A randomised, controlled single and multiple ascending dose trial of the safety, pharmacokinetics and pharmacodynamics of SN1011 in healthy subjects

• Published in: Clinical and translational science Vol. 16; no. 10; pp. 1982 - 1996
• Main Authors: Zhu, Leilei, Shi, Rong, Zhao, Tongfang, Ye, Yujie, Tang, Jie, Hu, Yihui, Peng, Peng, Wang, Dong, Chong, Clement, Xu, Guolin, Leung, Shui-On, Yuan, Wei'an
• Format: Journal Article
• Language: English
• Published: United States John Wiley & Sons, Inc 01.10.2023; John Wiley and Sons Inc; Wiley
• Subjects: Adverse events; Autoimmune diseases; Bruton's tyrosine kinase; Chemical bonds; Cytokines; Food; Kinases; Leukocytes (neutrophilic); Monocytes; Peripheral blood; Pharmacodynamics; Pharmacokinetics; Placebos; Protein-tyrosine kinase; Safety; Triglycerides; Vital signs
• ISSN: 1752-8054; 1752-8062
• DOI: 10.1111/cts.13606

To investigate the safety, tolerability, pharmacokinetics, and pharmacodynamics of SN1011, a novel Bruton tyrosine kinase (BTK) inhibitor, and food effects in healthy subjects. In this phase I trial, subjects received single ascending doses (SAD) of SN1011 (100 to 800 mg), multiple ascending doses (MAD) of SN1011 (200 to 600 mg) or placebo QD. Additionally, 12 subjects randomly received a single dose of SN1011 600 mg under fasting states and then fed states, vice versa. Safety was assessed per CTCAE v5.0. Pharmacokinetics parameters were calculated by non-compartmental analysis and BTK receptor occupancy in peripheral blood monocytes was determined. Seventy-one healthy subjects were dosed in 5 SAD cohorts, 3 MAD cohorts and one food effect cohort, with 57 receiving SN1011 and 14 receiving placebo. No serious adverse events (AEs) were reported. There was no correlation between AE occurrences and SN1011 exposure. The three most frequent AEs with SN1011 were increased blood triglycerides, decreased neutrophil count, and decreased leucocyte count. SN1011 exhibited a dose-proportional increase in C and AUC following single and multiple dose administrations, with an accumulation ratio of 1.5 to 2.2 after multiple dose administrations. No difference in SN1011 exposure was observed between fed states. BTK receptor occupancy remained above 83% over 24 h after single administration and remained above 80% for the MAD groups for 10 days of continuous QD administration. SN1011 was well tolerated and safe after single or multiple exposures to healthy subjects, supporting further clinical development of SN1011 for treatment of autoimmune diseases.