• 主题
高级搜索  >
历史搜索 清空历史
首页> 外文期刊>Nucleic Acid Therapeutics >Immunogenicity Assessment of Inotersen, a 2 '-O-(2-Methoxyethyl) Antisense Oligonucleotide in Animals and Humans: Effect on Pharmacokinetics, Pharmacodynamics, and Safety
【24h】

Immunogenicity Assessment of Inotersen, a 2 '-O-(2-Methoxyethyl) Antisense Oligonucleotide in Animals and Humans: Effect on Pharmacokinetics, Pharmacodynamics, and Safety

机译：在动物和人体中的Inotersen，2'-o-（2-甲氧基乙基）反义寡核苷酸的免疫原性评估：对药代动力学，药效学和安全的影响

获取原文
获取原文并翻译 | 示例
           
页面导航
  • 摘要
  • 著录项
  • 相似文献
  • 相关主题

摘要

Inotersen (TEGSEDI (TM)) is a 2 '-O-(2-methoxyethyl)-modified antisense oligonucleotide, intended for treating hereditary transthyretin (TTR) amyloidosis with polyneuropathy. The potential immunogenicity (IM) response to inotersen was evaluated in chronic nonclinical safety studies and the pivotal phase 2/3 clinical study. The evaluation was designed to assess the characteristics of antidrug antibodies (ADAs) and their effects on the pharmacokinetics, pharmacodynamics, clinical efficacy, and safety in animals and humans. No immunogenic response was observed after long-term treatment with inotersen in mice. In monkeys, the incidence rate of IM to inotersen appeared to be dose dependent, with 28.6%-50.0% of animals developing ADAs after 36 weeks of treatment. This was characterized as late onset (median onset of 185 days) with low titers (median titer of 8, or 400 if minimum required dilution of 50 is included). The overall incidence rate of patients who developed ADAs was 30% after 65 weeks of treatment with median onset of 203 days and median peak titer of 300. IM had minimal effect on plasma peak (C-max) and total exposure (i.e. area under curve, AUC) of inotersen, but showed elevated plasma trough levels in both IM-positive animals and humans. However, ADAs had no effect on tissue exposure, TTR messenger RNA, or plasma TTR levels in the long-term monkey study. Similarly, IM showed no effect on plasma TTR levels in clinical studies. Thus, ADAs antibodies were binding antibodies, but not neutralizing antibodies. Finally, no association was observed between IM and toxicity findings (eg, platelet, complement activation, and histopathology findings) in the inotersen 9-month monkey study. In humans, no difference was observed in hematology, including platelets, kidney function tests, or incidence of adverse events between IM-positive and -negative patients. Overall, IM showed no effect on toxicity or safety of inotersen evaluated in both monkeys and humans. ClinicalTrials.govIdentifier: NCT01737398
机译：在塞内森（TEGSEDI（TM））是2'-O-（2-甲氧基乙基） - 制定的反义寡核苷酸，用于治疗遗传性Transthyretin（TTR）淀粉样蛋白腺苷病，其具有多种疾病。在慢性非临床安全性研究和关键阶段2/3临床研究中评估对Inotersen的潜在免疫原性（IM）反应。评估旨在评估抗抑化抗体（ADAS）的特征及其对药代动力学，药效学，临床疗效和动物和人类安全的影响。在用小鼠中的角蛋白的长期处理后，没有观察到免疫原性反应。在猴子中，IM至Inotersen的发病率似乎是剂量依赖性，28.6％-50.0％的动物在治疗36周后开发ADAS。这表征为延迟发作（185天的中位数发作），低滴度（如果包括最小50的最低要求稀释，则为8或400的中值滴度）。在65周的治疗后，用203天的中值峰值滴度为300分钟，患者的患者的总发病率为30％。IM对血浆峰值（C-MAX）和完全暴露的影响最小（即曲线区域Inotersen的AUC），但在IM阳性动物和人类中显示出升高的血浆槽水平。然而，ADAS对长期猴子研究中的组织暴露，TTR信使RNA或血浆TTR水平没有影响。同样，IM对临床研究中的血浆TTR水平没有影响。因此，ADAS抗体是结合抗体，但不中和抗体。最后，在Inotersen 9个月的猴子研究中，在IM和毒性结果（例如血小板，补体激活和组织病理学发现）之间没有观察到关联。在人类中，在血液学中没有观察到血液学，包括血小板，肾功能试验或IM阳性和阴性患者之间不良事件发生率。总体而言，我对猴子和人类评估的毒性或皮肤的毒性或安全性没有影响。 ClinicalTrials.govidentier：NCT01737398

著录项

相似文献

  • 外文文献
  • 中文文献
  • 专利
获取原文

客服邮箱：kefu@zhangqiaokeyan.com

京公网安备：11010802029741号 ICP备案号：京ICP备15016152号-6 六维联合信息科技 (北京) 有限公司©版权所有

  • 客服微信

  • 服务号