KL130008

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.

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.

A total of 79 subjects were enrolled, of whom 77 completed the study. After oral administration following at least a 10-h fast, KL130008 was rapidly absorbed and reached a maximum concentration (C_max) in 0.6-1.5 h. KL130008 exposure was approximately linear and dose-proportional. The drug showed exponential elimination with t_1/2 = 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.

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.

ChiCTR1800018743 (chictr.org); registered on October 7, 2018.