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

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 Chinese Clinical Trial Register (ChiCTR2000029360).