美国约翰霍普金斯大学医学院Michelle Petri团队研究了巴瑞替尼治疗系统性红斑狼疮的疗效与安全性。该项研究成果发表在2023年2月24日出版的《柳叶刀》杂志上。

巴瑞替尼是Janus激酶1和2的口服选择性抑制剂，被批准用于治疗类风湿关节炎、特应性皮炎和斑秃。在一项针对系统性红斑狼疮（SLE）患者的为期24周的二期研究中，与安慰剂相比，巴瑞替尼4 mg显著改善了SLE疾病的活动。研究组报道了在一项为期52周的iii期研究中，巴瑞替尼对SLE患者的疗效和安全性的评估。

在这项3期双盲、随机、安慰剂对照研究（SLE-BRAVE-II）中，接受稳定背景治疗的活动期SLE患者（年龄≥18岁）被按1:1:1随机分配，分别服用4 mg巴瑞替尼、2 mg巴瑞替尼或安慰剂，共52周。主要终点是与安慰剂相比，4 mg巴瑞昔尼治疗组第52周SLE反应指数（SRI）-4的患者比例。鼓励糖皮质激素减量，但不要求按照方案减量。

主要终点通过logistic回归分析与模型中的基线疾病活动、基线皮质类固醇剂量、区域和治疗组进行评估。对意向治疗人群进行疗效分析，包括随机分配并接受至少一剂试验药物的所有参与者，这些参与者在第一次基线后访视时未因随访失败而中断研究。对所有随机分配的参与者进行了安全性分析，这些参与者至少接受了一剂试验药物，并且没有停止服用。

共775名患者被随机分配，并接受至少一剂巴瑞替尼4 mg（n=258）、2 mg（n=261）或安慰剂（n=256）。在第52周时，服用4 mg巴瑞替尼（121[47%]；优势比1.07；与安慰剂相比差异1.5）、2 mg巴瑞替尼（120[46%]；1.05；0.8）和安慰剂（116[46%]]）的受试者中，SRI-4应答者比例的主要疗效结局无统计学差异。

未达到关键次要终点，包括糖皮质激素减量和首次严重发作的时间。在4 mg巴瑞替尼组29名（11%）、2 mg巴瑞替尼组35名（13%）和安慰剂组22名（9%）参与者中观察到严重不良事件。巴瑞替尼在SLE患者中的安全性与已知的巴瑞替尼安全性一致。

尽管2期数据表明巴瑞替尼在是SLE患者的潜在治疗方法，这在SLE-BRAVE-I中得到了支持，但这一结果在SLE-BRAVE-II中没有得到重现。未观察到新的安全信号。

附：英文原文

Title: Baricitinib for systemic lupus erythematosus: a double-blind, randomised, placebo-controlled, phase 3 trial (SLE-BRAVE-II)

Author: Michelle Petri, Ian N Bruce, Thomas Drner, Yoshiya Tanaka, Eric F Morand, Kenneth C Kalunian, Mario H Cardiel, Maria E Silk, Christina L Dickson, Gabriella Meszaros, Lu Zhang, Bochao Jia, Youna Zhao, Conor J McVeigh, Marta Mosca

Issue&Volume: 2023-02-24

Abstract:

Background

Baricitinib is an oral selective inhibitor of Janus kinase 1 and 2 approved for the treatment of rheumatoid arthritis, atopic dermatitis, and alopecia areata. In a 24-week phase 2 study in patients with systemic lupus erythematosus (SLE), baricitinib 4 mg significantly improved SLE disease activity compared with placebo. In this Article, we report the evaluation of efficacy and safety of baricitinib in patients with SLE in a 52-week phase 3 study.

Methods

In this phase 3 double-blind, randomised, placebo-controlled study, SLE-BRAVE-II, patients (aged ≥18 years) with active SLE receiving stable background therapy were randomly assigned 1:1:1 to baricitinib 4 mg, baricitinib 2 mg, or placebo once daily for 52 weeks. The primary endpoint was the proportion of patients with an SLE Responder Index (SRI)-4 response at week 52 in the baricitinib 4 mg treatment group compared with placebo. Glucocorticoid tapering was encouraged but not required per protocol. The primary endpoint was assessed by logistic regression analysis with baseline disease activity, baseline corticosteroid dose, region, and treatment group in the model. Efficacy analyses were done on an intention-to-treat population, comprising all participants who were randomly assigned and received at least one dose of investigational product and who did not discontinue from the study for the reason of lost to follow-up at the first post-baseline visit. Safety analyses were done on all randomly assigned participants who received at least one dose of investigational product and who did not discontinue. This study is registered with ClinicalTrials.gov, NCT03616964, and is complete.

Findings

A total of 775 patients were randomly assigned and received at least one dose of baricitinib 4 mg (n=258), baricitinib 2 mg (n=261), or placebo (n=256). There was no difference in the primary efficacy outcome of the proportion of SRI-4 responders at week 52 between participants who received baricitinib 4mg (121 [47%]; odds ratio 1·07 [95% CI 0·75 to 1·53]; difference with placebo 1·5 [95% CI –7·1 to 10·2]), 2 mg (120 [46%]; 1·05 [0·73 to 1·50]; 0·8 [–7·9 to 9·4]) and placebo (116 [46%]). None of the major secondary endpoints, including glucocorticoid tapering and time to first severe flare, were met. Serious adverse events were observed in 29 (11%) participants in the baricitinib 4 mg group, 35 (13%) in the baricitinib 2 mg group, and 22 (9%) in the placebo group. The safety profile of baricitinib in patients with SLE was consistent with the known baricitinib safety profile.

Interpretation

Although phase 2 data suggested baricitinib as a potential treatment for patients with SLE, which was supported in SLE-BRAVE-I, this result was not replicated in SLE-BRAVE-II. No new safety signals were observed.

DOI: 10.1016/S0140-6736(22)02546-6

Source: https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(22)02546-6/fulltext