Safety and Treatment Effects of Nusinersen in Longstanding Adult 5q-SMA Type 3-A Prospective Observational Study
Safety and Treatment Effects of Nusinersen in Longstanding Adult 5q-SMA Type 3-A Prospective Observational Study
复制标题
DOI：
10.3233/jnd-190416
复制
发表时间：
2019-01-01
影响因子：
3.3
通讯作者：
Schoser, Benedikt
中科院分区：
文献类型：
--
作者：
Walter, Maggie C.;Wenninger, Stephan;Schoser, Benedikt
目的：脊髓性肌萎缩症（SMA）是一种由SMN1基因缺失引起的进行性常染色体隐性运动神经元疾病。基于对1型和2型SMA儿童的随机临床试验，诺西那生已被批准为所有类型SMA的首种治疗方法，包括3型SMA成人患者。
方法：我们评估了诺西那生在长期患病的成人5q - SMA 3型患者中的安全性和治疗效果。患者在第1天、第14天、第28天和第63天接受鞘内负荷剂量治疗，之后每4个月接受一次维持剂量治疗，直至300天。我们在SMArtCARE项目中对患者进行监测，这是一项针对疾病进展、副作用和治疗疗效的前瞻性开放标签结果研究，包括临床检查，如医学研究委员会（MRC）总分、坐位肺活量（VC，VC%预计值）、肌萎缩侧索硬化功能评定量表（ALS - FRS）、6分钟步行试验（6MWT）、修订版上肢模块（RULM）和哈默史密斯功能评定量表（HFMSE）。我们还测量了脑脊液中的生物标志物（磷酸化神经丝重链pNFH、神经元特异性烯醇化酶NSE、蛋白质、β - 淀粉样蛋白1 - 40、β - 淀粉样蛋白1 - 42、tau蛋白和磷酸化tau蛋白）以及肌酸激酶（CK）。在基线、第63天（V4）、第180天（V5）和第300天（V6）进行评估。对于统计分析，我们使用配对样本t检验比较基线与V4、V5和V6。当存在显著差异时，我们添加科恩d值和效应量r来评估临床意义。
结果：纳入19例患者，其中17例完成了10个月（第300天，V6）的观察期。患者年龄为18至59岁，病程为6至53年。除6MWT、RULM和峰值咳嗽流量外，与基线相比，V4、V5或V6时所有功能结果评估均无相关的显著变化。对于6MWT，在第5次和第6次随访时有统计学上的显著改善。RULM评分在V6时显著提高，峰值咳嗽流量在第5次随访时提高。在生物标志物研究中，NSE和pTAU显著下降，蛋白质略有增加。在安全性分析中，总体而言，诺西那生的应用耐受性良好。11例患者报告了与研究程序相关的不良事件，包括7例患者的背痛和4例患者鞘内给药后的腰椎穿刺后头痛。腰椎穿刺后头痛在3名女性和1名男性中报告，共108次穿刺中有11次（10%）。未发生严重不良事件。
结论：这项前瞻性观察研究表明，诺西那生治疗10个月后，在长期患病的成人SMA3患者中具有轻微的治疗效果，这在该疾病的自然病程中从未出现过。在我们的队列中，最显著的结果指标是6MWT在第180天和第300天后有统计学上的显著变化，RULM在第300天后以及峰值咳嗽流量在第180天后有变化。
Objective: Spinal muscular atrophy (SMA) is a progressive autosomal recessive motor neuron disease caused by loss of the SMN1 gene. Based on randomized clinical trials in children with SMA type 1 and 2, Nusinersen has been approved as the first treatment for all types of SMA, including adults with SMA type 3.Methods: We evaluated the safety and treatment effects of Nusinersen in longstanding adult 5q-SMA type 3. Patients were treated with intrathecal loading doses at day 1, 14, 28 and 63, followed by maintenance dose every four months up to 300 days. We monitored the patients within SMArtCARE, a prospective open-label outcome study for disease progression, side effects and treatment efficacy, encompassing clinical examination including MRC sum score, vital capacity in sitting position (VC, VC %pred.), ALS Functional Rating Scale (ALS-FRS), 6-Minute-Walk-Test (6MWT), Revised Upper Limb Module (RULM), and Hammersmith Functional Rating Scale (HFMSE). We also measured biomarkers in the spinal fluid (phosphorylated neurofilament heavy chain pNFH, neuron-specific enolase NSE, proteins, beta-Amyloid 1-40,beta-Amyloid 1-42, tau and phospho-tau) and creatine kinase (CK). Assessments were performed at baseline, day 63 (V4), day 180 (V5) and day 300 (V6). For statistical analysis, we compared baseline to V4, V5 and V6, using the paired sample t-test. When there were significant differences, we added cohen's d and effect size r for evaluation of clinical meaningfulness.Results: 19 patients were included, 17 of them have completed the observation period of 10 months (day 300, V6). Patients were aged 18 to 59 years with disease duration ranging from 6 to 53 years. Except for the 6MWT, the RULM and the peak cough flow, there were no relevant significant changes in all functional outcome assessments at V4, V5 or V6, compared to baseline. For the 6MWT, there was a statistically significant improvement at visit 5 and at visit 6. RULM-score increased significantly at V6, and peak cough flow at visit 5. In biomarker studies, there was a significant decline in NSE and pTAU as well as a slight increase in proteins. In safety analysis, overall, Nusinersen applications were well tolerated. Eleven patients reported adverse events that were related to the study procedures, comprising back pain in seven patients and post-lumbar-puncture headache following intrathecal administration in four patients. Post-lumbar-puncture headache was reported in three females and one male, in total eleven times of 108 punctures (10%). No serious adverse events occurred.Conclusions: This prospective observational study indicates a mild treatment effect in adults with long-standing SMA3 after 10 months of treatment with Nusinersen, which had never occurred in the natural history of the disease. In our cohort, the most significant outcome measures were the 6MWT with statistically significant changes after day 180 and day 300, RULM after day 300 and peak cough flow after day 180.