Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of the MK2 Inhibitor ATI-450 in Healthy Subjects: A Placebo-Controlled, Randomized Phase 1 Study

Figures & data

Table 1 Summary of Demographic Characteristics

	Single Ascending Dose Group						Multiple Ascending Dose Group
	Placebo (n=8)	ATI-450				Overall (N=32)	Placebo (n=6)	ATI-450			Overall (N=30)
		10 mg (n=6)	30 mg (n=6)	50 mg (n=6)	100 mg (n=6)			10 mg BID (n=8)	30 mg BID (n=8)	50 mg BID (n=8)
Sex, n (%)
Female	6 (75.0)	5 (83.3)	6 (100.0)	5 (83.3)	5 (83.3)	27 (84.4)	3 (50.0)	5 (62.5)	4 (50.0)	5 (62.5)	17 (56.7)
Male	2 (25.0)	1 (16.7)	0	1 (16.7)	1 (16.7)	5 (15.6)	3 (50.0)	3 (37.5)	4 (50.0)	3 (37.5)	13 (43.3)
Race, n (%)
White	3 (37.5)	2 (33.3)	3 (50.0)	4 (66.7)	3 (50.0)	15 (46.9)	4 (66.7)	3 (37.5)	6 (75.0)	2 (25.0)	15 (50.0)
Black	4 (50.0)	3 (50.0)	3 (50.0)	1 (16.7)	3 (50.0)	14 (43.8)	2 (33.3)	4 (50.0)	2 (25.0)	5 (62.5)	13 (43.3)
Other	1 (12.5)	1 (16.7)	0	1 (16.7)	0	3 (9.4)	0	1 (12.5)	0	1 (12.5)	2 (6.7)
Ethnicity, n (%)
Hispanic or Latino	0	1 (16.7)	0	2 (33.3)	1 (16.7)	4 (12.5)	0	0	2 (25.0)	0	2 (6.7)
Not Hispanic or Latino	8 (100.0)	5 (83.3)	6 (100.0)	4 (66.7)	5 (83.3)	28 (87.5)	6 (100.0)	8 (100.0)	6 (75.0)	8 (100.0)	28 (93.3)
Age, y, mean ± SD	37.0 ± 7.5	32.2 ± 13.7	28.7 ± 8.8	25.2 ± 4.0	31.2 ± 3.7	31.2 ± 8.8	35.2 ± 6.9	36.3 ± 7.8	37.9 ± 8.0	37.9 ± 9.0	36.9 ± 7.7
Weight, kg, mean ± SD	76.4 ± 9.9	75.2 ± 16.8	72.8 ± 8.4	71.3 ± 8.2	61.5 ± 6.2	71.8 ± 11.2	79.7 ± 17.4	72.7 ± 10.7	77.2 ± 14.4	75.9 ± 9.1	76.1 ± 12.5
Height, cm, mean ± SD	166.1 ± 5.9	172.5 ± 10.5	159.5 ± 10.0	163.8 ± 6.9	165.0 ± 8.6	165.4 ± 8.9	170.7 ± 7.2	166.6 ± 7.1	168.1 ± 9.6	170.3 ± 10.5	168.8 ± 8.5
BMI, kg/m^2, mean ± SD	27.6 ± 2.6	25.1 ± 4.2	28.6 ± 2.1	26.6 ± 2.3	22.6 ± 1.1	26.2 ± 3.3	27.1 ± 4.4	26.2 ± 3.9	27.1 ± 2.5	26.3 ± 3.7	26.7 ± 3.5

Abbreviations: BID, twice daily; BMI, body mass index.

Table 2 Summary of Treatment-Emergent Adverse Events (TEAEs), Safety Set

Summary of Adverse Events in the SAD and MAD Cohorts
Safety Parameter	SAD Cohort		MAD Cohort
	ATI-450 (n=24)	Placebo (n=8)	ATI-450 (n=24)	Placebo (n=6)
Number of TEAEs	15	6	24	3
Patients reporting TEAEs, n (%)	7 (29.2)	4 (50.0)	12 (50.0)	3 (50.0)
Patients with treatment-related TEAEs, n (%)	4 (16.7)	0	9 (37.5)	2 (33.3)
Serious TEAEs	0	0	0	0
Discontinuations due to TEAEs	0	0	0	0
Deaths	0	0	0	0
Most Common TEAEs Occurring in 2 or More Subjects
TEAE	ATI-450, n (%) (n=48)		Placebo, n (%) (n=14)
Dizziness	6 (12.5)		0
Headache	10 (20.8)		2 (14.3)
Upper respiratory tract infection	3 (6.3)		1 (7.1)
Constipation	3 (6.3)		1 (7.1)
Nausea	2 (4.2)		1 (7.1)
Abdominal pain	2 (4.2)		0
Vomiting	0		2 (14.3)

Abbreviations: MAD, multiple ascending dose; SAD, single ascending dose.

Figure 1 Mean (SD) plasma concentration–time profiles of ATI-450 after a single dose under fasted conditions, semi-log scale. Hour 0 is the pre-dose value.

Table 3 ATI-450 Pharmacokinetic Parameters

Parameter	Single Ascending Dose Group				Multiple Ascending Dose Group
	ATI-450 10 mg (n=6)	ATI-450 30 mg (n=6)^a	ATI-450 50 mg (n=6)	ATI-450 100 mg (n=6)	ATI-450 10 mg BID (n=8)	ATI-450 30 mg BID (n=8)	ATI-450 50 mg BID (n=8)
Cmax, ng/mL	39.4 ± 10.4	122.0 ± 33.4	160.7 ± 20.4	426.0 ± 110.6	51.8 ± 15.8	146.5 ± 33.6	219.0 ± 77.8
tmax, h^b	2.0 (2.0–4.0)	4.0 (2.0–4.1)	3.0 (2.0–4.0)	2.0 (2.0–4.0)	2.0 (2.0–2.0)	2.0 (1.0–4.0)	3.0 (1.0–4.0)
AUC0-t, h*ng/mL	276.3 ± 77.8	1074.0 ± 243.5^a	1430.0 ± 254.0	3489.8 ± 475.7	364.6 ± 110.7	1204.6 ± 309.1	2260.3 ± 1074.7
AUC0-inf, h*ng/mL	285.3 ± 78.4	1102.4 ± 247.4^a	1464.7 ± 269.5	3654.8 ± 522.9	N/A	N/A	N/A
AUCtau, h*ng/mL	N/A	N/A	N/A	N/A	287.8 ± 81.5	908.9 ± 163.1	1507.8 ± 659.9
t1/2, h	8.5 ± 3.2	10.7 ± 3.3^a	9.1 ± 2.4	11.2 ± 5.8	9.6 ± 2.1	10.3 ± 3.2	11.6 ± 3.7
CL/F or CLss/F,^c L/h	37.0 ± 8.8	28.4 ± 7.1^a	35.1 ± 6.3	27.9 ± 4.3	37.4 ± 10.9	33.9 ± 5.9	37.3 ± 11.7
Vz/F or Vss/F,^c L	430.2 ± 124.0	451.4 ± 201.5^a	445.0 ± 94.7	439.8 ± 189.7	517.4 ± 203.2	483.1 ± 85.1	586.4 ± 163.2
Ctrough, ng/mL^d
Day 2	N/A	N/A	N/A	N/A	10.1 ± 4.7	37.5 ± 18.8	84.0 ± 40.6
Day 3	N/A	N/A	N/A	N/A	9.8 ± 4.5	44.1 ± 29.3	80.6 ± 44.2
Day 4	N/A	N/A	N/A	N/A	9.2 ± 5.0	36.8 ± 14.9	81.5 ± 49.6
Day 5	N/A	N/A	N/A	N/A	9.6 ± 4.7	34.9 ± 13.8	81.5 ± 43.9
Day 6	N/A	N/A	N/A	N/A	10.7 ± 4.9	38.9 ± 16.2	76.4 ± 38.6
Cmin, ng/mL	N/A	N/A	N/A	N/A	8.1 ± 3.1	28.8 ± 10.7	58.7 ± 32.8
Cavg, ng/mL	N/A	N/A	N/A	N/A	24.0 ± 6.8	75.6 ± 13.4	125.6 ± 55.0
Rac, Cmax	N/A	N/A	N/A	N/A	1.6 ± 0.6	1.2 ± 0.3	1.3 ± 0.5
Rac, AUCtau	N/A	N/A	N/A	N/A	1.4 ± 0.3	1.4 ± 0.3	1.3 ± 0.4

Notes: Data presented are means ± SD unless otherwise indicated. ^aOne subject was excluded for AUC_0-t, AUC_0-inf, t_1/2, CL/F, and V_z/F measurements due to withdrawn consent. No samples were collected past 12 hours. ^bData presented are medians (ranges). ^cValues for CL/F and Vz/F are for single doses and values for CL_ss/F and V_ss/F are for multiple doses. ^dC_trough values are presented for day 2 through day 6 for the MAD cohorts.

Abbreviations: AUC_0-inf, area under the plasma concentration–time curve from time 0 to time infinity; AUC_0-t, area under the plasma concentration–time curve from time 0 to time t; AUC_tau, area under the plasma concentration–time curve over the 12-hour dosing interval, tau; BID, twice daily; CL/F, clearance; CL_ss/F, clearance at steady state; C_avg, average plasma concentration after multiple dosing, on day 7; C_max, maximum plasma concentration; C_min, minimum plasma concentration; C_trough, measured concentration at the end of a dosing interval; N/A, not applicable; R_ac, AUC_tau, accumulation ratio for AUC_tau; R_ac, C_max, accumulation ratio for C_max; t_1/2, terminal elimination half-life; t_max, time to maximum plasma concentration; V_ss/F, volume of distribution at steady state; V_z/F, volume of distribution.

Figure 2 Mean (SD) plasma concentration–time profiles of ATI-450 after 7 days of BID dosing under fasted conditions, semi-log scale. Hour 0 is the pre-dose value.

Abbreviation: BID, twice daily.

Figure 3 Mean (± SEM) cytokine and biomarker levels for (A) TNF-α, (B) IL-1β, (C) IL-6, (D) IL-8, and (E) p-HSP27 in the BID dosing cohorts comparing day 1 pre-dose values (set to 100%) with day 7 values 4 hours post-dose (approximate C_max) and 12 hours post-dose (C_trough).

Abbreviations: BID, twice daily; C_max, maximum observed plasma concentration; C_trough, measured concentration at the end of a dosing interval; IL, interleukin; p-HSP27, phosphorylated heat shock protein 27; TNF, tumor necrosis factor.

Table 4 Cytokine and Biomarker IC₈₀ Values and Multiples Across the Dosing Interval in the 50 mg BID Dose Cohort

Biomarker	IC80^a (ng/mL)	Ctrough^b (Multiple of IC80)	Cmax^b (Multiple of IC80)
p-HSP27	36.7	2.4x	6.0x
TNF-α	62.6	1.4x	3.5x
IL-1β	40.8	2.2x	5.4x
IL-6	747.8	0.1x	0.3x
IL-8	38.8	2.3x	5.6x

Notes: ^aIC₈₀ values generated from combined SAD and MAD ATI-450 concentrations and ex vivo inhibition data using the WinNonlin inhibitory E_max model 104. ^bValues are from 50 mg BID MAD cohort on day 7; C_trough = 87.9 ng/mL and C_max = 219.0 ng/mL.

Abbreviations: BID, twice daily; C_max, maximum observed plasma concentration; C_trough, measured concentration at the end of a dosing interval; IC₈₀, concentration for 80% of maximal inhibition; IL, interleukin; MAD, multiple ascending dose; p-HSP27, phosphorylated heat shock protein 27; SAD, single ascending dose; TNF-α, tumor necrosis factor α.