Randomized, double-blinded, placebo-controlled phase I study of the pharmacokinetics, pharmacodynamics, and safety of KL130008, a novel oral JAK inhibitor, in healthy subjects
Na Li, Shuangqing Du, Ying Wang, Xiaohong Zhu, Shiqing Shu, Yuchun Men, Miao He, Fang Fang, Yongsheng Wang, Yimou Gong, Jing Chen, Liling Gu, Yezhe Cheng, Qiang He, Huifang Lu, Yuanyuan Niu, Ying Xu, Ping Feng
Abstract
BACKGROUND AND OBJECTIVES: KL130008 is a novel selective inhibitor of Janus kinase (JAK) 1/2 that may have therapeutic benefit against rheumatoid arthritis (RA) and other autoimmune diseases. Here, we developed a first-in-human trial of KL130008 to evaluate its pharmacokinetics (PK), pharmacodynamics (PD), and safety in healthy subjects. METHODS: Randomized, double-blinded, placebo-controlled phase I study was designed. Healthy Chinese subjects received KL130008 in single-ascending doses (1-20 mg) or multiple-ascending doses (2-6 mg) once daily for seven days, and data on PK, PD, and safety data including QT interval were evaluated. RESULTS: = 14-18 h, and 8-20% of KL130008 was excreted in the urine. Dose-dependent inhibition of the phosphorylated signal transduction and transcriptional activator 3 (p-STAT3) was observed in subjects who received single KL130008 doses of 4-20 mg, while multiple dosing of KL130008 at 2, 4, or 6 mg once daily for seven consecutive days sustainably inhibited p-STAT3. The rates of treatment-emergent adverse events were 88.7% with KL130008 and 81.3% with placebo. All such events were grade 1 or 2 and disappeared or resolved by the end of the study. The most frequent such events were a decrease in neutrophil percentage, which occurred in 30.6% of subjects on KL130008; a decrease in neutrophil count, which occurred in 29.0% of subjects on KL130008; and an increase in lymphocyte percentage, which occurred in 25.8% of subjects on KL130008. None of these three events occurred while subjects were on placebo. CONCLUSION: Our results support that KL130008 is a safe and well-tolerated oral JAK1/2 inhibitor. The present study may help optimize the KL130008 dosing regimen for a phase II study. CLINICAL TRIAL REGISTRATION NUMBER: ChiCTR1800018743 (chictr.org); registered on October 7, 2018.