JEWELFISH: 24-month results from an open-label study in non-treatment-naïve patients with SMA receiving treatment with risdiplam

Abstract 摘要

Risdiplam is a once-daily oral, survival of motor neuron 2 (SMN2) splicing modifier approved for the treatment of spinal muscular atrophy (SMA). JEWELFISH (NCT03032172) investigated the safety, tolerability, pharmacokinetics (PK), and PK/pharmacodynamic (PD) relationship of risdiplam in non-treatment-naïve patients with SMA. JEWELFISH enrolled adult and pediatric patients (N = 174) with confirmed diagnosis of 5q-autosomal recessive SMA who had previously received treatment with nusinersen (n = 76), onasemnogene abeparvovec (n = 14), olesoxime (n = 71), or were enrolled in the MOONFISH study (NCT02240355) of the splicing modifier RG7800 (n = 13). JEWELFISH was an open-label study with all participants scheduled to receive risdiplam. The most common adverse event (AE) was pyrexia (42 patients, 24%) and the most common serious AE (SAE) was pneumonia (5 patients, 3%). The rate of AEs and SAEs decreased by > 50% from the first to the second year of treatment, and there were no treatment-related AEs that led to withdrawal from treatment. An increase in SMN protein in blood was observed following risdiplam treatment and sustained over 24 months of treatment irrespective of previous treatment. Exploratory efficacy assessments of motor function showed an overall stabilization in mean total scores as assessed by the 32-item Motor Function Measure, Hammersmith Functional Motor Scale—Expanded, and Revised Upper Limb Module. The safety profile of risdiplam in JEWELFISH was consistent with previous clinical trials of risdiplam in treatment-naïve patients. Exploratory efficacy outcomes are reported but it should be noted that the main aim of JEWELFISH was to assess safety and PK/PD, and the study was not designed for efficacy analysis.

Risdiplam 是一种每日口服一次的运动神经元 2 (SMN2) 存活剪接修饰剂，已被批准用于治疗脊髓性肌萎缩症 (SMA)。JEWELFISH (NCT03032172)研究了利司扑兰在未接受治疗的SMA患者中的安全性、耐受性、药代动力学（PK）和PK/药效学（PD）关系。JEWELFISH招募了确诊为5q常染色体隐性SMA的成人和儿童患者（N = 174），这些患者曾接受过nusinersen（n = 76）、onasemnogene abeparvovec（n = 14）、oleoxime（n = 71）治疗，或参加过剪接修饰剂RG7800的MOONFISH研究（NCT02240355）（n = 13）。JEWELFISH是一项开放标签研究，所有参与者都计划接受利西地平治疗。最常见的不良事件（AE）是发热（42 名患者，24%），最常见的严重不良事件（SAE）是肺炎（5 名患者，3%）。从治疗的第一年到第二年，AE 和 SAE 的发生率下降了 50%以上，没有出现导致停药的治疗相关 AE。利斯地普仑治疗后观察到血液中的SMN蛋白增加，并在24个月的治疗中持续增加，与之前的治疗无关。运动功能的探索性疗效评估显示，32项运动功能测量、哈默史密斯功能性运动量表扩展版和修订版上肢模块评估的平均总分总体趋于稳定。在JEWELFISH中，利斯地普仑的安全性与之前在治疗无效患者中进行的利司扑兰临床试验一致。该研究报告了探索性疗效结果，但应注意的是，JEWELFISH 的主要目的是评估安全性和 PK/PD，该研究并非为疗效分析而设计。

Introduction 导言

Spinal muscular atrophy (SMA) is a genetic disorder that affects motor neurons, resulting in muscle weakness [1]. It is caused by mutations in the survival of motor neuron 1 (SMN1) gene that lead to low levels of functional SMN protein [2].

脊髓性肌萎缩症（SMA）是一种影响运动神经元、导致肌肉无力的遗传性疾病[1]。它是由运动神经元 1（SMN1）生存基因突变导致功能性 SMN 蛋白水平低下引起的[2]。

Three disease-modifying therapies (DMTs) are currently approved for the treatment of SMA: nusinersen (SPINRAZA®), an intrathecally administered antisense oligonucleotide that alters the splicing of SMN2 pre-mRNA [3, 4]; onasemnogene abeparvovec (ZOLGENSMA®), an intravenously administered gene therapy designed to deliver a functional copy of the SMN1 gene into motor neurons [5, 6]; and risdiplam (EVRYSDI®), an orally administered small molecule designed to selectively modify splicing of SMN2 pre-mRNA and promote inclusion of exon 7 thus increasing levels of functional SMN protein [7, 8].

目前有三种疾病改变疗法（DMT）被批准用于治疗 SMA：nusinersen (SPINRAZA ® ) 是一种经皮下注射的反义寡核苷酸，可改变 SMN2 前 mRNA 的剪接[3, 4]；onasemnogene abeparvovec (ZOLGENSMA ® ) 是一种静脉注射的基因疗法，旨在向运动神经元递送 SMN1 基因的功能拷贝[5, 6]；和 risdiplam（EVRYSDI ® ），这是一种口服小分子药物，旨在选择性地改变 SMN2 前 mRNA 的剪接，促进外显子 7 的包含，从而提高功能性 SMN 蛋白的水平 [ 7，8]。

With the availability of three treatment options, treatments may be administered sequentially or in combination [9]. Patients may wish to switch treatments or explore a combination of therapies if they do not perceive a benefit from their treatment or due to patient preferences regarding routes of administration [10,11,12].

由于有三种治疗方法可供选择，因此可以按顺序或联合使用治疗方法[9]。如果患者没有从治疗中获益，或者由于患者对给药途径的偏好，他们可能会希望更换治疗方法或尝试联合治疗[10, 11, 12]。

JEWELFISH was the first clinical trial to investigate sequential treatment of SMA with DMTs. Furthermore, there are limited data from real-world clinical settings that evaluated the safety and efficacy of combination or sequential treatment [13,14,15,16].

JEWELFISH是首个研究DMTs序贯治疗SMA的临床试验。此外，来自真实世界临床环境的评估联合或序贯治疗安全性和有效性的数据也很有限[13, 14, 15, 16]。

The JEWELFISH study was designed to assess the safety, tolerability, pharmacokinetics (PK), and PK/pharmacodynamic (PD) relationship of risdiplam in non-treatment-naïve adult and pediatric patients with SMA. The interim results after 12 months of treatment have previously been reported [17]. Here we report the primary analysis after 24 months of risdiplam treatment.

JEWELFISH 研究旨在评估利司扑兰在非治疗前成人和儿童 SMA 患者中的安全性、耐受性、药代动力学 (PK) 和 PK/ 药效学 (PD) 关系。此前已报告了治疗 12 个月后的中期结果[ 17]。在此，我们报告了利司扑兰治疗 24 个月后的主要分析结果。

Study design and participants

研究设计和参与者

JEWELFISH is a multicenter, open-label study of daily risdiplam that includes patients with SMA previously enrolled in the MOONFISH study (NCT02240355) [18], or those treated with nusinersen, onasemnogene abeparvovec, or olesoxime [19]. Patients previously treated with nusinersen were included if they had received ≥ 4 doses of nusinersen, provided that the last dose was received ≥ 90 days prior to screening. Patients previously treated with onasemnogene abeparvovec were included provided that the time of treatment was ≥ 12 months prior to screening. Patients previously treated with olesoxime were included provided that the last dose was received ≤ 18 months and ≥ 90 days prior to screening. Patients aged 6 months to 60 years of age at screening were eligible if they had a confirmed diagnosis of 5q-SMA, including genetic confirmation of a biallelic mutation (homozygous deletion or heterozygosity predictive of loss of function of the SMN1 gene) and clinical history, signs, or symptoms attributable to SMA. Patients were excluded if they met any of the following criteria: participation in any investigational drug or device study with the exception of studies of olesoxime, nusinersen, or onasemnogene abeparvovec ≥ 90 days prior to screening; any history of gene or cell therapy with the exception of onasemnogene abeparvovec; initiation of an oral salbutamol or oral β2-adrenergic agonist within 6 weeks prior to enrollment; any prior use of FMO1 or FMO3 inhibitor or inducer, or OCT-2 and MATE substrates within 2 weeks prior to risdiplam treatment; any prior use of any agents anticipated to increase or decrease muscle strength 90 days prior to enrollment or medications known or suspected of causing retinal toxicity within 1 year prior to enrollment. Patients were excluded if they had a recent history (< 1 year) of ophthalmologic diseases that would interfere with study assessments. Patients aged < 2 years were excluded if they had been hospitalized for a pulmonary event within 2 months prior to screening and pulmonary function had not fully recovered. There were no exclusion criteria based on SMA type, SMN2 copy number, baseline motor function, comorbidities, or respiratory/feeding support. Patients > 2 years of age were considered ambulant if they had the ability to walk unassisted for ≥ 10 m. Full inclusion and exclusion criteria for JEWELFISH have been published [17]. Based upon practical considerations the study size was set at 180 patients [17]. Assuming the underlying adverse event (AE) rate is 1.4%, a study of 180 patients exposed to risdiplam would have a 92% chance of detecting an AE in ≥ 1 patient. Patients received risdiplam orally once daily at the approved dosing regimen based on body weight and age. For patients aged 2–60 years, the dose is 5 mg for patients with a body weight of ≥ 20 kg, and 0.25 mg/kg for a body weight < 20 kg. For patients aged 6 months to < 2 years, the dose is 0.2 mg/kg [17].

JEWELFISH是一项多中心、开放标签的日用利司扑兰研究，包括既往参加过MOONFISH研究（NCT02240355）[18]的SMA患者，或接受过nusinersen、onasemnogene abeparvovec或oleoxime治疗的患者[19]。既往接受过诺西奈森治疗的患者，如果接受过≥4次诺西奈森治疗，只要最后一次治疗是在筛查前≥90天接受的，即可纳入。曾接受过onasemnogene abeparvovec治疗的患者，只要治疗时间在筛查前≥12个月，也可纳入。既往接受过奥利唑肟治疗的患者，只要最后一次服药时间在筛查前18个月且≥90天，也可纳入筛查。筛查时年龄在6个月到60岁之间的患者，如果确诊为5q-SMA，包括双倍突变的基因确认（同基因缺失或杂合性可预测SMN1基因功能缺失）以及可归因于SMA的临床病史、体征或症状，则符合筛查条件。符合以下任何一项标准的患者均被排除在外：筛查前≥ 90 天参加过任何研究性药物或器械研究，但奥利昔肟、诺西那生或onasemnogene abeparvovec 研究除外；有基因或细胞治疗史，但onasemnogene abeparvovec 除外；入组前 6 周内开始口服沙丁胺醇或口服β2-肾上腺素能激动剂；入组前 2 周内曾使用过 FMO1 或 FMO3 抑制剂或诱导剂，或 OCT-2 和 MATE 底物；入组前 90 天内曾使用过任何预期会增加或减少肌肉力量的药物，或入组前 1 年内曾使用过已知或怀疑会导致视网膜毒性的药物。如果患者近期（小于 1 年）有可能影响研究评估的眼科疾病史，则排除在外。年龄小于 2 岁的患者如果在筛查前 2 个月内曾因肺部疾病住院，且肺功能尚未完全恢复，则排除在外。没有基于SMA类型、SMN2拷贝数、基线运动功能、合并症或呼吸/喂养支持的排除标准。年龄大于 2 岁的患者如果能够在无辅助情况下行走≥ 10 米，则被视为行动自如。JEWELFISH 的全部纳入和排除标准已经公布[ 17]。基于实际考虑，研究规模定为 180 例患者[17]。假设基本不良事件（AE）发生率为 1.4%，那么在 180 例暴露于利地普仑的患者中，有 92% 的几率在≥ 1 例患者中发现 AE。患者根据体重和年龄按照批准的剂量方案每天口服一次利司腺胺。 对于 2-60 岁的患者，体重≥ 20 千克的剂量为 5 毫克，体重＜ 20 千克的剂量为 0.25 毫克/千克。对于 6 个月至小于 2 岁的患者，剂量为 0.2 毫克/千克[ 17]。

Patients were enrolled across 24 different centers in Belgium, France, Germany, Italy, the Netherlands, Poland, Switzerland, the UK, and the USA. After 24 months of treatment, participants were invited to participate in the open-label extension phase to continue treatment for up to an additional 3 years.

比利时、法国、德国、意大利、荷兰、波兰、瑞士、英国和美国的 24 个不同中心招募了患者。经过24个月的治疗后，参与者被邀请参加开放标签延长阶段，继续接受长达3年的治疗。

Study assessments and outcomes

研究评估和成果

The primary objectives were to evaluate the safety and tolerability of risdiplam and to investigate the PK of risdiplam and metabolites, as appropriate. The secondary objective was to investigate the PK/PD relationship of risdiplam. Investigation of the PD included the analyses of SMN2 mRNA splice forms and SMN protein.

首要目标是评估利司扑兰的安全性和耐受性，并酌情研究利司扑兰及其代谢物的PK。次要目标是研究利司扑兰的PK/PD关系。对PD的研究包括分析SMN2 mRNA剪接形式和SMN蛋白。

Key exploratory objectives included evaluations of the efficacy of treatment with risdiplam in terms of motor and respiratory function. Functional assessments were dependent on the age of the patients. Patients aged 2–60 years were assessed using the 32-item Motor Function Measure (MFM32), the Hammersmith Functional Motor Scale—Expanded (HFMSE), and the Revised Upper Limb Module (RULM). Following the start of the study, the 6-min walk test (6MWT) was added as an exploratory endpoint for ambulant patients 6–60 years of age and therefore not all patients have baseline measurements. Patients aged ≤ 2 years were assessed using the Bayley Scales of Infant and Toddler Development, third edition (BSID-III), and achievement of motor milestones was assessed through the Hammersmith Infant Neurological Examination, Module 2 (HINE-2).

主要的探索性目标包括从运动和呼吸功能方面评估利司扑兰的疗效。功能评估取决于患者的年龄。2-60 岁的患者使用 32 项运动功能量表 (MFM32)、哈默史密斯运动功能量表扩展版 (HFMSE) 和修订版上肢模块 (RULM) 进行评估。研究开始后，针对 6-60 岁的步行患者增加了 6 分钟步行测试 (6MWT) 作为探索性终点，因此并非所有患者都进行了基线测量。使用贝利婴幼儿发育量表第三版（BSID-III）对年龄小于 2 岁的患者进行评估，并通过哈默史密斯婴儿神经系统检查模块 2（HINE-2）评估运动里程碑的实现情况。

Respiratory function was assessed in patients aged 6–60 years by spirometry tests and patients aged 2–60 years performed the sniff nasal inspiratory pressure test. Patient-reported independence in activities of daily living among patients aged 12–60 years and caregiver-reported independence for patients aged 2–60 years were assessed through the SMA Independence Scale–Upper Limb Module (SMAIS–ULM). This assessment was implemented after the study started and, therefore, not all patients have a baseline assessment.

6-60岁患者的呼吸功能通过肺活量测试进行评估，2-60岁患者则进行嗅鼻吸气压力测试。通过SMA独立性量表-上肢模块（SMAIS-ULM）对12-60岁患者的日常生活独立性和2-60岁患者的护理独立性进行评估。该评估是在研究开始后实施的，因此并非所有患者都有基线评估。

Safety data were reported for all patients and by previous treatment. Additional methods and exploratory efficacy data are reported in Online Resource 3.

报告了所有患者的安全性数据以及先前治疗的安全性数据。其他方法和探索性疗效数据见在线资料 3。

Results 成果

Patients 患者

In this analysis, patients had received risdiplam for ≥ 24 months by the clinical cut-off date (CCOD) of January 31, 2022. Between March 2017 and January 2020, a total of 182 patients were screened for eligibility with 174 participants meeting the recruitment criteria. Of the 174 patients enrolled in the study, one patient previously treated with olesoxime withdrew from the study at baseline prior to receiving risdiplam due to poor venous access as assessed by their physician. A total of 173 patients received risdiplam.

在这项分析中，截至 2022 年 1 月 31 日临床截止日期（CCOD），患者已接受利地普仑治疗≥ 24 个月。2017 年 3 月至 2020 年 1 月期间，共筛选出 182 名患者符合条件，其中 174 人符合招募标准。在174名参与研究的患者中，有一名曾接受奥利昔肟治疗的患者在接受利地普仑治疗前的基线阶段退出了研究，原因是经医生评估，其静脉通路不畅。共有 173 名患者接受了利血平治疗。

Patients were grouped according to their previous treatment types: 71 patients were previously treated with olesoxime in the OLEOS study (NCT02628743); 13 patients had previously been enrolled in the MOONFISH study, 10 of whom received RG7800 (RO6885237) and three who received placebo; 76 patients were previously treated with nusinersen, three of whom had also previously received olesoxime; 14 patients were previously treated with onasemnogene abeparvovec. One patient in the onasemnogene abeparvovec group had also received subsequent treatment with nusinersen. A total of 153 patients (87.9%) completed 24 months of treatment. Fifteen patients withdrew prior to the completion of 24 months of treatment, five patients did not attend the week 104 visit as of the CCOD and therefore are still represented as being in the open-label treatment period and one patient never received treatment (Fig. 1).

患者根据之前的治疗类型进行分组：71名患者曾在OLEOS研究（NCT02628743）中接受过奥利唑肟治疗；13名患者曾参加过MOONFISH研究，其中10人接受了RG7800（RO6885237）治疗，3人接受了安慰剂治疗；76名患者曾接受过nusinersen治疗，其中3人也曾接受过奥利唑肟治疗；14名患者曾接受过onasemnogene abeparvovec治疗。在onasemnogene abeparvovec组中，有一名患者随后也接受了nusinersen治疗。共有 153 名患者（87.9%）完成了 24 个月的治疗。15名患者在完成24个月的治疗前退出了治疗，5名患者没有参加CCOD第104周的访视，因此仍被视为处于开放标签治疗期，还有1名患者从未接受过治疗（图1）。

Baseline characteristics 基线特征

The patient population was broad and heterogeneous, covering a wide range of ages and baseline motor functions, and included patients with a high degree of motor impairment and other SMA comorbidities.

患者的年龄和基线运动功能各不相同，包括高度运动障碍和其他 SMA 合并症患者。

The median age of the JEWELFISH population at enrollment was 14 years (range 1–60); the median age at enrollment for patients who previously received nusinersen or onasemnogene abeparvovec was 12.0 years (range 1–60 and 2.0 years (range 1–5), respectively. The majority of patients had three SMN2 copies (78%). The median duration from symptom onset to first risdiplam administration was 134.5 months for patients who previously received nusinersen and 29 months for patients who previously received onasemnogene abeparvovec. The median time to first risdiplam administration from the last nusinersen dose was 4.6 months (range 3.5–19.3) and from treatment with onasemnogene abeparvovec was 16.8 months (range 13.3–21.4). In the subgroup of patients aged 2–60 years, 83% had scoliosis and 48% had received scoliosis surgery. Additionally, 63% had a baseline total score of <10 on the HFMSE. Detailed baseline characteristics can be found in Table 1. Fifteen patients with Type 3 SMA were ambulatory and had a median age at enrollment of 15 years (range 5–46).

JEWELFISH 患者入组年龄的中位数为 14 岁（1-60 岁不等）；之前接受过 nusinersen 或 onasemnogene abeparvovec 治疗的患者入组年龄的中位数分别为 12.0 岁（1-60 岁不等）和 2.0 岁（1-5 岁不等）。大多数患者有三个SMN2拷贝（78%）。曾接受过纽西奈森治疗的患者从症状出现到首次服用利血平的中位时间为134.5个月，曾接受过onasemnogene abeparvovec治疗的患者从症状出现到首次服用利血平的中位时间为29个月。从最后一次服用nusinersen到首次服用risdiplam的中位时间为4.6个月（3.5-19.3个月），从接受onasemnogene abeparvovec治疗到首次服用risdiplam的中位时间为16.8个月（13.3-21.4个月）。在 2-60 岁的患者分组中，83% 的患者患有脊柱侧弯，48% 的患者接受过脊柱侧弯手术。此外，63%的患者基线HFMSE总分小于10分。详细基线特征见表 1。15名3型SMA患者可以行走，入组年龄中位数为15岁（5-46岁）。

Safety 安全

The median duration of exposure to risdiplam was 26.8 months (range 0.9–59) and the median dose intensity (i.e., the number of doses received divided by the expected number of doses) of risdiplam in all patients was 99.7% (range 24.7–100%). Safety results in all patients enrolled in JEWELFISH (n = 174) are summarized in Table 2. Overall, 96% of patients reported ≥ 1 AE, and 20% of patients reported ≥ 1 SAE. In patients previously treated with nusinersen, 96% reported ≥ 1 AE and 21% ≥ 1 SAE. All patients previously treated with onasemnogene abeparvovec experienced ≥ 1 AE, whereas 29% had ≥ 1 SAE. There was one SAE (Grade 2 supraventricular tachycardia) that was considered related to risdiplam treatment in a patient previously treated with olesoxime. There were no treatment-related SAEs in any patients who were previously enrolled in the MOONFISH study or who had previously received treatment with nusinersen or onasemnogene abeparvovec.

所有患者暴露于利地普仑的中位持续时间为 26.8 个月（范围为 0.9-59），利地普仑的中位剂量强度（即接受的剂量数除以预期剂量数）为 99.7%（范围为 24.7-100%）。表 2 总结了 JEWELFISH 所有入组患者（n = 174）的安全性结果。总体而言，96%的患者报告了≥1次AE，20%的患者报告了≥1次SAE。在既往接受过诺西奈森治疗的患者中，96%报告的AE≥1次，21%报告的SAE≥1次。所有曾接受过onasemnogene abeparvovec治疗的患者均发生了≥1次AE，而29%的患者发生了≥1次SAE。有1例SAE（2级室上性心动过速）被认为与利血平治疗有关，该患者曾接受过奥来肟治疗。曾参加 MOONFISH 研究或曾接受过 nusinersen 或 onasemnogene abeparvovec 治疗的患者均未发生与治疗相关的 SAE。

The proportion of patients with Grade 3–5 AEs in the overall safety population was 21%. When separated by patients previously treated with nusinersen or onasemnogene abeparvovec, the proportion was 25% and 21%, respectively. Six Grade 4 AEs occurred in three patients, which were unrelated to risdiplam and resolved without dose modification, and there were no patients with Grade 5 AEs.

在总体安全性人群中，出现 3-5 级 AEs 的患者比例为 21%。如果按曾接受过nusinersen或onasemnogene abeparvovec治疗的患者划分，这一比例分别为25%和21%。有3名患者出现了6例4级AE，这些AE与利血平无关，无需调整剂量即可缓解，没有患者出现5级AE。

Across all patients, the most common AEs were pyrexia (24%), upper respiratory tract infection (URTI, 21%), and headache (18%). Patients previously treated with nusinersen experienced pyrexia (30%), diarrhea, headache, and URTI (22% for each), whereas patients previously treated with onasemnogene abeparvovec experienced pyrexia (43%), nasopharyngitis (36%), and URTI (29%) as common AEs. Pneumonia (3%) was the most reported SAE for all JEWELFISH patients, including those previously treated with nusinersen (4%) or onasemnogene abeparvovec (7%).

在所有患者中，最常见的不良反应是热病（24%）、上呼吸道感染（URTI，21%）和头痛（18%）。曾接受过 nusinersen 治疗的患者会出现发热（30%）、腹泻、头痛和 URTI（各占 22%），而曾接受过 onasemnogene abeparvovec 治疗的患者会出现发热（43%）、鼻咽炎（36%）和 URTI（29%）等常见 AEs。肺炎（3%）是所有 JEWELFISH 患者报告最多的 SAE，包括之前接受过 nusinersen（4%）或 onasemnogene abeparvovec（7%）治疗的患者。

When adjusted for patient-years (PY) at risk, the overall AE and SAE rates for all patients during the total treatment period were 334.66 events per 100 PY (95% confidence interval [CI] 316.91–353.15) and 19.14 events per 100 PY (95% CI 15.08–23.95), respectively. The rate of AEs and SAEs decreased over the duration of the JEWELFISH study (Fig. 2). During the first 6 months of treatment, the AE rate was 653.86 events per 100 PY (95% CI 600.77–710.38; total PY at risk: 85.5 years) and remained stable for the following three 6-month periods. Over the period of 0–12 months of treatment, the AE rate was 475.51 events per 100 PY (95% CI 443.17–509.59; total PY at risk: 168.7 years) and the SAE rate was 25.50 events per PY (95% CI 18.45–34.34). Comparing the 0–12 months treatment period with the 12–24 months treatment period, a 50% decrease in the rate of AEs was observed, with 225.65 AEs per 100 PY (95% CI 203.04–250.10; total PY at risk: 160.9 years) and 9.95 SAEs per 100 PY (95% CI 5.69–16.15).

经风险患者年（PY）调整后，在整个治疗期间，所有患者的总体 AE 和 SAE 发生率分别为每 100 PY 334.66 例（95% 置信区间 [CI] 316.91-353.15）和每 100 PY 19.14 例（95% 置信区间 [CI] 15.08-23.95）。在 JEWELFISH 研究期间，AEs 和 SAEs 的发生率有所下降（图 2）。在治疗的前 6 个月，AE 发生率为 653.86 例/100 PY（95% CI 600.77-710.38；风险总 PY：85.5 年），并在随后的三个 6 个月期间保持稳定。在 0-12 个月的治疗期间，AE 发生率为每百人 475.51 例（95% CI 443.17-509.59；总风险年限：168.7 年），SAE 发生率为每百人 25.50 例（95% CI 18.45-34.34）。将 0-12 个月的治疗期与 12-24 个月的治疗期进行比较，观察到 AEs 发生率下降了 50%，每 100 人中有 225.65 例 AEs（95% CI 203.04-250.10；风险总人数：160.9 岁），每 100 人中有 9.95 例 SAEs（95% CI 5.69-16.15）。

The decline in the overall rate of AEs was reflected in decreases in the rates of the most common AEs. Comparing the rates of the common AEs per 100 PY between the first and fourth 6-month treatment periods (0 to ≤ 6 months vs. > 18 to ≤ 24 months) showed declines in pyrexia (31.58 to 13.93), URTI (37.43 to 13.93), and headache (44.45 to 7.60); the rate of the most common SAE of pneumonia also decreased (4.68 to 1.27). There were no treatment-related safety findings that led to a withdrawal.

AEs总发生率的下降反映在最常见AEs发生率的下降上。比较第一个和第四个 6 个月治疗期（0 至 ≤ 6 个月 vs. > 18 至 ≤ 24 个月）每 100 人次的常见 AEs 发生率，发现热病（31.58 至 13.93）、尿崩症（37.43 至 13.93）和头痛（44.45 至 7.60）的发生率有所下降；肺炎这种最常见的 SAE 发生率也有所下降（4.68 至 1.27）。没有发现导致停药的治疗相关安全性问题。

A review of all available safety laboratory results, vital signs, electrocardiograms, and ophthalmologic assessments did not show any clinically significant adverse findings compared with baseline. As of the CCOD, there have been no safety findings in patients reflective of potential risks previously identified from non-clinical toxicology studies (effects on epithelial tissues, retinal toxicity, or hematologic effects).

对所有可用的安全性实验室结果、生命体征、心电图和眼科评估进行的审查显示，与基线值相比，没有发现任何具有临床意义的不良反应。截至 CCOD，尚未在患者中发现任何反映先前在非临床毒理学研究中发现的潜在风险（对上皮组织的影响、视网膜毒性或血液学影响）的安全性结果。

Secondary endpoint 次要终点

PK/PD of risdiplam 利司扑兰的 PK/PD

Risdiplam exposure was comparable across the JEWELFISH patient population at the selected dosing regimen and the mean area under the concentration–time curve from 0–24 h (AUC0–24) was 1700 ng.h/mL. Details of the PK/PD from JEWELFISH will be reported as part of a full analysis of the PK/PD across the risdiplam clinical trial program.

JEWELFISH患者在选定给药方案下的利司扑兰暴露量相当，0-24小时的平均浓度-时间曲线下面积（AUC 0–24 ）为1700纳克/小时/毫升。JEWELFISH的PK/PD详情将作为整个risdiplam临床试验项目PK/PD全面分析的一部分进行报告。

At baseline, the concentration of SMN protein in blood was comparable across all treatment groups. After 4 weeks of treatment with risdiplam, SMN protein levels in blood showed a two-fold change from baseline in all groups, regardless of previous treatment, and sustained increases in the level of SMN protein in blood were observed over 24 months of treatment (Fig. 3).

基线时，所有治疗组的血液中 SMN 蛋白浓度相当。使用利司扑兰治疗 4 周后，所有治疗组的血液中 SMN 蛋白水平都比基线高出两倍，与之前的治疗无关，并且在 24 个月的治疗中观察到血液中 SMN 蛋白水平持续上升（图 3）。

At month 24, the median fold (minimum–maximum) change in SMN protein levels in whole blood was 1.87 (0.60–4.17) and 1.52 (0.23–3.19) in patients previously treated with nusinersen and onasemnogene abeparvovec, respectively.

第 24 个月时，曾接受过诺西能森和奥那西莫金阿帕沃韦治疗的患者全血中 SMN 蛋白水平的中位折叠（最小-最大）变化分别为 1.87（0.60-4.17）和 1.52（0.23-3.19）。

Key exploratory efficacy endpoints

主要探索性疗效终点

Motor function in patients aged 2–60 years

2-60 岁患者的运动功能

Exploratory motor function outcomes (assessed by the MFM32, RULM, and HFMSE scales) were analyzed from the ITT population, which included 167 patients aged 2–60 years (Fig. 4a-c, Table 3). Stabilization of the MFM32 total score was observed from baseline to month 24 (Fig. 4a), with a mean change of –0.17 (95% CI –1.03 to 0.68, n = 137).

对包括 167 名 2-60 岁患者在内的 ITT 群体的探索性运动功能结果（通过 MFM32、RULM 和 HFMSE 量表评估）进行了分析（图 4a-c，表 3）。从基线到第 24 个月，观察到 MFM32 总分趋于稳定（图 4a），平均变化为-0.17（95% CI -1.03 至 0.68，n = 137）。

Stabilization in upper limb function as shown by the mean RULM total score was also observed from baseline to month 24 (Fig. 4b, Table 3). At month 24, the mean change from baseline in RULM total score was 0.71 (95% CI 0.17–1.26, n = 133). On average, the HFMSE total score was stable at month 24 compared with baseline (Fig. 4c, Table 3). At month 24, the mean change from baseline in the HFMSE total score was –0.11 (95% CI –0.98 to 0.76, n = 132). Exploratory motor function endpoints (MFM32, RULM, and HFMSE) at month 12 and month 24 are reported in Online Resource 3 (Table S1).

从基线到第 24 个月，RULM 总分的平均值也显示上肢功能趋于稳定（图 4b，表 3）。第 24 个月时，RULM 总分与基线相比的平均变化为 0.71（95% CI 0.17-1.26，n = 133）。平均而言，与基线相比，第 24 个月的 HFMSE 总分保持稳定（图 4c，表 3）。第 24 个月时，HFMSE 总分与基线相比的平均变化为-0.11（95% CI -0.98-0.76，n = 132）。在线资料 3（表 S1）中报告了第 12 个月和第 24 个月的探索性运动功能终点（MFM32、RULM 和 HFMSE）。

An increase in the caregiver-reported SMAIS–ULM total score was observed from baseline to month 24. At month 24, the mean change from baseline in caregiver-reported SMAIS–ULM total score was 1.90 (95% CI 0.70–3.10, n = 110). Respiratory function, as measured by the sniff nasal inspiratory pressure test, showed a mean change of 0.14% (95% CI –2.64 to 2.92, n = 113) from baseline to month 24. Full details on the SMAIS–ULM and respiratory function can be found in Online Resource 3.

从基线到第 24 个月，护理人员报告的 SMAIS-ULM 总分有所增加。第 24 个月时，护理人员报告的 SMAIS-ULM 总分与基线相比的平均变化为 1.90（95% CI 0.70-3.10，n = 110）。通过嗅鼻吸气压力测试测量的呼吸功能从基线到第 24 个月的平均变化为 0.14%（95% CI -2.64-2.92，n = 113）。有关 SMAIS-ULM 和呼吸功能的详细信息，请参阅在线资料 3。

A post hoc analysis of motor function measures (MFM32, RULM, and HFMSE) among a subgroup of patients aged 25–60 years was also performed. Stabilization after 24 months of treatment with risdiplam was observed within this age group (Table S2).

此外，还对 25-60 岁患者分组的运动功能指标（MFM32、RULM 和 HFMSE）进行了事后分析。该年龄组的患者在使用利司扑兰治疗 24 个月后病情趋于稳定（表 S2）。

Analyses of motor function measures by previous treatment

按先前治疗方法分析运动功能测量结果

Exploratory motor function measures following 24 months of treatment with risdiplam are reported for nusinersen (n = 59) and onasemnogene abeparvovec patients (n = 9) aged 2–60 years (Table S1). For patients who were previously treated with nusinersen, the mean (95% CI) change from baseline to month 24 in the MFM32 total score was –1.25 (–2.55 to 0.04, n = 59); the change in RULM total score was 0.50 (–0.20 to 1.20, n = 58); and the change in HFMSE total score was –1.21 (–2.79 to 0.36, n = 56).

报告了2-60岁的nusinersen患者（n = 59）和onasemnogene abeparvovec患者（n = 9）接受利司扑兰治疗24个月后的运动功能探索性测量结果（表S1）。对于之前接受过纽西奈森治疗的患者，MFM32总分从基线到第24个月的平均变化（95% CI）为-1.25（-2.55到0.04，n = 59）；RULM总分的变化为0.50（-0.20到1.20，n = 58）；HFMSE总分的变化为-1.21（-2.79到0.36，n = 56）。

For patients who had previously received onasemnogene abeparvovec, an increase from baseline to month 24 was observed in each of the motor function scales: for the MFM32 total score, the mean (95% CI) change was 6.25 (0.31–12.19, n = 9); for the RULM total score, the change was 6.11 (2.11–10.11, n = 9); and for the HFMSE total score, the change was 7.11 (3.93–10.29, n = 9).

对于之前接受过onasemnogene abeparvovec治疗的患者，从基线到第24个月，每项运动功能评分都有所提高：MFM32总分的平均（95% CI）变化为6.25（0.31-12.19，n = 9）；RULM总分的变化为6.11（2.11-10.11，n = 9）；HFMSE总分的变化为7.11（3.93-10.29，n = 9）。

6MWT in ambulant patients

步行患者的 6MWT

Overall, 15 patients with Type 3 SMA were ambulant at baseline. Of the 14 ambulant patients aged ≥ 6 years, 13 patients were assessed with the 6MWT at any time point during the study. All 13 ambulant patients maintained their ability to walk. Among the eight patients who were evaluated both at baseline and at month 24 (all eight patients were previously treated with nusinersen) there was a mean (95% CI) increase from baseline in the total distance walked of 30.88 m (–5.54 to 67.29, n = 8) at month 24 (Table S1).

总体而言，有 15 名 3 型 SMA 患者在基线时可以行走。在 14 名年龄≥ 6 岁的步行患者中，有 13 名患者在研究期间的任何时间点接受了 6MWT 评估。所有 13 名行动自如的患者都保持了行走能力。在基线和第 24 个月都接受评估的 8 名患者中（所有 8 名患者之前都接受过诺西奈森治疗），第 24 个月时总步行距离比基线平均（95% CI）增加了 30.88 米（-5.54 到 67.29 米，n = 8）（表 S1）。

The two ambulant patients who did not perform the 6MWT were assessed with regard to their ability to walk using the HFMSE (achieving a score of 2 points on Item 20, ‘stepping’). These two patients scored 2 on all assessments. Therefore, all ambulant patients maintained their ability to walk.

对两名未进行 6MWT 的行动不便患者使用 HFMSE 进行了步行能力评估（在第 20 项 "迈步 "上获得 2 分）。这两名患者在所有评估中均为 2 分。因此，所有行动自如的患者都保持了行走能力。

Motor function in patients aged < 2 years

年龄小于 2 岁患者的运动功能

The ITT population included six patients aged < 2 years, three had previously received nusinersen and three had previously received onasemnogene abeparvovec (Table 1). Sitting for 5 s (Item 22 of the BSID-III Gross Motor Scale) was present at baseline in one (33.3%) patient previously treated with nusinersen, and in two patients (66.6%) previously treated with onasemnogene abeparvovec; by month 24, all six patients (100%) were sitting for 5 s.

ITT人群包括6名年龄小于2岁的患者，其中3人曾接受过诺西奈森治疗，3人曾接受过onasemnogene abeparvovec治疗（表1）。一名患者（33.3%）和两名患者（66.6%）在基线时都能坐5秒（BSID-III粗大运动量表第22项），前者曾接受过诺西奈森治疗，后者曾接受过onasemnogene abeparvovec治疗；到第24个月时，所有六名患者（100%）都能坐5秒。

Sitting without support for ≥ 30 s (Item 26 of the BSID-III Gross Motor Scale) was present in two patients (33%) at baseline; by month 24, three patients (50%) had achieved the milestone.

基线时，有两名患者（33%）在无支撑的情况下坐立时间≥30 秒（BSID-III 粗大运动量表第 26 项）；到第 24 个月时，有三名患者（50%）达到了这一里程碑。

At month 24 of treatment, all six patients (100%) were classified as motor milestone responders. An infant was classified as a motor milestone responder if more motor milestones on the HINE-2 showed improvement than showed worsening compared with baseline.

在治疗的第 24 个月，所有六名患者（100%）都被归类为运动里程碑反应者。如果与基线相比，HINE-2 运动里程碑的改善次数多于恶化次数，则婴儿被归类为运动里程碑应答者。

Post hoc analyses of safety data

安全数据的事后分析

Comparison between non-treatment-naïve and treatment-naïve patients

未接受治疗和接受治疗患者的比较

The rates of AEs and SAEs in patients in the JEWELFISH study were compared with the rates observed in treatment-naïve patients in the FIREFISH [22, 23] and SUNFISH [24] trials based upon SMA type (Fig. 5). In patients with Type 1 SMA in JEWELFISH, the overall AE rate was 323.40 events per 100 PY (95% CI 263.69–392.58) versus 465.53 events per 100 PY (95% CI 436.20–496.39) in the previously treatment-naïve patients with Type 1 SMA treated with risdiplam in the FIREFISH study. In patients with Types 2 and 3 SMA treated with risdiplam in JEWELFISH, the overall AE rate was 335.63 events per 100 PY (95% CI 317.11–354.95) versus 542.31 events per 100 PY (95% CI 513.00–572.87) in previously treatment-naïve patients with Types 2 and 3 SMA treated with risdiplam in the SUNFISH Part 2 study.

根据 SMA 类型，将 JEWELFISH 研究中患者的 AE 和 SAE 发生率与 FIREFISH [ 22, 23] 和 SUNFISH [ 24] 试验中治疗无效患者的发生率进行了比较（图 5）。在 JEWELFISH 试验中，1 型 SMA 患者的总体 AE 发生率为每 100 人 323.40 例（95% CI 263.69-392.58），而在 FIREFISH 试验中，先前接受过利地平治疗的 1 型 SMA 患者的 AE 发生率为每 100 人 465.53 例（95% CI 436.20-496.39）。在JEWELFISH研究中，接受利司扑兰治疗的2型和3型SMA患者的总AE发生率为每100 PY 335.63例（95% CI 317.11-354.95），而在SUNFISH Part 2研究中，接受利司扑兰治疗的2型和3型SMA患者的总AE发生率为每100 PY 542.31例（95% CI 513.00-572.87）。

A decline in the rates of AEs and SAEs was observed for both non-treatment-naïve and treatment-naïve patients in the risdiplam pivotal trials over a 24-month period (Fig. 5).

在为期24个月的利司扑兰关键试验中，未接受治疗和接受治疗的患者的AEs和SAEs发生率均有所下降（图5）。

Discussion 讨论

This analysis of the JEWELFISH study examined the safety of risdiplam after 24 months of treatment in patients who had previously received an SMA DMT or were previously enrolled in a trial of an investigational therapy for SMA. Based on the review of all available safety data, risdiplam was well tolerated and the safety profile was in accordance with the known safety profile of risdiplam irrespective of previous treatment. The safety profile of risdiplam in JEWELFISH is consistent with results from treatment-naïve individuals who received risdiplam in the FIREFISH and SUNFISH studies.

这项对JEWELFISH研究的分析考察了曾接受过SMA DMT治疗或曾参加过SMA研究性疗法试验的患者在接受24个月治疗后使用利司扑兰的安全性。根据对所有可用安全性数据的审查，利司扑兰的耐受性良好，安全性与利司扑兰的已知安全性相符，与之前的治疗无关。在JEWELFISH研究中，利司扑兰的安全性与FIREFISH和SUNFISH研究中接受利司扑兰治疗的未接受治疗者的结果一致。

The majority of AEs were reflective of underlying disease, and most AEs were mild to moderate in intensity. There was a considerable decline in the AE rate after the first 6 months of treatment and a decrease in the overall rate of SAEs per 100 PY over time. More specifically, the AE rate declined by over 50% between the first and second years of risdiplam treatment, and this decrease was reflected in the most common AEs (pyrexia, URTI, and headache). No treatment-related safety findings have led to withdrawal from treatment.

大多数 AE 反映了潜在的疾病，大多数 AE 的强度为轻度至中度。治疗头 6 个月后，AE 发生率大幅下降，每百人年的 SAE 总发生率也随时间推移而下降。更具体地说，在利司扑兰治疗的第一年和第二年之间，AE发生率下降了50%以上，这种下降体现在最常见的AE（发热、尿路感染和头痛）上。没有任何与治疗相关的安全性结果导致患者放弃治疗。

Risdiplam treatment led to a median two-fold increase in blood SMN protein levels after 4 weeks of treatment and increased SMN protein was observed for the 24 months of follow-up, irrespective of previous treatment.

利司扑兰治疗 4 周后，血液中 SMN 蛋白水平的中位数增加了两倍，在 24 个月的随访中，无论之前是否接受过治疗，都观察到了 SMN 蛋白的增加。

Following 24 months of risdiplam treatment in this weak patient population, the exploratory efficacy data show stabilization in motor function as assessed by the MFM32, RULM, and HFMSE. Although direct comparisons with published data cannot be made, longitudinal studies of untreated patients consistently report a considerable decline in measures of motor function [25,26,27,28,29]. For instance, natural history studies evaluating untreated patients with Types 2 and 3 SMA have reported a decline in mean MFM32 total score over 24 months (–2.08 points; patients aged 2–30 years) [26], in median RULM total score over 24 months (–0.79 points; patients aged 5–56 years) [27], and mean HFMSE total score over 24 months (–1.74 points; patients aged 2–34 years) [29]. A survey that captures patient expectations at the time when DMTs were made available, identified that stabilization of clinical condition is a benefit [30].

在对这一体质较弱的患者群体进行 24 个月的利西地平治疗后，探索性疗效数据显示，通过 MFM32、RULM 和 HFMSE 评估，患者的运动功能趋于稳定。虽然无法与已发表的数据进行直接比较，但对未接受治疗的患者进行的纵向研究一致报告称，患者的运动功能会显著下降[25, 26, 27, 28, 29]。例如，对未经治疗的 2 型和 3 型 SMA 患者进行的自然史评估研究报告称，24 个月内 MFM32 平均总分下降（-2.08 分；患者年龄为 2-30 岁）[26]，24 个月内 RULM 中位总分下降（-0.79 分；患者年龄为 5-56 岁）[27]，24 个月内 HFMSE 平均总分下降（-1.74 分；患者年龄为 2-34 岁）[29]。一项调查收集了患者在获得 DMTs 时的期望值，发现稳定临床状况是一项益处[30]。

Among ambulant patients, an increase in the total distance walked in the 6MWT was observed after 24 months of risdiplam treatment. In a natural history study of patients of a similar age, there was a decline in the total distance walked in the 6MWT (–20.8 m per year, patients 11–19 years of age) [31]. None of the ambulant patients assessed by the 6MWT lost their ability to walk.

在接受利司扑兰治疗 24 个月后，在行动自如的患者中，6MWT 步行总距离有所增加。在一项对年龄相仿的患者进行的自然史研究中，6MWT步行总距离有所下降（每年-20.8米，11-19岁患者）[ 31]。在接受 6MWT 评估的患者中，没有人丧失行走能力。

Overall, the coronavirus disease 2019 (COVID-19) pandemic did not significantly impact the ability to monitor and manage patient safety during the study, and treatment compliance, as reflected by the dose intensity, was high across all patients (99.7% of planned doses were received). The oral dosing regimen reduced the need for travel to the hospital to receive treatment and was particularly beneficial when participants may have been limited by travel restrictions. For many patients who enrolled towards the end of the recruitment period, the 6-month visit fell during the first peak of the pandemic and so attendance to the clinical sites was affected due to restriction measures at site and national levels. On-site visit attendance improved after the COVID-19 travel restrictions were relaxed, as demonstrated by the high percentage of patients who completed visits at month 12 and month 24.

总体而言，2019 年冠状病毒病（COVID-19）大流行并未对研究期间监测和管理患者安全的能力产生重大影响，而且所有患者的治疗依从性都很高（99.7% 的患者接受了计划剂量的治疗），这一点从剂量强度上就能反映出来。口服给药方案减少了患者前往医院接受治疗的次数，在参与者可能受到旅行限制的情况下，口服给药方案尤其有益。对于许多在招募期末期加入的患者来说，6 个月的就诊时间正值大流行的第一个高峰期，因此由于现场和国家层面的限制措施，临床现场的就诊率受到了影响。COVID-19 旅行限制放宽后，现场就诊率有所提高，第 12 个月和第 24 个月完成就诊的患者比例很高，就证明了这一点。

Limitations 局限性

JEWELFISH was an open-label study; there was no control group and all efficacy endpoints were exploratory. Therefore, caution should be taken in making conclusions from the efficacy data.

JEWELFISH 是一项开放标签研究；没有对照组，所有疗效终点都是探索性的。因此，从疗效数据中得出结论应谨慎。

Potentially, the broad inclusion criteria of JEWELFISH, which enrolled patients who had previously received other SMA treatments, may have been biased towards a patient population that had not optimally responded to previous treatment and/or who subjectively felt they needed more treatment efficacy.

JEWELFISH 采用了广泛的纳入标准，纳入了之前接受过其他 SMA 治疗的患者，这可能偏向于对之前的治疗没有最佳反应和/或主观上认为需要更多疗效的患者群体。

Furthermore, caution should be taken when interpreting the HFMSE score in weak patients due to floor effects [32], and for the JEWELFISH population, other motor function scores such as the MFM32 or RULM may be more informative. Caution should be also taken with the interpretation of the subgroup data analyses which were conducted with a small sample of patients. Also, differences in the demographics between the subgroups, in particular, those previously treated with nusinersen or onasemnogene abeparvovec, make comparisons of efficacy difficult to interpret. There is a lack of a single universal functional outcome that can sensitively measure functional changes among this broad and heterogeneous patient group, thus making the interpretation of efficacy challenging.

此外，由于底限效应，在解释虚弱患者的 HFMSE 评分时应谨慎[32]，对于 JEWELFISH 群体，其他运动功能评分（如 MFM32 或 RULM）可能更有参考价值。此外，在解释亚组数据分析时也应谨慎，因为亚组数据分析是在少量患者样本的基础上进行的。此外，各亚组之间的人口统计学差异，尤其是既往接受过纽西奈森或onasemnogene abeparvovec治疗的患者，也使得疗效比较难以解释。目前还缺乏一种通用的功能结果，可以灵敏地测量这一广泛而异质的患者群体的功能变化，因此疗效的解释具有挑战性。

Some assessments may have been affected due to travel restrictions during the COVID-19 pandemic. Although these restrictions may have contributed to lower rates of AEs between months 6 and 12 of the study, when patients were required to spend more time indoors with limited in-person socialization, the exact impact cannot be determined.

由于 COVID-19 大流行期间的旅行限制，一些评估可能受到了影响。在研究的第 6 个月和第 12 个月期间，患者需要在室内度过更多时间，人际交往受到限制，因此这些限制可能导致 AEs 发生率降低，但具体影响尚无法确定。

Conclusions 结论

The safety profile of risdiplam in the JEWELFISH study was consistent with results from the FIREFISH [22, 23] and SUNFISH studies [24]. A similar PD response was observed in this patient population; a median two-fold increase in SMN protein levels was achieved across all subgroups regardless of prior treatment, and the increase was consistent with results observed in treatment-naïve patients from the FIREFISH and SUNFISH trials. Although efficacy endpoints were exploratory, overall stabilization of motor function was observed in treated patients from baseline to month 24. All ambulant patients retained their ability to walk.

在 JEWELFISH 研究中，利司扑兰的安全性与 FIREFISH [ 22, 23] 和 SUNFISH [ 24] 研究的结果一致。在这一患者群体中观察到了类似的PD反应；所有亚组的SMN蛋白水平中位数增加了两倍，与之前的治疗无关，这一增加与FIREFISH和SUNFISH试验中在治疗无效患者中观察到的结果一致。虽然疗效终点是探索性的，但从基线到第24个月，接受治疗的患者运动功能总体趋于稳定。所有行动自如的患者都保持了行走能力。

Results from the analysis of JEWELFISH after 24 months provide further evidence that risdiplam can be safely received by patients who have previously been treated with nusinersen or onasemnogene abeparvovec. The JEWELFISH open-label extension phase is ongoing and will provide further long-term safety data on risdiplam in this non-treatment-naïve patient population.

JEWELFISH 24 个月后的分析结果进一步证明，之前接受过 nusinersen 或 onasemnogene abeparvovec 治疗的患者可以安全地接受利司扑兰治疗。JEWELFISH开放标签扩展阶段正在进行中，它将进一步提供利司扑兰在这一非治疗无效患者群体中的长期安全性数据。