Gowda Vasantha, Atherton Mark, Murugan Archana, Servais Laurent, Sheehan Jennie, Standing Emma, Manzur Adnan, Scoto Mariacristina, Baranello Giovanni, Munot Pinki, McCullagh Gary, Willis Tracey, Tirupathi Sandya, Horrocks Iain, Dhawan Anil, Eyre Michael, Vanegas Maria, Fernandez-Garcia Miguel A, Wolfe Amy, Pinches Laura, Illingworth Marjorie, Main Marion, Abbott Lianne, Smith Hayley, Milton Emily, D'Urso Sarah, Vijayakumar Kayal, Marco Silvia Sanchez, Warner Sinead, Reading Emily, Douglas Isobel, Muntoni Francesco, Ong Min, Majumdar Anirban, Hughes Imelda, Jungbluth Heinz, Wraige Elizabeth
Children's Neurosciences, Evelina London Children's Hospital, Guy's and St Thomas' NHS Foundation Trust, London, United Kingdom.
Sheffield Children's NHS Foundation Trust, Sheffield, United Kingdom.
Lancet Reg Health Eur. 2023 Dec 11;37:100817. doi: 10.1016/j.lanepe.2023.100817. eCollection 2024 Feb.
Real-world data on the efficacy and safety of onasemnogene abeparvovec (OA) in spinal muscular atrophy (SMA) are needed, especially to overcome uncertainties around its use in older and heavier children. This study evaluated the efficacy and safety of OA in patients with SMA type 1 in the UK, including patients ≥2 years old and weighing ≥13.5 kg.
This observational cohort study used data from patients with genetically confirmed SMA type 1 treated with OA between May 2021 and January 2023, at 6 infusion centres in the United Kingdom. Functional outcomes were assessed using age-appropriate functional scales. Safety analyses included review of liver function, platelet count, cardiac assessments, and steroid requirements.
Ninety-nine patients (45 SMA therapy-naïve) were treated with OA (median age at infusion: 10 [range, 0.6-89] months; median weight: 7.86 [range, 3.2-20.2] kg; duration of follow-up: 3-22 months). After OA infusion, mean ± SD change in CHOP-INTEND score was 11.0 ± 10.3 with increased score in 66/78 patients (84.6%); patients aged <6 months had a 13.9 points higher gain in CHOP-INTEND score than patients ≥2 years (95% CI, 6.8-21.0; < 0.001). Asymptomatic thrombocytopenia (71/99 patients; 71.7%), asymptomatic troponin-I elevation (30/89 patients; 33.7%) and transaminitis (87/99 patients; 87.9%) were reported. No thrombotic microangiopathy was observed. Median steroid treatment duration was 97 (range, 28-548) days with dose doubled in 35/99 patients (35.4%). There were 22.5-fold increased odds of having a transaminase peak >100 U/L (95% CI, 2.3-223.7; = 0.008) and 21.2-fold increased odds of steroid doubling, as per treatment protocol (95% CI, 2.2-209.2; = 0.009) in patients weighing ≥13.5 kg versus <8.5 kg. Weight at infusion was positively correlated with steroid treatment duration (r = 0.43; < 0.001). Worsening transaminitis, despite doubling of oral prednisolone, led to treatment with intravenous methylprednisolone in 5 children. Steroid-sparing immunosuppressants were used in 5 children to enable steroid weaning. Two deaths apparently unrelated to OA were reported.
OA led to functional improvements and was well tolerated with no persistent clinical complications, including in older and heavier patients.
Novartis Innovative Therapies AG provided a grant for independent medical writing services.
需要有关onasemnogene abeparvovec（OA）治疗脊髓性肌萎缩症（SMA）的疗效和安全性的真实世界数据，尤其是为了克服在年龄较大和体重较重的儿童中使用该药的不确定性。本研究评估了OA在英国1型SMA患者中的疗效和安全性，包括年龄≥2岁且体重≥13.5千克的患者。
这项观察性队列研究使用了2021年5月至2023年1月期间在英国6个输液中心接受OA治疗的基因确诊1型SMA患者的数据。使用适合年龄的功能量表评估功能结局。安全性分析包括肝功能、血小板计数、心脏评估和类固醇需求的审查。
99例患者（45例未接受过SMA治疗）接受了OA治疗（输注时的中位年龄：10[范围，0.6 - 89]个月；中位体重：7.86[范围，3.2 - 20.2]千克；随访时间：3 - 22个月）。OA输注后，CHOP - INTEND评分的平均±标准差变化为11.0±10.3，74，78例患者中有66例（84.6%）评分增加；年龄<6个月的患者CHOP - INTEND评分比年龄≥2岁的患者高13.9分（95%CI，6.8 - 21.0；P<0.001）。报告了无症状血小板减少症（71/99例患者；71.7%）、无症状肌钙蛋白 - I升高（30/89例患者；33.7%）和转氨酶升高（87/99例患者；87.9%）。未观察到血栓性微血管病。类固醇治疗的中位持续时间为97（范围，28 - 548）天，99例患者中有35例（35.4%）剂量加倍。与体重<8.5千克的患者相比，体重≥13.5千克的患者转氨酶峰值>100 U/L的几率增加22.5倍（95%CI，2.3 - 223.7；P = 0.008），按照治疗方案类固醇剂量加倍的几率增加21.2倍（95%CI，2.2 - 209.2；P = 0.009）。输注时的体重与类固醇治疗持续时间呈正相关（r = 0.43；P<0.001）。尽管口服泼尼松龙剂量加倍，但转氨酶升高恶化，导致5名儿童接受静脉注射甲泼尼龙治疗。5名儿童使用了节省类固醇的免疫抑制剂以实现类固醇减量。报告了2例显然与OA无关的死亡病例。
OA导致功能改善且耐受性良好，没有持续性临床并发症，包括在年龄较大和体重较重的患者中。
诺华创新疗法股份公司为独立医学写作服务提供了资助。
