Efficacy and safety of cemdisiran siRNA in myasthenia gravis (NIMBLE): a double-blind, randomised, placebo-controlled, phase 3 trial.

Newer targeted therapies lower overall antibody concentrations or inhibit complement activity.

较新的靶向治疗降低了总体抗体浓度或抑制了补体活性。

We aimed to evaluate an siRNA (cemdisiran) targeting complement component 5 (C5) as monotherapy and in combination with a C5 antibody (pozelimab) in generalised myasthenia gravis.

我们旨在评估针对补体成分5（C5）的小干扰RNA（cemdisiran）作为单药治疗以及与C5抗体（pozelimab）联合使用的疗效，用于治疗全身性重症肌无力。

Methods

NIMBLE is a randomised, double-blind, placebo-controlled, phase 3 trial conducted at 86 centres in 13 countries.

NIMBLE是一项随机、双盲、安慰剂对照的III期临床试验，在13个国家的86个中心进行。

We enrolled patients aged 18 years or older with a diagnosis of generalised myasthenia gravis, positive serology for anti-AChR or anti-LRP4 antibodies, and a Myasthenia Gravis-Activities of Daily Living (MG-ADL) score of 6 or greater.

我们招募了年龄在18岁或以上的患者，这些患者被诊断为全身性重症肌无力，抗乙酰胆碱受体或抗LRP4抗体血清学阳性，以及重症肌无力-日常生活活动（MG-ADL）评分6分或以上。

Patients were randomly allocated to receive cemdisiran monotherapy (600 mg every 12 weeks; cemdisiran group), pozelimab monotherapy (200 mg every 4 weeks; pozelimab group), combined cemdisiran (200 mg every 4 weeks) and pozelimab (200 mg every 4 weeks; combination group), or placebo, all administered subcutaneously, during a 24-week double-blindtreatment period.

患者在24周的双盲治疗期间被随机分配接受cemdisiran单药治疗（每12周600毫克；cemdisiran组）、pozelimab单药治疗（每4周200毫克；pozelimab组）、cemdisiran（每4周200毫克）和pozelimab（每4周200毫克）联合治疗（联合组），或安慰剂，所有药物均通过皮下注射给药。

The primary endpoint was change from baseline in MG-ADL scores at week 24, assessed in the modified intention-to-treat(mITT) primary analysis set (the first 245 randomly allocated patients who received any dose of study treatment and had at least one post-baseline assessment).

主要终点是第24周时MG-ADL评分从基线的变化，评估在修改后的意向治疗(mITT)主要分析集（前245名随机分配的患者，他们接受了任何剂量的研究治疗，并至少有一次基线后评估）。

A prespecified hierarchal statistical testing strategy was used; multiplicity was controlled for comparisons of cemdisiran versus placebo and combination versus placebo (pozelimab was not statistically tested against placebo and was used only to assess the contribution of components to the combination treatment).

使用了预先设定的分层统计测试策略；通过比较cemdisiran与安慰剂和联合治疗与安慰剂的比较来控制多重性（pozelimab没有与安慰剂进行统计测试，仅用于评估对联合治疗的贡献）。

Safety was mainly assessed by recording of treatment-emergent adverse events in all patients who received any dose of study treatment.

安全性主要通过记录接受研究治疗任何剂量的所有患者出现的治疗后不良事件来评估。

This study is registered with ClinicalTrials.gov (NCT05070858); the current status is active, not recruiting.

该研究已在ClinicalTrials.gov注册（NCT05070858）；当前状态为活跃，但不招募。

Results

Between Jan 20, 2022 and July 18, 2025, 390 participants were screened and, as of the data cut-off presented in this report (July 8, 2025), 284 were randomly allocated to the cemdisiran group (79 [28%] patients), pozelimab group (50 [18%]), combination group (80 [28%]), and placebo group (75 [26%]).

在2022年1月20日至2025年7月18日期间，共筛选了390名参与者。根据本报告中呈现的数据截止日期（2025年7月8日），284名参与者被随机分配到cemdisiran组（79名[28%]患者）、pozelimab组（50名[18%]）、联合治疗组（80名[28%]）和安慰剂组（75名[26%]）。

Of 277 patients who received any study treatment, 263 (95%) completed the double-blindtreatment period.

在277名接受任何研究治疗的患者中，有263名（95%）完成了双盲治疗期。

In the mITT primary analysis set, at week 24, the least-squares mean change from baseline in MG-ADL total score was -4·5 (SE 0·4) in the cemdisiran group (n=64), -4·0 (0·4) in the combination group (n=67), and -2·2 (0·5) in the placebo group (n=59).

在mITT主要分析集的第24周，从基线开始的MG-ADL总分的最小二乘平均变化为：cemdisiran组（n=64）为-4.5（标准误0.4），联合治疗组（n=67）为-4.0（标准误0.4），安慰剂组（n=59）为-2.2（标准误0.5）。

Placebo-adjusted least-squares mean differences in MG-ADL score at week 24 were -2·3 (SE 0·7; 95% CI -3·6 to -1·0; p=0·0005) in the cemdisiran group and -1·7 (0·7; -3·0 to -0·4; p=0·0086) in the combination group.

在第24周，调整安慰剂后的MG-ADL评分的最小二乘平均差异为：cemdisiran组为-2.3（标准误0.7；95%置信区间-3.6至-1.0；p=0.0005），联合治疗组为-1.7（标准误0.7；95%置信区间-3.0至-0.4；p=0.0086）。

The proportion of participants with at least one adverse eventduring the double-blindtreatment period was 54 (69%) of 78 in the cemdisiran group, 65 (81%) of 80 in the combination group, 40 (82%) of 49 in the pozelimab group, and 54 (77%) of 70 in the placebo group.

在双盲治疗期间，至少发生一次不良事件的受试者比例为cemdisiran组的78人中有54人（69%），联合组的80人中有65人（81%），pozelimab组的49人中有40人（82%），安慰剂组的70人中有54人（77%）。

The most common adverse eventin the cemdisiran group was upper respiratory tract infection (nine [12%] of 78 patients), which occurred at a similar incidencein the placebo group (eight [11%] of 70).

cemdisiran组中最常见的不良事件是上呼吸道感染，78名患者中有9人（12%）出现此症状，与安慰剂组的发生率相似，安慰剂组70名患者中有8人（11%）出现上呼吸道感染。

No serious or meningococcal infections occurred in the cemdisiran group.

cemdisiran组中未发生严重或脑膜炎球菌感染事件。

Adverse events leading to treatment discontinuation occurred in two participants (3%) in the placebo group and one participant (2%) in the pozelimab group.

导致治疗中断的不良事件在安慰剂组的两名参与者（3%）和pozelimab组的一名参与者（2%）中发生。

No deaths occurred during the double-blindtreatment period.

在双盲治疗期间没有发生死亡事件。

Two deaths occurred after the double-blindtreatment period, one of which was assessed as treatment-related by the investigator but not treatment-related by the sponsor.

双盲治疗期后发生了两例死亡，其中一例被研究者评估为与治疗相关，但赞助商认为与治疗无关。

interpretation

Cemdisiran monotherapy and combination therapy were effective in the treatment of generalised myasthenia gravis, and were generally well tolerated.

Cemdisiran单药治疗和联合治疗在治疗全身型重症肌无力方面均有效，且通常耐受性良好。

Subcutaneous dosing of cemdisiran, administered every 3 months, could provide a convenient treatment approach for generalised myasthenia gravis.

每3个月皮下给药一次的cemdisiran，可能为全身型重症肌无力提供一种便捷的治疗方式。

funding

Regeneron Pharmaceuticals.

再生元制药公司。