Five-Year Results With Patisiran for Hereditary Transthyretin Amyloidosis With Polyneuropathy: A Randomized Clinical Trial With Open-Label Extension.

IF 20.4 1区 医学 Q1 CLINICAL NEUROLOGY
David Adams, Jonas Wixner, Michael Polydefkis, John L Berk, Isabel M Conceição, Angela Dispenzieri, Amanda Peltier, Mitsuharu Ueda, Shaun Bender, Kelley Capocelli, Patrick Y Jay, Elena Yureneva, Laura Obici
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引用次数: 0

Abstract

Importance: There is a lack of long-term efficacy and safety data on hereditary transthyretin amyloidosis with polyneuropathy (hATTR-PN) and on RNA interference (RNAi) therapeutics in general. This study presents the longest-term data to date on patisiran for hATTR-PN.

Objective: To present the long-term efficacy and safety of patisiran in adults with hATTR-PN.

Design, setting, and participants: This global open-label extension (OLE) of the APOLLO randomized clinical trial and phase 2 OLE study enrolled patients from 43 hospitals or clinical centers across 19 countries between July 2015 and August 2017, with follow-up until November 2022. Of 212 eligible patients with hATTR who completed the phase 3 APOLLO or phase 2 OLE parent studies, 211 enrolled in and 138 completed the global OLE.

Intervention: Patisiran, 0.3 mg/kg, intravenously once every 3 weeks for up to 5 years.

Main outcomes and measures: Outcomes evaluated at year 5 of the global OLE included disability (polyneuropathy disability [PND] score); polyneuropathy severity (Neuropathy Impairment Score [NIS]), nutritional status (modified body mass index [mBMI]), quality of life (Norfolk Quality of Life-Diabetic Neuropathy [Norfolk QOL-DN]), and Rasch-Built Overall Disability Scale (R-ODS), with no statistical hierarchy. Safety, survival probability, and mortality were also assessed.

Results: At the global OLE baseline, the mean (SD) age was 61.3 (12.3) years, and 156 patients (73.9%) were male. In 138 patients completing the study, PND scores remained stable or improved in 89 patients (65.0%), NISs showed a mean (SD) change of 10.9 (14.7), and mean (SD) mBMI (calculated as weight in kilograms divided by height in meters squared times serum albumin in grams per liter) increased by 46.4 (120.7) over 5 years from baseline. Norfolk QOL-DN and R-ODS scores showed mean (SD) changes of 4.1 (16.7) and -3.7 (6.2), respectively. Adverse events (AEs) leading to study withdrawal occurred in 47 patients (22.3%). Infusion-related reactions were the most common treatment-related AE (n = 34 [16.1%]). Overall, 41 patients (19.4%) died during the study. Patisiran treatment in the parent study and low familial amyloid polyneuropathy score at parent study baseline were associated with significantly improved survival.

Conclusions and relevance: In the longest study of an RNAi therapeutic for any disease, patisiran treatment resulted in modest changes for patients with hATTR-PN with an acceptable safety profile. These results highlight the importance of initiating early treatment for hATTR and the potential of RNAi therapeutics in medicine.

Trial registration: ClinicalTrials.gov Identifier: NCT02510261.

帕西兰治疗遗传性甲状腺转蛋白淀粉样变性伴多神经病变的5年疗效:一项开放标签扩展的随机临床试验
重要性:遗传性甲状腺素转淀粉样变合并多神经病变(hatr - pn)和RNA干扰(RNAi)治疗缺乏长期疗效和安全性数据。这项研究提供了迄今为止关于hatr - pn患者的长期数据。目的:观察帕西兰治疗成人hat - pn的长期疗效和安全性。设计、环境和参与者:这项APOLLO随机临床试验和二期OLE研究的全球开放标签扩展(OLE)在2015年7月至2017年8月期间招募了来自19个国家43家医院或临床中心的患者,随访至2022年11月。在完成3期APOLLO或2期OLE父母研究的212例符合条件的hATTR患者中,211例入组,138例完成全球OLE。干预措施:Patisiran, 0.3 mg/kg,静脉注射,每3周1次,持续5年。主要结果和测量方法:全球OLE第5年评估的结果包括残疾(多神经病变残疾[PND]评分);多神经病变严重程度(Neuropathy Impairment Score [NIS])、营养状况(modified body mass index [mBMI])、生活质量(Norfolk quality of life - diabetes Neuropathy [Norfolk QOL-DN])和Rasch-Built Overall Disability Scale (R-ODS),无统计学分级。安全性、生存率和死亡率也进行了评估。结果:在全球OLE基线,平均(SD)年龄为61.3(12.3)岁,156例(73.9%)为男性。在完成研究的138名患者中,89名患者(65.0%)的PND评分保持稳定或改善,NISs的平均(SD)变化为10.9(14.7),平均(SD) mBMI(计算方法为体重(公斤)除以身高(米)平方乘以血清白蛋白(克/升))在5年内比基线增加了46.4(120.7)。Norfolk QOL-DN和R-ODS评分的平均(SD)变化分别为4.1(16.7)和-3.7(6.2)。不良事件(ae)导致47例患者(22.3%)退出研究。输液相关反应是最常见的治疗相关AE (n = 34[16.1%])。总体而言,41名患者(19.4%)在研究期间死亡。亲本研究中的帕西兰治疗和亲本研究基线的低家族性淀粉样蛋白多发性神经病变评分与生存率显著提高相关。结论和相关性:在对任何疾病的RNAi治疗的最长研究中,patisiran治疗导致hatr - pn患者的适度变化,具有可接受的安全性。这些结果强调了对hATTR进行早期治疗的重要性以及RNAi疗法在医学上的潜力。试验注册:ClinicalTrials.gov标识符:NCT02510261。
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来源期刊
JAMA neurology
JAMA neurology CLINICAL NEUROLOGY-
CiteScore
41.90
自引率
1.70%
发文量
250
期刊介绍: JAMA Neurology is an international peer-reviewed journal for physicians caring for people with neurologic disorders and those interested in the structure and function of the normal and diseased nervous system. The Archives of Neurology & Psychiatry began publication in 1919 and, in 1959, became 2 separate journals: Archives of Neurology and Archives of General Psychiatry. In 2013, their names changed to JAMA Neurology and JAMA Psychiatry, respectively. JAMA Neurology is a member of the JAMA Network, a consortium of peer-reviewed, general medical and specialty publications.
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