Early data on long-term efficacy and safety of inotersen in patients with hereditary transthyretin amyloidosis: a 2-year update from the open-label extension of the NEURO-TTR trial
Early data on long-term efficacy and safety of inotersen in patients with hereditary transthyretin amyloidosis: a 2-year update from the open-label extension of the NEURO-TTR trial
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DOI：
10.1111/ene.14285
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发表时间：
2020-05-29
影响因子：
5.1
通讯作者：
Gertz, M.
中科院分区：
文献类型：
--
作者：
Brannagan, T. H.;Wang, A. K.;Gertz, M.
背景和目的遗传性转甲状腺素蛋白（hATTR）淀粉样变性会导致进行性多发性神经病，这是由转甲状腺素蛋白（TTR）淀粉样蛋白沉积在全身（包括周围神经）引起的。 inotersen（一种 TTR 蛋白产生的反义寡核苷酸抑制剂）的有效性和安全性已在针对 hATTR 多发性神经病患者的关键 NEURO-TTR 研究中得到证实。在这里，inotersen 的长期疗效和安全性在一项正在进行的开放标签扩展 (OLE) 研究中进行评估。方法完成 NEURO-TTR 的患者有资格参加 OLE (NCT02175004)。疗效评估包括改良的神经病变损伤评分加上七项神经生理学测试综合评分 (mNIS + 7)、诺福克生活质量 - 糖尿病神经病变 (Norfolk QOL-DN) 问卷总分和简式 36 健康调查 (SF-36) 身体成分摘要 (PCS) 评分。还评估了安全性和耐受性。 结果 总体而言，完成 NEURO-TTR 的患者中有 97% (135/139) 参加了 OLE。在 NEURO-TTR 和 OLE 中接受inotersen累计39个月的患者继续显示出获益；在 OLE 中从安慰剂换为inotersen 的患者通过 mNIS + 7、Norfolk QOL-DN 和 SF-36 PCS 证明神经系统疾病进展得到改善或稳定。没有发现新的安全问题。没有证据表明4级血小板减少症或严重肾脏事件的风险随着inotersen暴露时间的延长而增加。结论 Inotersen减缓了hATTR多发性神经病患者的疾病进展并减少了生活质量的恶化。与延迟开始治疗相比，早期使用inotersen治疗可实现更好的长期疾病稳定。常规血小板和肾脏安全监测有效；没有观察到新的安全信号。
Background and purpose Hereditary transthyretin (hATTR) amyloidosis causes progressive polyneuropathy resulting from transthyretin (TTR) amyloid deposition throughout the body, including the peripheral nerves. The efficacy and safety of inotersen, an antisense oligonucleotide inhibitor of TTR protein production, were demonstrated in the pivotal NEURO-TTR study in patients with hATTR polyneuropathy. Here, the long-term efficacy and safety of inotersen are assessed in an ongoing open-label extension (OLE) study.Methods Patients who completed NEURO-TTR were eligible to enroll in the OLE (NCT02175004). Efficacy assessments included the modified Neuropathy Impairment Score plus seven neurophysiological tests composite score (mNIS + 7), the Norfolk Quality of Life - Diabetic Neuropathy (Norfolk QOL-DN) questionnaire total score and the Short-Form 36 Health Survey (SF-36) Physical Component Summary (PCS) score. Safety and tolerability were also assessed.Results Overall, 97% (135/139) of patients who completed NEURO-TTR enrolled in the OLE. Patients who received inotersen for 39 cumulative months in NEURO-TTR and the OLE continued to show benefit; patients who switched from placebo to inotersen in the OLE demonstrated improvement or stabilization of neurological disease progression by mNIS + 7, Norfolk QOL-DN and SF-36 PCS. No new safety concerns were identified. There was no evidence of increased risk for grade 4 thrombocytopenia or severe renal events with increased duration of inotersen exposure.Conclusion Inotersen slowed disease progression and reduced deterioration of quality of life in patients with hATTR polyneuropathy. Early treatment with inotersen resulted in greater long-term disease stabilization than delayed initiation. Routine platelet and renal safety monitoring were effective; no new safety signals were observed.