PA9159 (previously named VSG159) is a structurally novel and highly potent glucocorticoid that plays a role in the late development of autoimmune and inflammatory diseases. The current first-in-human ascending-dose study of the PA9159 nasal spray was conducted in healthy Chinese volunteers to evaluate its pharmacokinetics, safety, and tolerability. In addition, the effects of PA9159 on serum cortisol secretion were investigated.This was a double-blinded, randomized, placebo-controlled clinical study that included four single-dose groups in the single ascending dose cohort (SAD) and two multiple-dose groups in the multiple ascending dose cohort (MAD), with dose ranges of 10-80 μg and 20-40 μg, respectively. PA9159 was administered bilaterally via nasal spray once only or once daily for seven days. Pharmacokinetic, safety, and tolerability profiles were evaluated.A total of 60 participants completed the study. PA9159 doses of up to 80 μg in the SAD and up to 40 μg in the MAD were shown to be safe and tolerable. The most common treatment-related AEs were mild and transient local nasal AEs. Morning serum cortisol levels approximately remained unchanged in both the single-dose and multiple-dose groups. PA9159 was quantified in 41.8% (368/880) of the samples in all treatment groups, including 25.2% (105/416) of the SAD and 56.7% (263/464) of the MAD. The majority (>80.0%) of PA9159 plasma concentrations ranged from 0.5 to 2 pg/mL in determined samples. The mean AUC0-t of PA9159 in the SAD was 0.91, 1.39±0.68, 11.40±9.91, and 46.30±25.80 h*pg/mL in the 10 to 80 ug single group. The mean terminal half-life time (t1/2) was 8.43 h and 8.97±2.28 h in 40 ug and 80 ug single group, respectively. The mean AUCss of PA9159 in the MAD was 31.70±7.04, 44.20±20.60 h*pg /mL, and the t1/2 was 16.00±4.18 h, 21.20±10.20 h in the 20 ug and 40 ug multiple groups, respectively. The median Tmax was approximately 6 hours in both the SAD and MAD cohorts.The PA9159 nasal spray was generally safe and well tolerated, and the effects of PA9159 on serum cortisol levels were limited. The plasma concentration and systemic exposure to PA9159 were very low. These findings support the necessity for further clinical studies on PA9159 nasal spray in patients suffering from allergic rhinitis.Copyright © 2024. Published by Elsevier B.V.