Division of Rheumatology and Immunology, Duke University Department of Medicine, Durham, NC, USA.
Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Nat Med. 2024 Jun;30(6):1583-1592. doi: 10.1038/s41591-024-03009-3. Epub 2024 Jun 5.
Sjögren's disease (SjD) is a chronic, systemic autoimmune disease with no approved disease-modifying therapies. Dazodalibep (DAZ), a novel nonantibody fusion protein, is a CD40 ligand antagonist that blocks costimulatory signals between T and B cells and antigen-presenting cells, and therefore may suppress the wide spectrum of cellular and humoral responses that drive autoimmunity in SjD. This study was a phase 2, randomized, double-blinded, placebo (PBO)-controlled trial of DAZ with a crossover stage in two distinct populations of participants with SjD. Population 1 had moderate-to-severe systemic disease activity and population 2 had an unacceptable symptom burden and limited systemic organ involvement. All participants had a diagnosis of SjD, with 21.6% and 10.1% having an associated connective tissue disease (rheumatoid arthritis or systemic lupus erythematosus) in populations 1 and 2, respectively. The remaining participants would be considered as having primary Sjögren's syndrome. The primary endpoint for population 1 (n = 74) was the change from baseline in the European League Against Rheumatism Sjögren's Syndrome Disease Activity Index at day 169. The primary endpoint for population 2 (n = 109) was the change from baseline in the European League Against Rheumatism Sjögren's Syndrome Patient Reported Index at day 169. The primary endpoints (least squares mean ± standard error) were achieved with statistical significance for both population 1 (DAZ, -6.3 ± 0.6; PBO, -4.1 ± 0.6; P = 0.0167) and population 2 (DAZ, -1.8 ± 0.2; PBO, -0.5 ± 0.2; P = 0.0002). DAZ was generally safe and well tolerated. Among the most frequently reported adverse events were COVID-19, diarrhea, headache, nasopharyngitis, upper respiratory tract infection, arthralgia, constipation and urinary tract infection. In summary, DAZ appears to be a potential new therapy for SjD and its efficacy implies an important role for the CD40/CD40 ligand pathway in its pathogenesis. ClinicalTrials.gov identifier: NCT04129164 .
干燥综合征（SjD）是一种慢性、系统性自身免疫性疾病，目前尚无批准的疾病修正疗法。Dazodalibep（DAZ）是一种新型的非抗体融合蛋白，是一种 CD40 配体拮抗剂，可阻断 T 和 B 细胞及抗原呈递细胞之间的共刺激信号，因此可能抑制 SjD 中广泛的细胞和体液反应驱动的自身免疫。这项研究是一项在两个不同的 SjD 患者群体中进行的 2 期、随机、双盲、安慰剂（PBO）对照的 DAZ 试验，其中包括一个交叉阶段。人群 1 具有中度至重度全身疾病活动度，人群 2 具有不可接受的症状负担和有限的全身器官受累。所有参与者均被诊断为 SjD，人群 1 中有 21.6%和 10.1%分别合并有结缔组织病（类风湿关节炎或系统性红斑狼疮），人群 2 中有 10.1%。其余参与者将被视为原发性干燥综合征。人群 1（n=74）的主要终点是第 169 天从基线到欧洲抗风湿病联盟干燥综合征疾病活动指数的变化。人群 2（n=109）的主要终点是第 169 天从基线到欧洲抗风湿病联盟干燥综合征患者报告指数的变化。主要终点（最小二乘均数±标准误差）在人群 1（DAZ，-6.3±0.6；PBO，-4.1±0.6；P=0.0167）和人群 2（DAZ，-1.8±0.2；PBO，-0.5±0.2；P=0.0002）均具有统计学意义。DAZ 通常是安全且耐受良好的。最常报告的不良事件包括 COVID-19、腹泻、头痛、鼻咽炎、上呼吸道感染、关节痛、便秘和尿路感染。总之，DAZ 似乎是 SjD 的一种潜在新疗法，其疗效表明 CD40/CD40 配体通路在其发病机制中起着重要作用。临床试验.gov 标识符：NCT04129164。
