Placebo-controlled trial of pharmacokinetics, pharmacodynamics and tolerability of KL130008 capsule in patients with rheumatoid arthritis

作者：Yue Cheng, Xiaohong Zhu, Zhihui Liu, Ying Wang, Yuchun Men, Huifang Wang, Miao He, Man Chen, Shuangqing Du, Bingjie Wu, Yezhe Cheng, Xiaoping Jin, Junyou Ge, Hui Lin, Ping Feng · 发表于：Expert Opinion on Investigational Drugs · 年份：2025 · DOI：10.1080/13543784.2025.2599454 · 被引用次数：1 · 研究领域：Rheumatoid Arthritis Research and Therapies、Chronic Myeloid Leukemia Treatments、Interstitial Lung Diseases and Idiopathic Pulmonary Fibrosis

BACKGROUND: KL130008, a novel selective JAK1/JAK2 inhibitor demonstrated acceptable safety and tolerability in Phase I studies involving healthy volunteers. This proof-of-concept trial aimed to characterize the pharmacokinetic/pharmacodynamics relationship and preliminary efficacy of KL130008 in rheumatoid arthritis (RA) patients. RESEARCH DESIGN AND METHODS: In this randomized, double-blind, single-center trial involving 30 RA patients, 24 received oral KL130008 and 6 received placebo. Pharmacokinetics and pharmacodynamics were evaluated based on drug concentrations and on inhibition of phospho-signal transducer and activator of transcription-3 (pSTAT3). Safety and efficacy outcomes were assessed. RESULTS: Pharmacokinetics were linear over the dose from 1-4 mg; the drug showed the half-life of 14.34-18.14 h and accumulation factor of 1.27-1.76. The drug inhibited pSTAT3 with a dose-dependent trend, achieving maximal inhibition of 37.61% (1 mg), 61.28% (2 mg), and 71.87% (4 mg). The American College of Rheumatology 20 responses (≥20% improvement from baseline) were 25.0-37.5% across the dose range of 1-4 mg after two weeks of multiple dosing, higher than 16.7% for placebo. Treatment-emergent adverse events, all mild, occurred in two-thirds of patients receiving KL130008. CONCLUSION: In RA patients, oral KL130008 shows linear pharmacokinetics, pSTAT3 inhibition, and promising safety. Efficacy are exploratory given the small sample size. TRIAL REGISTRATION: Registered in the Ch...