英国伯明翰医院NHS基金会Simon J Bowman团队研究了皮下注射ianalumab治疗原发性干燥综合征患者的安全性和有效性。该项研究成果发表在2021年11月30日出版的《柳叶刀》杂志上。

原发性干燥综合征是一种自身免疫性疾病，其特征是眼睛和口腔干燥、全身受累和生活质量下降。目前尚无针对该病的有效治疗方法。一种新的生物制剂，ianalumab（VAY736），具有两种抑制B细胞的模式，先前已显示出初步疗效。该剂量发现试验旨在评估不同皮下剂量的ianalumab治疗中重度原发性干燥综合征患者的安全性和有效性。

研究组在19个国家的56个中心进行了一项随机、平行、双盲、安慰剂对照、临床2b期剂量发现研究，招募18-75岁的原发性干燥综合征患者，均为中重度疾病活动（欧洲风湿病学协会联盟[EULAR]干燥综合征疾病活动指数[ESSDAI]评分≥6分） 和中重度症状严重程度（EULAR Sjögren综合征患者报告的指数得分≥5分） 。

将参与者按1:1:1:1随机分配，每4周接受皮下注射安慰剂或ianalumab（5 mg、50 mg或300 mg），持续24周。根据基线时的ESSDAI评分对随机分组进行分层（≥10或<10）。主要结局是所有患者从基线检查到24周ESSDAI评分的变化。从基线检查到第24周，疾病活动的剂量相关变化（ESSDAI）通过多重比较程序和建模分析进行评估。对至少服用一剂研究药物的患者进行安全性评估。

2017年6月27日至2018年12月6日，研究组共筛查了293名患者，其中190名患者被随机分配，安慰剂49名，ianalumab 5 mg组47名，ianalumab 50 mg组47名，ianalumab 300 mg组47名。在五种受试剂量反应模型中，有四种模型的总体疾病活动（ESSDAI评分）出现了具有统计意义的剂量反应。

所有ianalumab组的ESSDAI评分均较基线检查时有所下降，ianalumab 300 mg组的ESSDAI评分较基线检查时降低最多：经安慰剂校正后的最小二乘平均值降低1.92分。在3名被认为与治疗相关的患者中发生4起严重不良事件：安慰剂组肺炎1例，胃肠炎1例；ianalumab 50 mg组1例患者同时患有阑尾炎和输卵管卵巢脓肿。

这项研究达到了它的主要目标，显示在第24周时通过ESSDAI测量的疾病活动与剂量相关的下降。总的来说，ianalumab耐受性和安全性良好，且未增加感染。

附：英文原文

Title: Safety and efficacy of subcutaneous ianalumab (VAY736) in patients with primary Sjgren's syndrome: a randomised, double-blind, placebo-controlled, phase 2b dose-finding trial

Author: Simon J Bowman, Robert Fox, Thomas Drner, Xavier Mariette, Athena Papas, Thomas Grader-Beck, Benjamin A Fisher, Filipe Barcelos, Salvatore De Vita, Hendrik Schulze-Koops, Robert J Moots, Guido Junge, Janice N Woznicki, Monika A Sopala, Wen-Lin Luo, Wolfgang Hueber

Issue&Volume: 2021-11-30

Abstract:

Background

Sjgren's syndrome is an autoimmune disease characterised by dry eyes and mouth, systemic features, and reduced quality of life. There are no disease-modifying treatments. A new biologic, ianalumab (VAY736), with two modes of suppressing B cells, has previously shown preliminary efficacy. This dose-finding trial aimed to assess the safety and efficacy of different subcutaneous doses of ianalumab in patients with moderate to severe primary Sjgren's syndrome.

Methods

VAY736A2201 was a randomised, parallel, double-blind, placebo-controlled, phase 2b dose-finding study done in 56 centres in 19 countries. Patients aged 18–75 years with primary Sjgren's syndrome with moderate to severe disease activity (European Alliance of Associations for Rheumatology [EULAR] Sjgren's Syndrome Disease Activity Index [ESSDAI] score ≥6) and symptom severity (EULAR Sjgren's Syndrome Patient Reported Index score ≥5) were eligible. Participants were randomly assigned (1:1:1:1) to receive subcutaneous placebo or ianalumab (5 mg, 50 mg, or 300 mg) every 4 weeks for 24 weeks using a secure, online randomisation system. Randomisation was stratified by the ESSDAI score at baseline (≥10 or <10). Study personnel and patients were masked to treatment assignment. The primary outcome was the change in ESSDAI score from baseline to 24 weeks in all randomly assigned patients. Dose-related change in disease activity (ESSDAI) from baseline at week 24 was assessed by multiple comparison procedure with modelling analysis. Safety was measured in all patients who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, NCT02962895.

Findings

Between June 27, 2017, and Dec 06, 2018, 293 patients were screened, 190 of whom were randomly assigned (placebo n=49, ianalumab 5 mg n=47, ianalumab 50 mg n=47, ianalumab 300 mg n=47). Statistically significant dose-responses were seen for overall disease activity (ESSDAI score) in four of the five dose-response models tested (p<0·025 in four models, p=0·060 in one model). The ESSDAI score decreased from baseline in all ianalumab groups, with the maximal ESSDAI score change from baseline observed in the ianalumab 300 mg group: placebo-adjusted least-squares mean change from baseline 1·92 points (95% CI 4·15 to 0·32; p=0·092). There were four serious adverse events in three patients considered treatment-related (pneumonia [n=1] and gastroenteritis [n=1] in the placebo group; appendicitis plus tubo-ovarian abscess in the same patient in the ianalumab 50 mg group).

Interpretation

The study met its primary objective, showing a dose-related decrease in disease activity as measured by ESSDAI at week 24. Overall, ianalumab was well tolerated and safe, with no increase in infections. To our knowledge, this is the first large, randomised, controlled trial in primary Sjgren's syndrome that met its primary endpoint, and its results mean there is potential for more studies of this mechanism in the future.

DOI: 10.1016/S0140-6736(21)02251-0

Source: https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(21)02251-0/fulltext