澳大利亚莫纳什大学克莱顿分校Eric F Morand团队研究了巴瑞替尼治疗系统性红斑狼疮3期试验的疗效与安全性。这一研究成果发表在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性关节炎、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2期研究中，与安慰剂相比，4 mg巴瑞替尼显著改善了SLE疾病活动。该试验旨在在一项为期52周的3期研究中评估巴瑞替尼对活动期SLE患者的疗效和安全性。

在一项多中心、双盲、随机、安慰剂对照、平行组、3期研究（SLE-BRAVE-I）中，接受稳定背景治疗的活动期SLE患者（年龄≥18岁）按照1:1:1的比例随机分配给4 mg、2 mg的巴瑞替尼或安慰剂，共52周，每天一次，进行标准护理。鼓励糖皮质激素减量，但不要求按照方案减量。主要终点是与安慰剂相比，4 mg巴瑞替尼治疗组在第52周达到SLE反应指数（SRI）-4反应的患者比例。

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。对改良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。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，并且在第一次基线后访视时没有因随访失败而中断研究。

760名受试者被随机分配，并接受至少一剂巴瑞替尼4 mg（n=252）、2 mg（n=255）或安慰剂（n=253）。与安慰剂组相比，接受4 mg巴瑞替尼（142[57%]；优势比1.57；与安慰剂组的差异为10.8）的参与者达到SRI-4应答的比例明显高于安慰剂组（116[46%]），但接受2 mg巴瑞替尼（126[50%]；1.14；3.9）的参与者与安慰剂组相比差异不显著。

与安慰剂组相比，两组患者达到关键次要终点（包括糖皮质激素减量和首次严重发作时间）的比例无显著差异。26名（10%）服用4 mg巴瑞替尼的参与者出现严重不良事件，4 mg巴瑞替尼组有24名（9%），安慰剂组有18名（7%）。系统性红斑狼疮患者中巴瑞替尼的安全性与已知的巴瑞替尼安全性一致。

研究结果表明，4 mg巴瑞替尼组符合该研究的主要终点。然而，关键次要终点并非如此。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-I)

Author: Eric F Morand, Edward M Vital, Michelle Petri, Ronald van Vollenhoven, Daniel J Wallace, Marta Mosca, Richard A Furie, Maria E Silk, Christina L Dickson, Gabriella Meszaros, Bochao Jia, Brenda Crowe, Inmaculada de la Torre, Thomas Drner

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. The objective of this trial was to evaluate the efficacy and safety of baricitinib in patients with active SLE in a 52-week phase 3 study.

Methods

In a multicentre, double-blind, randomised, placebo-controlled, parallel-group, phase 3 study, SLE-BRAVE-I, patients (aged ≥18 years) with active SLE receiving stable background therapy were randomly assigned 1:1:1 to baricitinib 4 mg, 2 mg, or placebo once daily for 52 weeks with standard of care. Glucocorticoid tapering was encouraged but not required per protocol. The primary endpoint was the proportion of patients reaching an SLE Responder Index (SRI)-4 response at week 52 in the baricitinib 4 mg treatment group compared with placebo. 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 a modified intention-to-treat population, comprising all participants who were randomly assigned and received at least one dose of investigational product. Safety analyses were done on all randomly assigned participants who 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. This study is registered with ClinicalTrials.gov, NCT03616912.

Findings

760 participants were randomly assigned and received at least one dose of baricitinib 4 mg (n=252), baricitinib 2 mg (n=255), or placebo (n=253). A significantly greater proportion of participants who received baricitinib 4 mg (142 [57%]; odds ratio 1·57 [95% CI 1·09 to 2·27]; difference with placebo 10·8 [2·0 to 19·6]; p=0·016), but not baricitinib 2 mg (126 [50%]; 1·14 [0·79 to 1·65]; 3·9 [–4·9 to 12·6]; p=0·47), reached SRI-4 response compared with placebo (116 [46%]). There were no significant differences between the proportions of participants in either baricitinib group reaching any of the major secondary endpoints compared with placebo, including glucocorticoid tapering and time to first severe flare. 26 (10%) participants receiving baricitinib 4 mg had serious adverse events, 24 (9%) participants receiving baricitinib 2 mg, and 18 (7%) participants receiving placebo. The safety profile of baricitinib in participants with SLE was consistent with the known baricitinib safety profile.

Interpretation

The primary endpoint in this study was met for the 4 mg baricitinib group. However, key secondary endpoints were not. No new safety signals were observed.

DOI: 10.1016/S0140-6736(22)02607-1

Source: https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(22)02607-1/fulltext