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.