Design of the First-in-Human Study of IONIS-MAPTRx, a Tau-lowering Antisense Oligonucleotide, in Patients With Alzheimer Disease (S2.006)
Design of the First-in-Human Study of IONIS-MAPTRx, a Tau-lowering Antisense Oligonucleotide, in Patients With Alzheimer Disease (S2.006)
复制标题
IONIS-MAPTRx（一种降低 Tau 的反义寡核苷酸）在阿尔茨海默病患者中的首次人体研究设计 (S2.006)
作者：
L. Mignon;H. Kordasiewicz;R. Lane;Anne V Smith;T. Miller;P. Narayanan;E. Swayze;D. Norris;B. Fitzsimmons;F. Bennett
目的：设计一项研究，以测试IONIS-MAPT Rx，这是一种反义寡核苷酸（阿索），开发用于特异性、有效和安全地降低tau蛋白病患者的MAPT mRNA。背景资料：Tau病理与阿尔茨海默病（AD）中的神经变性在时间和区域上相关，强调其在转导Aβ连锁神经毒性中的作用。减少所有细胞类型中的Tau mRNA将导致tau的任何同种型、翻译后修饰和构象的减少，从而潜在地影响所有tau蛋白病。小鼠内源性tau蛋白的纯合子和半合子敲除可保护小鼠免受Aβ损伤。在人tau蛋白病小鼠模型中使用阿索治疗导致人MAPT前mRNA减少，阻断tau蛋白病理学，防止接种活性，逆转已建立的tau蛋白病理学，延长生存期并改善功能结局（DeVos et al. Science Translational Medicine，2017）。设计/方法：设计并筛选ASO以确定最佳候选药物。在啮齿动物和非人灵长类动物中进行的毒理学研究确定了候选物的安全性、药代动力学和药效学特征。结果：IONIS-MAPT Rx是第二代2′-O-甲氧基乙基嵌合阿索，旨在降低tau蛋白表达。在非人灵长类动物中鞘内注射IONIS-MAPT Rx显示，额叶皮质和海马中的MAPT mRNA平均降低77%，无剂量限制性副作用。这些发现为这种降低tau蛋白的阿索的第一次临床试验的设计提供了信息。Ionis-MAPT Rx CS 1（NCT 03186989）是一项多中心、随机、安慰剂对照、多次给药剂量递增研究，旨在评估轻度AD患者重复鞘内注射的安全性、耐受性和药代动力学参数。研究终点（包括CSF生物标志物、神经影像学和临床结局）既可作为安全性指标，也可作为药效学效应的探索性指标。结论：IONIS-MAPT Rx是一项全面的药物发现工作的结果，旨在设计一种对人MAPT mRNA具有高度特异性的耐受性良好的强效阿索。这种治疗原发性和继发性tau蛋白病的有前景的方法最近开始在轻度AD患者中给药。披露：Mignon博士因咨询、在科学咨询委员会任职、演讲或与Ionis制药公司开展其他活动而获得个人报酬。Kordasiewcz博士因咨询、在科学咨询委员会任职、演讲或与Ionis制药公司开展其他活动而获得个人报酬。莱恩博士因咨询、在科学咨询委员会任职、演讲或与Ionis制药公司开展其他活动而获得个人报酬。史密斯博士因咨询、在科学咨询委员会任职、演讲或与Ionis Pharmaceuticals开展其他活动而获得个人报酬。米勒博士因咨询、在科学顾问委员会任职、演讲或与Cytokerase、Biogen、Ionis的其他活动而获得个人报酬。米勒博士已从C2 N收到版税、许可费或合同权利付款。米勒博士得到了Biogen的研究支持。纳拉亚南博士因咨询、在科学咨询委员会任职、演讲或与Ionis制药公司开展其他活动而获得个人报酬。Swayze博士因在Ionis Pharmaceuticals的咨询、科学咨询委员会服务、演讲或其他活动而获得个人报酬。Norris博士因咨询、在科学咨询委员会任职、演讲或与Ionis Pharmaceuticals的其他活动而获得个人报酬。菲茨西蒙斯博士因咨询、在科学咨询委员会任职、演讲或与Ionis制药公司开展其他活动而获得个人报酬。班尼特博士没有什么可透露的。
Objective: To design a study to test IONIS-MAPT Rx an antisense oligonucleotide (ASO) developed to specifically, potently and safely reduce MAPT mRNA in patients with tauopathies. Background: Tau pathology is temporally and regionally related to neurodegeneration in Alzheimer disease (AD), emphasizing its role in transducing Aβ-linked neurotoxicity. Reducing Tau mRNA in all cell types will lead to reductions of any isoforms, post-translational modifications, and conformations of tau, thus potentially impacting all tauopathies. Homozygous and hemizygous knockout of endogenous tau in mice protects against Aβ insults. Treatment with ASO in a mouse model of human tauopathy leads to the reduction of the human MAPT pre-mRNA, blocking tau pathology, preventing seeding activity, reversing established tau pathology, extending survival and improving functional outcomes (DeVos et al. Science Translational Medicine, 2017). Design/Methods: ASOs were designed and screened to identify the optimal drug candidate. Toxicology studies, performed in rodents and non-human primates, established the candidate’s safety, pharmacokinetic and pharmacodynamic profiles. Results: IONIS-MAPT Rx is a second generation 2′-O-methoxyethyl chimeric ASO designed to reduce tau expression. Intrathecal administrations of IONIS-MAPT Rx in nonhuman primates showed a mean MAPT mRNA reduction of 77% in frontal cortex and 74% in hippocampus without dose-limiting side effects. These findings informed the design of the first clinical trial of this tau- lowering ASO. Ionis-MAPT Rx CS1 (NCT03186989) is a multi-center, randomized, placebo-controlled multiple-ascending dose study assessing the safety, tolerability and pharmacokinetic parameters of repeated intrathecal injections in patients with mild AD. The study endpoints, including CSF biomarker, neuroimaging, and clinical outcomes, serve both as safety measures and as exploratory measures of pharmacodynamic effects. Conclusions: IONIS-MAPT Rx is the result of a comprehensive drug discovery effort to design a well-tolerated, potent ASO with high specificity to human MAPT mRNA. This promising therapeutic approach for primary and secondary tauopathies recently initiated dosing in patients with mild AD. Disclosure: Dr. Mignon has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Ionis Pharmaceuticals. Dr. Kordasiewcz has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Ionis Pharmaceuticals. Dr. Lane has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Ionis Pharmaceuticals. Dr. Smith has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Ionis Pharmaceuticals. Dr. Miller has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Cytokinetics, Biogen, Ionis. Dr. Miller has received royalty, license fees, or contractual rights payments from C2N. Dr. Miller has received research support from Biogen. Dr. Narayanan has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Ionis Pharmaceuticals. Dr. Swayze has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Ionis Pharmaceuticals. Dr. Norris has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Ionis Pharmaceuticals. Dr. Fitzsimmons has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Ionis Pharmaceuticals. Dr. Bennett has nothing to disclose.