一项针对活动性类风湿关节炎患者的CDK4/6抑制剂TCK-276的双盲、安慰剂对照、随机多剂量1b期试验。

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

作者信息

Tasaki Daisuke, Tsuruda Kazuoki, Sun Shosho, Tsumura Yoshinori, Asano Satoshi, Suzuki Yuki, Tsujimoto Shunsuke, Miura Daishiro, Sato Hiroaki

机构信息

Global Development Department, Teijin Pharma Limited, Tokyo, Japan.

Teijin America, Inc., Sausalito, CA, USA.

出版信息

Rheumatology (Oxford). 2025 Mar 1;64(3):1036-1044. doi: 10.1093/rheumatology/keae357.

DOI:10.1093/rheumatology/keae357

PMID:39002122

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.

摘要

目的

本研究旨在评估新型细胞周期蛋白依赖性激酶4/6（CDK4/6）抑制剂TCK-276在活动性类风湿关节炎（RA）患者中多次口服给药7天后的安全性、耐受性、药代动力学及疗效（作为探索性终点）。

方法

本多中心、随机、安慰剂对照、剂量递增、双盲、1b期多剂量研究纳入32例活动性RA患者，分为4个队列，每个队列8例患者（6例活性药物组和2例匹配安慰剂组），每组每天口服一剂TCK-276或匹配安慰剂，共7天。TCK-276的剂量分别为10、25、75和175mg/天。评估安全性和药代动力学终点以及RA的探索性疾病活动参数。

结果

未发生死亡、严重不良事件、显著的具有临床意义的实验室检查结果（包括血液学变化）、具有临床意义的生命体征变化或具有临床意义的心电图或心脏遥测变化。TCK-276吸收迅速，半衰期约为6至12小时。未观察到明显蓄积，TCK-276暴露量的增加与剂量成正比。在第7天，TCK-276剂量为25、75和175mg/天时，分别有40%、80%和66.7%的患者达到疾病活动评分28（DAS28）-C反应蛋白（CRP）反应（欧洲抗风湿病联盟（EULAR）良好或中度反应），而安慰剂组为12.5%；美国风湿病学会（ACR）20反应分别为33.3%、60%和50%，安慰剂组无反应。