背景:遗传性转甲状腺素蛋白淀粉样变性(hATTR/ATTRv)是由于错误折叠的转甲状腺素蛋白(TTR)在整个身体中的沉积,包括周围神经。Inotersen,肝脏TTR产生的反义寡核苷酸抑制剂,在NEURO-TTR(NCT01737398)研究中,在与hATTR相关的多发性神经病患者中表现出良好的疗效和安全性.我们报告了inotersen的长期疗效和安全性数据,中位治疗暴露时间为3年。
方法:在其开放标签扩展(OLE)研究中招募了满意完成NEURO-TTR的患者。疗效评估包括改良的神经病变损伤评分+7(mNIS+7),诺福克生活质量-糖尿病神经病变(诺福克QoL-DN)问卷总分,和简短表格36(SF-36v2)健康调查身体成分汇总评分。还评估了安全性和耐受性。报告了居住在欧洲和北美的患者的疗效(该队列在这些地区以外的其余患者组前约9个月完成了研究);安全性报告为完整的安全性数据集,包括生活在欧洲的病人,北美,和拉丁美洲/澳大拉西亚。这项研究在ClinicalTrials.gov注册,标识符NCT02175004。
结果:在NEURO-TTR研究的欧洲和北美队列中,113/141名患者(80.1%)完成了研究,109名患者参与了OLE研究。共有70名患者继续接受inotersen(inotersen-inotersen),39名患者从安慰剂转换为inotersen(安慰剂-inotersen)。安慰剂-inotersen组显示通过mNIS+7测量的神经系统疾病进展持续改善,与基于NEURO-TTR安慰剂数据(估计的自然史)的预测恶化相比。inotersen-inotersen集团表现出持续的利益,根据MNIS+7,诺福克QoL-DN,和SF-36v2,与估计的自然史相比,以及与安慰剂-inotersen组相比。最大暴露时间为6.2年,在OLE研究中,inotersen与任何额外的安全问题或毒性增加无关.在OLE研究中,血小板和肾脏监测可有效降低严重不良事件的风险。
结论:Inotersen治疗>3年可减缓与hATTR相关的多发性神经病的进展,且未观察到新的安全性信号.
BACKGROUND: Hereditary transthyretin amyloidosis (hATTR/ATTRv) results from the deposition of misfolded transthyretin (TTR) throughout the body, including peripheral nerves. Inotersen, an antisense oligonucleotide inhibitor of hepatic TTR production, demonstrated a favorable efficacy and safety profile in patients with the polyneuropathy associated with hATTR in the NEURO-TTR (NCT01737398) study. We report longer-term efficacy and safety data for inotersen, with a median treatment exposure of 3 years.
METHODS: Patients who satisfactorily completed NEURO-TTR were enrolled in its open-label extension (OLE) study. Efficacy assessments included the modified Neuropathy Impairment Score + 7 (mNIS + 7), Norfolk Quality of Life-Diabetic Neuropathy (Norfolk QoL-DN) questionnaire total score, and the Short Form 36 (SF-36v2) Health Survey Physical Component Summary score. Safety and tolerability were also assessed. Efficacy is reported for patients living in Europe and North America (this cohort completed the study approximately 9 months before the remaining group of patients outside these regions); safety is reported for the full safety dataset, comprising patients living in Europe, North America, and Latin America/Australasia. This study is registered with ClinicalTrials.gov, identifier NCT02175004.
RESULTS: In the Europe and North America cohort of the NEURO-TTR study, 113/141 patients (80.1%) completed the study, and 109 patients participated in the OLE study. A total of 70 patients continued to receive inotersen (inotersen-inotersen) and 39 switched from placebo to inotersen (placebo-inotersen). The placebo-inotersen group demonstrated sustained improvement in neurological disease progression as measured by mNIS + 7, compared with predicted worsening based on projection of the NEURO-TTR placebo data (estimated natural history). The inotersen-inotersen group demonstrated sustained benefit, as measured by mNIS + 7, Norfolk QoL-DN, and SF-36v2, compared with estimated natural history as well as compared with the placebo-inotersen group. With a maximum exposure of 6.2 years, inotersen was not associated with any additional safety concerns or increased toxicity in the OLE study. Platelet and renal monitoring were effective in reducing the risk of severe adverse events in the OLE study.
CONCLUSIONS: Inotersen treatment for > 3 years slowed progression of the polyneuropathy associated with hATTR, and no new safety signals were observed.