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期刊来源：JAMA

文献发表时间：2023-09-28

原文链接：https://jamanetwork.com/journals/jama/article-abstract/2810248

关键点内容如下：

问题

在伴有多发性神经病的遗传性甲状腺素运载蛋白（ATTRV）淀粉样变性患者中，反义寡核苷酸Eplontersen与血清甲状腺素运载蛋白浓度的变化和神经病症状的改善是否相关？

调查结果

在这项纳入了168名患者（144名接受皮下注射Eplontersen）和60名既往安慰剂患者的开放标签研究中，与既往安慰剂组相比，Eplontersen治疗组从基线到第65/66周的变化与显著降低的血清甲状腺素运载蛋白浓度（-81.7%vs-11.2%）、更少的神经病变损伤和更好的生活质量一致。

意义

在患有多发性神经病的成人中，与历史上的安慰剂相比，Eplontersen治疗组的血清甲状腺素运载蛋白浓度较低，神经病变程度较轻，生活质量较好。

摘要内容如下：

重要性

甲状腺素运载蛋白基因沉默是治疗遗传性甲状腺素运载蛋白（ATTRV）淀粉样变性的新策略。

目的

评估Eplontersen（一种研究用配体偶联的反义寡核苷酸）在ATTRV多发性神经病中的作用。

研究设计和参与者

Neuro-tTransform是一项开放标签、单组、3期试验，在15个国家的40个地点（2019年12月至2023年4月）对168名患有Coutinho 1期或2期ATTRV多发性神经病、神经病损伤评分为10-130和记录的TTR变异的成人进行了试验。用Neuro-TTR（NCT01737398的安慰剂治疗的患者；2013年3月-2017年11月），一项具有类似合格标准和终点的Inotersen试验，作为历史安慰剂（“安慰剂”）组。

暴露

皮下注射Eplontersen（45mg，每4周一次；N=144）；一个小的参照组每周接受皮下注射Inotersen（300毫克；n=24个）；Neuro-TTR皮下每周安慰剂（；N=60）。

主要结局和措施

第65/66周的主要疗效终点是血清甲状腺素运载蛋白浓度相对于基线的变化，改良神经病变损伤评分+7（MNIS+7）综合评分（评分范围为-22.3至346.3；得分越高表明功能越差）和诺福克生活质量问卷-糖尿病神经病变（诺福克QOL-DN）总分（得分范围，-4至136；得分越高表明）的生活质量越差。疗效终点分析基于混合效应模型，通过倾向评分权重调整重复测量。

结果

在144名接受Eplontersen治疗的患者中，（平均年龄为53.0岁；69%的男性），136名（，94.4%的）完成了66周的随访；在60名服用安慰剂的患者中，（平均年龄为59.5岁；68%男性），52名（，86.7%）完成66周随访。在第65周，血清甲状腺素运载蛋白的校正平均百分比减少在Eplontersen组为-81.7%，在安慰剂组为-11.2%（差异，-70.4%[95%CI，-75.2%至-65.7%]；P<.001）。从基线到第66周的调整后的平均变化是，Eplontersen与安慰剂相比，MNIS+7综合评分（0.3比25.1的）更低（更好；差异，−24.8[95%CI，−31.0至−18.6；P<.001）和诺福克QOL-DN（-5.5 vs 14.2；差异，−19.7[95%CI，−25.6至−13.8]；P<.001）。截至第66周，导致研究药物停药的不良事件在Eplontersen组中有6例（4%），而在安慰剂组中有2例（3%）。到第66周，Eplontersen组有2例死亡，符合已知的疾病相关后遗症（心律失常；脑内出血）；安慰剂组无死亡。

结论和相关性

在ATTRV多发性神经病患者中，与历史上的安慰剂相比，Eplontersen治疗组表现出与显著降低的血清甲状腺素运载蛋白浓度、更少的神经病变损伤和更好的生活质量一致的变化。

英文原文如下：

Key Points

Question  Is the antisense oligonucleotide eplontersen associated with changes in serum transthyretin concentration and improvement in neuropathy symptoms among adults with hereditary transthyretin (ATTRv) amyloidosis with polyneuropathy?

Findings  In this open-label study that enrolled 168 patients (144 assigned to subcutaneous eplontersen) and included 60 historical placebo patients, the eplontersen treatment group demonstrated changes from baseline to week 65/66 consistent with significantly lower serum transthyretin concentration (−81.7% vs −11.2%), less neuropathy impairment, and better quality of life compared with the historical placebo group.

Meaning  Among adults with ATTRv polyneuropathy, the eplontersen treatment group had lower serum transthyretin concentration, less neuropathy impairment, and better quality of life compared with a historical placebo.

Abstract

Importance  Transthyretin gene silencing is an emerging treatment strategy for hereditary transthyretin (ATTRv) amyloidosis.

Objective  To evaluate eplontersen, an investigational ligand-conjugated antisense oligonucleotide, in ATTRv polyneuropathy.

Design, Setting, and Participants  NEURO-TTRansform was an open-label, single-group, phase 3 trial conducted at 40 sites across 15 countries (December 2019-April 2023) in 168 adults with Coutinho stage 1 or 2 ATTRv polyneuropathy, Neuropathy Impairment Score 10-130, and a documented TTR variant. Patients treated with placebo from NEURO-TTR (NCT01737398; March 2013–November 2017), an inotersen trial with similar eligibility criteria and end points, served as a historical placebo (“placebo”) group.

Interventions  Subcutaneous eplontersen (45 mg every 4 weeks; n = 144); a small reference group received subcutaneous inotersen (300 mg weekly; n = 24); subcutaneous placebo weekly (in NEURO-TTR; n = 60).

Main Outcomes and Measures  Primary efficacy end points at week 65/66 were changes from baseline in serum transthyretin concentration, modified Neuropathy Impairment Score +7 (mNIS+7) composite score (scoring range, –22.3 to 346.3; higher scores indicate poorer function), and Norfolk Quality of Life Questionnaire–Diabetic Neuropathy (Norfolk QoL-DN) total score (scoring range, –4 to 136; higher scores indicate poorer quality of life). Analyses of efficacy end points were based on a mixed-effects model with repeated measures adjusted by propensity score weights.

Results  Among 144 eplontersen-treated patients (mean age, 53.0 years; 69% male), 136 (94.4%) completed week-66 follow-up; among 60 placebo patients (mean age, 59.5 years; 68% male), 52 (86.7%) completed week-66 follow-up. At week 65, adjusted mean percentage reduction in serum transthyretin was −81.7% with eplontersen and −11.2% with placebo (difference, −70.4% [95% CI, −75.2% to −65.7%]; P < .001). Adjusted mean change from baseline to week 66 was lower (better) with eplontersen vs placebo for mNIS+7 composite score (0.3 vs 25.1; difference, −24.8 [95% CI, −31.0 to −18.6; P < .001) and for Norfolk QoL-DN (−5.5 vs 14.2; difference, −19.7 [95% CI, −25.6 to −13.8]; P < .001). Adverse events by week 66 that led to study drug discontinuation occurred in 6 patients (4%) in the eplontersen group vs 2 (3%) in the placebo group. Through week 66, there were 2 deaths in the eplontersen group consistent with known disease-related sequelae (cardiac arrhythmia; intracerebral hemorrhage); there were no deaths in the placebo group.

Conclusions and Relevance  In patients with ATTRv polyneuropathy, the eplontersen treatment group demonstrated changes consistent with significantly lowered serum transthyretin concentration, less neuropathy impairment, and better quality of life compared with a historical placebo.

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