A double-blind, placebo-controlled, randomized multiple dose phase 1b trial of a CDK4/6 inhibitor, TCK-276, in patients with active rheumatoid arthritis

Abstract Objective The purpose of this study was to evaluate the safety, tolerability, pharmacokinetics and efficacy (as an exploratory endpoint) of TCK-276, a novel CDK4/6 inhibitor, after multiple oral doses for 7 days in patients with active RA. Methods This multicentre, randomized, placebo-controlled, dose-ascending, double-blind, phase 1b, multiple-dose study included 32 patients with active RA in four cohorts of 8 patients (6 active and 2 matching placebo), each receiving an oral dose of TCK-276 or matching placebo for 7 days (once daily). The doses of TCK-276 were 10, 25, 75 and 175 mg/day. Safety and pharmacokinetic endpoints, and exploratory disease activity parameters for RA were assessed. Results There were no deaths, serious adverse events, notable clinically meaningful laboratory findings (including haematological changes), clinically meaningful vital sign changes or clinically meaningful ECG or cardiac telemetry changes. TCK-276 was rapidly absorbed and the half-life time ranged approximately from 6 to 12 h. No obvious accumulation was observed, and the increase in TCK-276 exposure was dose proportional. At day 7, DAS28-CRP responses (EULAR good or moderate responses) were observed in 40%, 80% and 66.7% at 25, 75 and 175 mg/day TCK-276, respectively, vs 12.5% in placebo; ACR20 responses were 33.3%, 60% and 50%, respectively, vs none in placebo. Conclusion TCK-276 (≤175 mg) was well tolerated with no clinically meaningful safety signals in patients with active RA. Together with the preliminary efficacy (≥25 mg/day), these data warrant further study of TCK-276 for the treatment of active RA. Trial registration ClinicalTrails.gov, NCT05437419.