 1, 2, 3, 4, 4.25, 4.5, 5, and 6 hours [h]) after a single oral administration of HMS5552 at various doses.