HELIOS-A 3 期研究中基线神经病变严重程度对 Vutrisiran 治疗反应的影响。

IF 3.9 3区医学 Q1 CLINICAL NEUROLOGY

Neurology and Therapy Pub Date : 2024-06-01 Epub Date: 2024-03-21 DOI:10.1007/s40120-024-00595-9

Marco Luigetti, Dianna Quan, John L Berk, Isabel Conceição, Yohei Misumi, Chi-Chao Chao, Shaun Bender, Emre Aldinc, John Vest, David Adams

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引用次数: 0

摘要

导言：遗传性转甲状腺素淀粉样变性病（ATTRv，v代表变体）是一种罕见的、进行性的、致命的疾病，具有多系统表现，由转甲状腺素（TTR）基因的致病变体引起。在三期 HELIOS-A 研究（NCT03759379）中，Vutrisiran 是一种能快速敲除 TTR 的 RNA 干扰疗法，与外用安慰剂相比，它能改善 ATTRv 淀粉样变性伴多发性神经病患者的神经病变和生活质量（QOL）。这项事后分析评估了基线神经病变严重程度对vutrisiran治疗反应的影响：患者被随机（3:1）分配到武曲西兰（n = 122；25 毫克皮下注射，每 3 个月一次）或帕替西兰（n = 42；0.3 毫克/千克静脉注射，每 3 周一次），后者作为参照组。在这项事后分析中，根据基线神经病变损害评分（NIS）的增加情况，将患者分为四分位组：四分位数 (Q)1 ≥ 5.0 至 ≤ 20.5；Q2 > 20.5 至 ≤ 44.1；Q3 > 44.1 至 ≤ 73.1；Q4 > 73.1 至 ≤ 127.0。按四分位数总结了一系列疗效终点从基线到第18个月的平均变化：在所有基线NIS四分位数中，vutrisiran与外用安慰剂相比，在神经病变严重程度（改良NIS + 7）、QOL（诺福克生活质量-糖尿病神经病变）、残疾（Rasch-built总体残疾量表）、步速（10米步行测试）和营养状况（改良体重指数）等方面均显示出疗效。总体而言，基线NIS四分位数较低与较高（神经病变程度较轻）的患者在第18个月时的得分保持较高水平。外用安慰剂组患者在第18个月时所有指标均逐渐恶化：在所有四个基线神经病变严重程度四分位数中，Vutrisiran 在神经功能和其他关键疗效指标方面均优于外用安慰剂。在病程早期开始接受武曲西兰治疗的患者在18个月后仍能保持最高的神经功能水平，这凸显了早期诊断和治疗的重要性：试验注册号：ClinicalTrials.gov：试验注册号：ClinicalTrials.gov: NCT03759379。

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Impact of Baseline Neuropathy Severity on Vutrisiran Treatment Response in the Phase 3 HELIOS-A Study.

Introduction: Hereditary transthyretin (ATTRv, v for variant) amyloidosis is a rare, progressive, fatal disease with multisystem manifestations, caused by pathogenic variants in the transthyretin (TTR) gene. Vutrisiran, an RNA interference therapeutic that results in rapid TTR knockdown, improved neuropathy and quality of life (QOL) versus external placebo in patients with ATTRv amyloidosis with polyneuropathy in the phase 3 HELIOS-A study (NCT03759379). This post hoc analysis evaluates the impact of baseline neuropathy severity on response to vutrisiran treatment.

Methods: Patients were randomized (3:1) to vutrisiran (n = 122; 25 mg subcutaneous injection once every 3 months) or patisiran (n = 42; 0.3 mg/kg intravenous infusion once every 3 weeks), which served as a reference group. In this post hoc analysis, patients were grouped into quartiles of increasing baseline Neuropathy Impairment Score (NIS): Quartile (Q)1 ≥ 5.0 to ≤ 20.5; Q2 > 20.5 to ≤ 44.1; Q3 > 44.1 to ≤ 73.1; Q4 > 73.1 to ≤ 127.0. Mean change from baseline to Month 18 was summarized by quartile for a range of efficacy endpoints.

Results: Across all baseline NIS quartiles, vutrisiran demonstrated benefit versus external placebo in measures of neuropathy severity (modified NIS + 7), QOL (Norfolk Quality of Life-Diabetic Neuropathy), disability (Rasch-built Overall Disability Scale), gait speed (10-m walk test), and nutritional status (modified body mass index). Overall, patients in lower versus higher NIS quartiles (less severe neuropathy) at baseline maintained better scores at Month 18. The external placebo group progressively worsened in all measures at Month 18.

Conclusions: Vutrisiran demonstrated benefit in neurologic function and other key efficacy measures versus external placebo across all four baseline neuropathy severity quartiles. Patients initiating vutrisiran earlier in their disease course retained the highest neurologic function level after 18 months, highlighting the importance of early diagnosis and treatment.

Trial registration number: ClinicalTrials.gov: NCT03759379.

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来源期刊

Neurology and Therapy CLINICAL NEUROLOGY-

CiteScore

5.40

自引率

8.10%

发文量

103

审稿时长

6 weeks

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