在干燥综合征中使用非戈替尼、拉那芦替尼和替拉鲁替尼的安全性和疗效：一项随机、2 期、双盲、安慰剂对照研究。

Safety and efficacy of filgotinib, lanraplenib and tirabrutinib in Sjögren's syndrome: a randomized, phase 2, double-blind, placebo-controlled study.

机构信息

Department of Rheumatology, Great Western Hospital, Swindon.

Centre for Experimental Medicine and Rheumatology, William Harvey Research Institute, Queen Mary University of London, London.

出版信息

Rheumatology (Oxford). 2022 Nov 28;61(12):4797-4808. doi: 10.1093/rheumatology/keac167.

OBJECTIVE

The aim of this study was to characterize the safety and efficacy of filgotinib, lanraplenib and tirabrutinib in patients with active SS.

METHODS

This multicentre, double-blind study randomized patients with active primary or secondary SS [EULAR SS disease activity index (ESSDAI) ≥5) to receive filgotinib 200 mg (Janus kinase-1 inhibitor), lanraplenib 30 mg (spleen tyrosine kinase inhibitor), tirabrutinib 40 mg (Bruton's tyrosine kinase inhibitor), or placebo. The composite primary end point was the week-12 proportion of patients fulfilling protocol-specified improvement criteria (based on CRP and SS-related symptoms). The EULAR SS patient-reported index (ESSPRI) and the ESSDAI change from baseline (CFB) were secondary end points. Exploratory end points included disease-related biomarkers. Treatment-emergent adverse events (AEs) represented safety outcomes.

RESULTS

The mean of the baseline ESSDAI was 10.1, and of ESSPRI was 6.2 in the 150 patients who were treated; 125 completed the 24-week placebo-controlled treatment period. At week 12, 43.3% of the filgotinib group achieved the primary end point (P = 0.17 vs placebo) vs 42.3% (P = 0.16), 34.7% (P = 0.33), and 26.7% of lanraplenib, tirabrutinib, and placebo groups, respectively. Neither secondary end point was met. Biomarker reductions included immunoglobulins classically associated with SS disease activity. Filgotinib ESSDAI CFB appeared more pronounced in subgroups with baseline ESSDAI ≥14 or without DMARDs/CSs. Most AEs were Grade 1 or 2.

CONCLUSION

Three drugs with disparate mechanisms were tested, but no significant differences vs placebo in primary or secondary end points were observed. These results may be considered hypothesis-generating, given the drug tolerability, subgroup analysis, and biomarker findings.

TRIAL REGISTRATION

ClinicalTrials.gov, https://clinicaltrials.gov, NCT03100942.

目的

本研究旨在评估 ﬁlgotinib、lanraplenib 和 tirabrutinib 在原发性或继发性干燥综合征（SS）患者中的安全性和疗效。

方法

这是一项多中心、双盲研究，将活动期原发性或继发性 SS 患者（EULAR SS 疾病活动指数[ESSDAI]≥5）随机分配至ﬁlgotinib 200mg（Janus 激酶-1 抑制剂）、lanraplenib 30mg（脾酪氨酸激酶抑制剂）、tirabrutinib 40mg（Bruton 酪氨酸激酶抑制剂）或安慰剂组。主要复合终点为第 12 周符合方案改善标准（基于 CRP 和 SS 相关症状）的患者比例。次要终点为 EULAR SS 患者报告指数（ESSPRI）和 ESSDAI 自基线变化（CFB）。探索性终点包括疾病相关生物标志物。治疗出现的不良事件（AE）代表安全性结果。

结果

150 例接受治疗的患者的基线 ESSDAI 平均值为 10.1，ESSPRI 平均值为 6.2；125 例患者完成了 24 周安慰剂对照治疗期。第 12 周，43.3%的ﬁlgotinib 组达到主要终点（P=0.17 与安慰剂相比），分别为 42.3%（P=0.16）、34.7%（P=0.33）、lanraplenib、tirabrutinib 和安慰剂组，分别为 34.7%（P=0.33）和 26.7%。两个次要终点均未达到。生物标志物减少包括与 SS 疾病活动相关的经典免疫球蛋白类。在基线 ESSDAI≥14 或无 DMARDs/CSs 的亚组中，ﬁlgotinib 的 ESSDAI CFB 似乎更为明显。大多数 AE 为 1 级或 2 级。