Ianalumab用于治疗干燥综合征患者
完整摘要 · 中文译文
背景：干燥综合征是一种复杂的系统性自身免疫病，目前尚无获批的靶向治疗药物。Ianalumab 是一种 IgG1 单克隆抗体，具有双重作用机制，既可通过抗体依赖性细胞介导的细胞毒作用清除 B 细胞，又可通过阻断 B 细胞活化因子受体抑制 B 细胞的活化和存活。 方法：我们开展了两项为期 52 周、双盲、随机、安慰剂对照试验，纳入活动性干燥综合征患者。NEPTUNUS-1 试验中的患者按 1:1 比例分配接受皮下注射 ianalumab（每月 300 mg）或安慰剂；NEPTUNUS-2 试验中的患者按 1:1:1 比例分配接受每月 300 mg ianalumab、每 3 个月 300 mg ianalumab 或安慰剂。主要终点是第 48 周时欧洲抗风湿病联盟（EULAR）干燥综合征疾病活动指数（ESSDAI）评分相对于基线的变化（评分范围为 0～123 分，分数越高表示疾病活动度越高）。NEPTUNUS-1 试验层级检验计划中的首个关键次要终点是第 48 周时的 ESSDAI 应答（评分降低 ≥5 分）；NEPTUNUS-2 试验的首个关键次要终点是第 48 周时干燥综合征症状日记（SSSD）评分或 EULAR 干燥综合征患者报告指数（ESSPRI）评分相对于基线的变化。 结果：总体上，NEPTUNUS-1试验中有275例患者接受了随机分组（ianalumab每月一次组，137例；安慰剂组，138例），NEPTUNUS-2试验中有504例患者接受了随机分组（ianalumab每月一次组，168例；ianalumab每3个月一次组，167例；安慰剂组，169例）。在两项试验中，ianalumab每月一次组第48周时ESSDAI评分的下降幅度均显著大于安慰剂组，NEPTUNUS-1试验中组间差异为-1.3分（95%置信区间[CI]，-2.6至0.0；P = 0.0496），NEPTUNUS-2试验中组间差异为-1.0分（95% CI，-2.0至0.0；P = 0.04）。第48周时，两组在ESSDAI应答的发生率以及SSSD或ESSPRI评分相对于基线的变化方面均未观察到显著差异。ianalumab组与安慰剂组的严重不良事件发生率相似。非严重的局部注射部位反应和全身性注射相关反应在ianalumab组中更为常见。 结论：在这两项纳入活动性干燥综合征患者的试验中，ianalumab以300 mg每月一次的剂量给药，第48周时疾病活动度的下降幅度显著大于安慰剂，但在ESSDAI应答的发生率以及SSSD或ESSPRI症状评分相对于基线的变化方面未观察到显著差异。（由诺华制药资助；NEPTUNUS-1和NEPTUNUS-2的ClinicalTrials.gov注册号分别为NCT05350072和NCT05349214。）
完整摘要 · 英文原文
BACKGROUND: Sjögren's disease is a complex, systemic autoimmune disease with no approved targeted therapies. Ianalumab is an IgG1 monoclonal antibody with a dual mechanism of action, depleting B cells through antibody-dependent cellular cytotoxicity and inhibiting B-cell activation and survival through blockade of B-cell activating factor receptor. METHODS: We conducted two 52-week, double-blind, randomized, placebo-controlled trials involving patients with active Sjögren's disease. Patients in the NEPTUNUS-1 trial were assigned in a 1:1 ratio to receive subcutaneous ianalumab (300 mg monthly) or placebo; patients in the NEPTUNUS-2 trial were assigned in a 1:1:1 ratio to receive 300 mg of ianalumab monthly or every 3 months or placebo. The primary end point was the change from baseline in the score on the European Alliance of Associations for Rheumatology (EULAR) Sjögren's Syndrome Disease Activity Index (ESSDAI) at week 48 (scores range from 0 to 123, with higher scores indicating greater disease activity). The first key secondary end point in the hierarchical plan for the NEPTUNUS-1 trial was an ESSDAI response (≥5-point reduction) at week 48; for the NEPTUNUS-2 trial, it was the change from baseline in the score on the Sjögren's Syndrome Symptom Diary (SSSD) or EULAR Sjögren's Syndrome Patient Reported Index (ESSPRI) at week 48. RESULTS: Overall, 275 patients underwent randomization in the NEPTUNUS-1 trial (ianalumab monthly, 137 patients; placebo, 138 patients) and 504 in the NEPTUNUS-2 trial (ianalumab monthly, 168 patients; ianalumab every 3 months, 167 patients; and placebo, 169 patients). In both trials, ianalumab monthly led to a significantly greater decrease in the ESSDAI score at week 48 than placebo, with a between-group difference of -1.3 points (95% confidence interval [CI], -2.6 to 0.0; P = 0.0496) in NEPTUNUS-1 and -1.0 points (95% CI, -2.0 to 0.0; P = 0.04) in NEPTUNUS-2. No significant differences in the incidence of an ESSDAI response or in the change from baseline in SSSD or ESSPRI scores were observed at week 48. The incidence of serious adverse events was similar with ianalumab and placebo. Nonserious local injection-site and systemic injection-related reactions were more common in the ianalumab groups. CONCLUSIONS: In these two trials involving patients with active Sjögren's disease, ianalumab at a dose of 300 mg monthly resulted in a significantly greater decrease in disease activity at week 48 than placebo, although there were no significant differences in the incidence of an ESSDAI response or in the change from baseline in SSSD or ESSPRI symptom scores. (Funded by Novartis Pharma; NEPTUNUS-1 and NEPTUNUS-2 ClinicalTrials.gov numbers, NCT05350072 and NCT05349214, respectively.).