Safety, Tolerability, and Pharmacokinetics of Mirikizumab in Chinese Healthy Subjects: Results From a Phase 1 Study

Introduction: Mirikizumab (Miri) is being developed for the treatment of immune-mediated diseases involving the IL-23 pathway, such as ulcerative colitis and Crohn’s disease. The analyses aim to evaluate the safety, tolerability, and pharmacokinetics (PK) of Miri after a single dose in Chinese healthy adults. Methods: This study (NCT04137380) is a randomized, subject and investigator blinded, placebo-controlled, phase 1 single-dose study. The study consisted of 5 planned dose cohorts: 3 intravenous (IV) dose cohorts (300, 600, and 1200 mg) and 2 subcutaneous (SC) dose cohorts (200 and 400 mg). Subjects were randomized within each cohort to receive Miri (10 subjects) or placebo (2 subjects). The primary objective is to assess the safety and tolerability of single Miri doses in Chinese healthy subjects. Frequencies of treatment-emergent adverse events (TEAEs) were summarized by treatment and visual analog scale (VAS) pain scores were summarized and plotted by time point. The secondary objective is to evaluate the PK of single Miri doses in Chinese healthy subjects. The PK parameters were calculated by standard noncompartmental methods of analysis and summarized by treatment. Results: Sixty subjects were enrolled in the study and 59 completed the study. One subject was discontinued due to physician decision as she was pregnant. Overall, 28 (56.0%) subjects who received Miri reported 49 TEAEs and 8 (80.0%) subjects who received placebo reported 18 TEAEs during the study. The majority of TEAEs were mild in severity. No death or serious adverse events occurred during the study. No injection site reaction TEAEs were reported in SC treatment groups. The distribution of VAS pain scores was similar across the SC treatment including placebo. Following IV doses of 300 to 1200 mg Miri, the geometric mean of both AUC(0-∞) and Cmax increased by approximately 3.5-fold, suggesting linear PK over IV dose range, and the geometric mean t1/2 ranged from 9.53 to 11.9 days. Following SC doses of 200 and 400 mg Miri, the median tmax was 2.98 days and the geometric mean t1/2 was 10.6 and 10.4 days, respectively. The geometric mean of both AUC(0-∞) and Cmax increased by approximately 1.6-fold, suggesting linear PK over SC dose range. Absolute bioavailability based on pooled IV and SC data was 38.2% (Table 1). Conclusion: Intravenous doses of Miri up to 1200 mg and SC doses up to 400 mg were well tolerated by Chinese healthy subjects, and the PK profile in Chinese subjects was comparable with that observed in the Caucasian population. Table 1. - Summary of Pharmacokinetic Parameters of Mirikizumab Following Intravenous or Subcutaneous Administration to Chinese Healthy Subjects Intravenous Parameter 300 mg (N=10) 600 mg (N=10) 1200 mg (N=10) n Geometric mean (Geometric CV%) n Geometric mean (Geometric CV%) n Geometric mean (Geometric CV%) AUC(0-tlast) (ug.day/mL) 5 964 (15%) 10 2010 (12%) 9 3300 (24%) AUC(0-∞) (ug.day/mL) 10 936 (12%) 10 2030 (12%) 10 3320 (23%) %AUC(tlast-∞) (%) 10 2.02 (553%) 10 0.547 (133%) 10 0.422 (299%) Cmax (ug/mL) 10 145 (6%) 10 266 (16%) 10 511 (10%) tmax (day)# 10 0.03 (0.03-0.25) 10 0.05 (0.05-0.06) 10 0.10 (0.09-0.10) t½ (day)* 10 9.53 (7.73-11.7) 10 11.9 (9.26-15.0) 10 10.4 (8.18-15.9) CL (L/day) 10 0.321 (12%) 10 0.296 (12%) 10 0.361 (23%) Vz (L) 10 4.41 (14%) 10 5.07 (17%) 10 5.41 (13%) Vss (L) 10 3.98 (12%) 10 4.38 (14%) 10 4.43 (13%) Subcutaneous Parameter 200 mg (N=10) 400 mg (N=10) n Geometric mean (Geometric CV%) n Geometric mean (Geometric CV%) AUC(0-tlast) (ug.day/mL) 7 248 (34%) 10 417 (46%) AUC(0-∞) (ug.day/mL) 10 263 (29%) 10 421 (46%) %AUC(tlast-∞) (%) 10 1.93 (139%) 10 0.779 (52%) Cmax (ug/mL) 10 14.9 (28%) 10 23.1 (44%) tmax (day)# 10 2.98 (2.97-6.95) 10 2.98 (2.97-7.04) t½ (day)* 10 10.6 (9.16-12.0) 10 10.4 (8.44-11.9) CL/F (L/day) 10 0.759 (29%) 10 0.951 (46%) Vz/F (L) 10 11.6 (25%) 10 14.2 (39%) Vss/F (L) 10 301 (27%) 10 377 (42%) F (%)† 10 42.8 10 34.2 Abbreviations: %AUC(tlast-∞) = percentage of AUC(0-∞) extrapolated; AUC(0-∞) = area under the concentration vs time curve from time zero to infinity; AUC(0-tlast) = area under the concentration vs time curve from time zero to time t, where t is the last time point with a measurable concentration; CL = total body clearance of drug calculated after intravenous administration; CL/F = total body clearance of drug calculated after extravascular administration; Cmax = maximum observed drug concentration; CV = coefficient of variation; F = absolute bioavailability; N = number of subjects; n = number of observations; t1/2 = half-life associated with the terminal rate constant in noncompartmental analysis; tmax = time of maximum observed drug concentration; Vss = volume of distribution at steady state after intravenous administration; Vss/F = apparent volume of distribution at steady state after extravascular administration; Vz = volume of distribution during the terminal phase after intravenous administration; Vz/F = apparent volume of distribution during the terminal phase after extravascular administration.#Median (minimum-maximum).*Geometric mean (minimum-maximum).†The geometric mean F (pooled), the absolute bioavailability of pooled 200 mg and 400 mg subcutaneous administration treatments (n=20), is 38.2%.