Clinical Trial and Postmarketing Safety of Onasemnogene Abeparvovec Therapy.
Clinical Trial and Postmarketing Safety of Onasemnogene Abeparvovec Therapy.
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DOI：
10.1007/s40264-021-01107-6
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发表时间：
2021-10
期刊：
影响因子：
4.2
通讯作者：
Chand DH
中科院分区：
文献类型：
--
作者：
Day JW;Mendell JR;Mercuri E;Finkel RS;Strauss KA;Kleyn A;Tauscher-Wisniewski S;Tukov FF;Reyna SP;Chand DH
这是静脉注射 onasemnogene abeparvovec 的安全性数据的首次描述，这是唯一被批准的针对脊髓性肌萎缩症的全身基因替代疗法。我们根据临床前研究、临床研究和上市后数据综合评估了静脉注射 Onasemnogene abeparvovec 的安全性。在新生小鼠和幼年或新生食蟹猴非人灵长类动物 (NHP) 中进行了单剂量毒性研究。提供的数据来自临床前研究、七项临床试验和上市后来源的综合数据（临床试验，n = 102 名患者；上市后监测，n = 665 例报告的不良事件 [AE] 病例）。在临床试验中，通过 AE 监测、生命体征和心脏评估、实验室评估、体检和伴随药物使用来评估安全性。对 AE 报告和上市后项目中可用的客观临床数据进行了评估。小鼠的主要毒性靶器官是心脏和肝脏。在 NHP 中观察到背根神经节 (DRG) 炎症。临床检查后，患者没有表现出感觉神经病变的证据。在临床试验中，101/102 名患者经历了至少一种治疗引起的 AE。总共有 50 名患者经历了严重的 AE，其中 11 名患者被认为与治疗相关。在临床试验中，泼尼松龙解决了与肝毒性一致的不良事件。检测到平均血小板计数短暂下降，但没有出血并发症。在上市后观察到血栓性微血管病（TMA）。对于 NHP 或患者，没有观察到心内血栓的证据。与 onasemnogene abeparvovec 相关的风险是可以预测、监测和管理的。泼尼松龙可解决肝毒性事件。血小板减少是暂时的。 TMA 可能需要医疗干预。重要的潜在风险包括心脏 AE 和 DRG 毒性。在线版本包含可在 10.1007/s40264-021-01107-6 获取的补充材料。
This is the first description of safety data for intravenous onasemnogene abeparvovec, the only approved systemically administered gene-replacement therapy for spinal muscular atrophy. We comprehensively assessed the safety of intravenous onasemnogene abeparvovec from preclinical studies, clinical studies, and postmarketing data. Single-dose toxicity studies were performed in neonatal mice and juvenile or neonatal cynomolgus nonhuman primates (NHPs). Data presented are from a composite of preclinical studies, seven clinical trials, and postmarketing sources (clinical trials, n = 102 patients; postmarketing surveillance, n = 665 reported adverse event [AE] cases). In clinical trials, safety was assessed through AE monitoring, vital-sign and cardiac assessments, laboratory evaluations, physical examinations, and concomitant medication use. AE reporting and available objective clinical data from postmarketing programs were evaluated. The main target organs of toxicity in mice were the heart and liver. Dorsal root ganglia (DRG) inflammation was observed in NHPs. Patients exhibited no evidence of sensory neuropathy upon clinical examination. In clinical trials, 101/102 patients experienced at least one treatment-emergent AE. In total, 50 patients experienced serious AEs, including 11 considered treatment related. AEs consistent with hepatotoxicity resolved with prednisolone in clinical trials. Transient decreases in mean platelet count were detected but were without bleeding complications. Thrombotic microangiopathy (TMA) was observed in the postmarketing setting. No evidence of intracardiac thrombi was observed for NHPs or patients. Risks associated with onasemnogene abeparvovec can be anticipated, monitored, and managed. Hepatotoxicity events resolved with prednisolone. Thrombocytopenia was transient. TMA may require medical intervention. Important potential risks include cardiac AEs and DRG toxicity. The online version contains supplementary material available at 10.1007/s40264-021-01107-6.
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影响因子：
11.2
作者：
Narver, Heather L.;Kong, Lingling;Burnett, Barrington G.;Choe, Dong W.;Bosch-Mare, Marta;Taye, Addis A.;Eckhaus, Michael A.;Sumner, Charlotte J.
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DOI：
10.1038/ejhg.2011.134
发表时间：
2012-01
期刊：
European journal of human genetics : EJHG
影响因子：
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作者：
通讯作者：
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DOI：
10.1007/978-1-61779-370-7_6
发表时间：
2011
期刊：
Methods in molecular biology (Clifton, N.J.)
影响因子：
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作者：
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Sands, Mark S.
影响因子：
9.9
作者：
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通讯作者：
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影响因子：
2.8
作者：
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通讯作者：
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