Safety and efficacy of satralizumab in patients with generalised myasthenia gravis (LUMINESCE): a randomised, double-blind, multicentre, placebo-controlled phase 3 trial.

We aimed to assess the safety and efficacy of satralizumab, a humanised monoclonal antibody targeting the IL-6 receptor, in patients with generalised myasthenia gravis.

我们的目标是评估satralizumab的安全性和有效性，这是一种针对IL-6受体的人源化单克隆抗体，用于治疗全身型重症肌无力患者。

Methods

LUMINESCE was a randomised, double-blind, placebo-controlled, multicentre, phase 3 study at 105 sites, including hospitals and clinics, globally.

LUMINESCE 是一项在105个地点进行的随机、双盲、安慰剂对照、多中心的III期研究，这些地点包括全球范围内的医院和诊所。

Eligible patients were aged 12 years and older, with seropositive generalised myasthenia gravis (autoantibodies to the acetylcholine receptor [AChR-IgG], muscle-specific kinase [MuSK-IgG], or low-density lipoprotein receptor-related protein 4 [LRP4-IgG]), a Myasthenia Gravis Foundation of America severity class II-IV, a Myasthenia Gravis Activities of Daily Living (MG-ADL) score of 5 or more (non-ocular contribution >50%), and use of stable background therapy.

符合条件的患者年龄在12岁及以上，患有血清阳性全身型重症肌无力（乙酰胆碱受体抗体[AChR-IgG]、肌肉特异性激酶[MuSK-IgG]或低密度脂蛋白受体相关蛋白4[LPR4-IgG]阳性），美国重症肌无力基金会严重程度为II-IV级，重症肌无力日常生活活动（MG-ADL）评分为5分或以上（非眼肌贡献>50%），并使用稳定的背景治疗。

Patients were randomly assigned (1:1) with a permuted-block randomisation method to receive subcutaneous satralizumab (120 mg for bodyweight ≤100 kg; 180 mg for bodyweight >100 kg) or placebo at weeks 0, 2, 4, and every 4 weeks thereafter until week 24.

患者按1:1的比例随机分配，使用交错分组随机化方法接受皮下注射沙塔利珠单抗（体重≤100公斤者120毫克；体重>100公斤者180毫克）或安慰剂，分别在第0、2、4周以及此后每4周一次，直至第24周。

Randomisation was stratified according to background therapy, autoantibody type, and geographical region.

随机化根据背景治疗、自身抗体类型和地理区域进行分层。

The primary efficacy endpoint was mean change from baseline in total MG-ADL score at week 24 in the modified intention-to-treatpopulation (all randomised AChR-IgG-positive patients who completed at least one post-baseline MG-ADL assessment).

主要疗效终点是24周时在改良意向治疗人群中基线平均肌无力活动评分（MG-ADL）的变化（所有随机化AChR-IgG阳性患者，至少完成一次基线后MG-ADL评估）。

Safety was assessed in all randomly assigned patients who received at least one dose of study drug.

所有接受至少一次研究药物剂量的随机分配患者均进行了安全性评估。

The open-label extension was terminated early because of the sponsor's decision to halt further development of satralizumab for treatment of generalised myasthenia gravis.

由于赞助商决定停止进一步开发萨特拉利珠单抗治疗全身型重症肌无力，开放标签扩展研究被提前终止。

This trial is registered with ClinicalTrials.gov, NCT04963270, and EudraCT, 2020-004436-21.

该试验已在ClinicalTrials.gov注册，注册号为NCT04963270，在EudraCT注册，注册号为2020-004436-21。

Results

Between Oct 19, 2021, and Aug 15, 2023, 188 patients were randomly assigned to satralizumab (n=96) or placebo (n=92). 166 AChR-IgG-positive patients (80 in the placebo group and 86 in the satralizumab group) were included in the modified intention-to-treatpopulation.

在2021年10月19日至2023年8月15日期间，共有188名患者被随机分配到satralizumab组(n=96)或安慰剂组(n=92)。在修改后的意向治疗人群中，包括了166名AChR-IgG阳性的患者（安慰剂组80名，satralizumab组86名）。

At week 24, statistically significant yet small improvements in MG-ADL score were observed with satralizumab versus placebo (adjusted mean -3·59, 95% CI -4·15 to -3·02 vs -2·57, -3·25 to -1·88; difference -1·02, -1·88 to -0·16; p=0·0120).

在第24周时，与安慰剂相比，satralizumab组的MG-ADL评分显示出统计学上显著但幅度较小的改善（调整后平均值-3·59，95%置信区间-4·15至-3·02，与-2·57，-3·25至-1·88相比；差异-1·02，-1·88至-0·16；p=0·0120）。

The proportion of patients with at least one adverse eventduring the double-blindperiod was slightly higher in patients treated with satralizumab compared with patients treated with placebo (86 [90%] patients vs 67 [73%] patients).

在双盲期间，接受萨特拉珠单抗治疗的患者中至少发生一次不良事件的比例略高于接受安慰剂治疗的患者（86 [90%] 例患者 vs 67 [73%] 例患者）。

Three serious adverse events (in three [3%] patients) were reported in the satralizumab group (pneumonia, pyelonephritis, and increased lipase) compared with nine (in six [7%] patients) serious adverse events in the placebo group (COVID-19, COVID-19 pneumonia, bacterial urinary tract infection, chest pain, back pain, and rosacea).

萨特拉珠单抗组报告了三例严重不良事件（三[3%]例患者），包括肺炎、肾盂肾炎和脂酶增加，而安慰剂组报告了九例严重不良事件（六[7%]例患者），包括COVID-19、COVID-19肺炎、细菌性尿路感染、胸痛、背痛和玫瑰糠疹。

There were no deaths or adverse events of special interest.

没有出现死亡或特别关注的不良事件。

interpretation

Satralizumab was well tolerated and resulted in small improvements in patient-reported and clinician-reported outcomes compared with placebo at week 24 in patients with AChR-IgG-positive generalised myasthenia gravis.

在AChR-IgG阳性全身型重症肌无力患者中，与安慰剂相比，萨特拉利珠单抗在第24周对患者报告和医生报告的结果有轻微改善，并且耐受性良好。

Further research analysing the immunological underpinnings of the observed clinical response to IL-6 signalling inhibition in patients with generalised myasthenia gravis and exploring the role of IL-6 in autoantibody-mediated diseases is warranted.

需要进一步研究分析在全身性重症肌无力患者中观察到的对IL-6信号抑制的临床反应的免疫学基础，并探索IL-6在自身抗体介导的疾病中的作用。

funding

F Hoffmann La Roche.

F Hoffmann La Roche公司。