Safety and efficacy of apitegromab in nonambulatory type 2 or type 3 spinal muscular atrophy (SAPPHIRE): a phase 3, double-blind, randomised, placebo-controlled trial.

Apitegromab, a fully human monoclonal antibody, selectively inhibits myostatin activation, improving muscle function.

Apitegromab是一种全人源单克隆抗体，选择性地抑制肌肉生长抑制素的激活，从而改善肌肉功能。

We aimed to assess the safety and efficacy of apitegromab in patients with nonambulatory type 2 or type 3 spinal muscular atrophy receiving nusinersen or risdiplam.

我们旨在评估apitegromab在接受nusinersen或risdiplam治疗的非行走型2型或3型脊髓性肌萎缩症患者中的安全性和有效性。

Methods

SAPPHIRE, a double-blind, placebo-controlled, phase 3 trial, was done in 48 hospitals in Belgium, France, Germany, Italy, Poland, Spain, the Netherlands, the UK, and the USA.

SAPPHIRE是一项双盲、安慰剂对照的3期试验，在比利时、法国、德国、意大利、波兰、西班牙、荷兰、英国和美国的48家医院进行。

Eligible participants were aged 2-21 years, had genetically documented SMN-deficient nonambulatory type 2 or type 3 spinal muscular atrophy, an estimated life expectancy greater than 2 years, Hammersmith Functional Motor Scale-Expanded (HFMSE) scores 10-45, and had received at least 10 months' nusinersen or at least 6 months' risdiplam therapy at screening.

符合条件的参与者年龄为2-21岁，具有遗传学记录的SMN缺乏型非行走性2型或3型脊髓性肌萎缩症，预计寿命超过2年，Hammersmith功能运动量表-扩展（HFMSE）评分在10-45之间，并且在筛查时至少接受了10个月的nusinersen治疗或至少6个月的risdiplam治疗。

Participants aged 2-12 years were randomly assigned 1:1:1 to receive apitegromab 20 mg/kg, apitegromab 10 mg/kg, or placebo every 4 weeks; participants aged 13-21 years were randomly assigned 2:1 to receive apitegromab 20 mg/kg or placebo every 4 weeks.

2-12岁的参与者被随机分配为1:1:1，每4周接受一次20 mg/kg或10 mg/kg的apitegromab或安慰剂；13-21岁的参与者被随机分配为2:1，每4周接受一次20 mg/kg的apitegromab或安慰剂。

All participants, parents or caregivers, investigators, and site personnel were unaware of the treatment assignment.

所有参与者、父母或监护人、调查人员以及现场人员均不知道治疗分配情况。

The primary endpoint, change from baseline in HFMSE at 12 months, was assessed in participants aged 2-12 years who received at least one dose of apitegromab or placebo and had at least one post-baseline evaluable HFMSE assessment (modified intention-to-treatset).

主要终点是评估2至12岁参与者在基线时的HFMSE评分在12个月时的变化，这些参与者接受了至少一剂apitegromab或安慰剂，并且至少有一次基线后可评估的HFMSE评估（修改意向治疗集）。

Comparisons of the combined apitegromab dose (20 mg/kg and 10 mg/kg) versus placebo and the 20 mg/kg dose versus placebo were done with a mixed-effects model with repeated measurement.

通过使用混合效应模型进行重复测量，比较了联合使用apitegromab剂量（20 mg/kg和10 mg/kg）与安慰剂，以及20 mg/kg剂量与安慰剂的效果。

Safety was analysed in all participants who received at least one dose of apitegromab or placebo through evaluation of adverse events, physical examinations, vital signs and cardiac assessments, laboratory evaluations, and concomitant medications.

通过评估不良事件、体格检查、生命体征和心脏评估、实验室检查以及合并用药，分析了所有接受至少一次apitegromab或安慰剂治疗的参与者的安全性。

SAPPHIRE is registered with ClinicalTrials.gov, NCT05156320, and is completed.

SAPPHIRE 已在 ClinicalTrials.gov 注册，注册号为 NCT05156320，并已完成。

Results

From March 28, 2022, to Sept 4, 2024, we enrolled 188 patients (156 in the population aged 2-12 years and 32 in the population aged 13-21 years); of whom 128 participants received apitegromab and 60 participants received placebo.

从2022年3月28日至2024年9月4日，我们共招募了188名患者（2-12岁年龄段156名，13-21岁年龄段32名）；其中128名参与者接受了apitegromab治疗，60名参与者接受了安慰剂。

At 12 months, least squares mean difference in HFMSE change from baseline was 1·8 (95% CI 0·30 to 3·32, p=0·019) points for participants aged 2-12 years receiving apitegromab versus placebo (least squares mean 0·6 vs -1·2).

在12个月时，2-12岁接受apitegromab治疗的参与者与安慰剂组相比，HFMSE从基线开始的最小二乘平均差异为1.8（95%置信区间0.30至3.32，p=0.019）点（最小二乘平均值为0.6对比-1.2）。

Least squares mean difference in HFMSE change from baseline was 1·4 (95% CI -0·34 to 3·13; p=0·11) for apitegromab 20 mg/kg versus placebo (least squares mean 0·2 vs -1·2).

对于接受apitegromab 20 mg/kg治疗的患者与安慰剂组相比，HFMSE从基线开始的最小二乘平均差异为1.4（95%置信区间-0.34至3.13；p=0.11）（最小二乘平均值为0.2对比-1.2）。

The incidenceand severity of adverse events were similar between apitegromab and placebo, and consistent with spinal muscular atrophy and background spinal muscular atrophy therapy.

Apitegromab与安慰剂之间不良事件的发生率和严重程度相似，并且与脊髓性肌萎缩症及其背景治疗相一致。

The most frequently reported adverse events were pyrexia (apitegromab, 33 [26%] of 128 vs placebo, 17 [28%] of 60), nasopharyngitis (32 [25%] vs 14 [23%]), cough (30 [23%] vs 12 [20%]), vomiting (29 [23%] vs ten [17%]), upper respiratory tract infection (28 [22%] vs 18 [30%]), and headache (27 [21%] vs 12 [20%]).

最常见的不良事件报告为发热（apitegromab，128人中有33人[26%]，与之相比安慰剂组60人中有17人[28%]），鼻咽炎（32人[25%]对比14人[23%]），咳嗽（30人[23%]对比12人[20%]），呕吐（29人[23%]对比10人[17%]），上呼吸道感染（28人[22%]对比18人[30%]），以及头痛（27人[21%]对比12人[20%]）。

No patients discontinued due to adverse events.

没有患者因不良事件而停药。

interpretation

Participants in the apitegromab treatment groups (combined 20 mg/kg and 10 mg/kg dose) achieved statistically significant improvements in motor function compared with placebo; however, the least squares mean difference was not significant between apitegromab 20 mg/kg and placebo.

接受apitegromab治疗的患者（结合20 mg/kg和10 mg/kg剂量组）在运动功能上与安慰剂相比实现了统计学上的显著改善；然而，apitegromab 20 mg/kg与安慰剂之间的最小二乘均值差异并不显著。

Overall, SAPPHIRE results build on findings from the phase 2 TOPAZ trial, showing improved motor function with a generally well tolerated safety profile, supporting the use of muscle-targeting therapy for spinal muscular atrophy.

总体而言，SAPPHIRE研究结果在第二阶段TOPAZ试验的基础上，显示了运动功能的改善以及一般良好耐受的安全性特征，支持针对肌肉的治疗用于脊髓性肌萎缩症。

funding

Scholar Rock.

Scholar Rock公司。