依洛瑟那治疗遗传性转甲状腺素蛋白淀粉样变性病患者。
Inotersen Treatment for Patients with Hereditary Transthyretin Amyloidosis.
机构信息
From the Indiana University School of Medicine, Indianapolis (M.D.B.); Centro de Estudos em Paramiloidose Antônio Rodrigues de Mello, National Amyloidosis Referral Center, University Hospital, Federal University of Rio de Janeiro, Rio de Janeiro (M.W.-C.); Amyloidosis Center, Boston University School of Medicine (J.L.B.) and Brigham and Women's Hospital, Harvard Medical School (A.M.S., S.D.S.), Boston; Johns Hopkins University, Baltimore (M.P.); Mayo Clinic, Rochester, MN (P.J.D., W.J.L., M.A.G.); University of California, Irvine, Irvine (A.K.W.); Amyloid Network-Hospital Henri Mondor-Assistance Publique-Hôpitaux de Paris (AP-HP)-Université Paris Est, Créteil, France (V.P.-B.); Institute for Neurologic Research Raúl Carrea, FLENI, Buenos Aires (F.A.B.); Amyloidosis Research and Treatment Center, Fondazione IRCCS Policlinico San Matteo, University of Pavia, Pavia (G.M., L.O.), and Unit of Neurology, University Hospital, Messina (G.V.) - both in Italy; Hospital AACD (Associação de Assistência à Criança Deficiente), São Paulo (M.S.); Columbia University Medical Center (T.H.B.) and Mount Sinai Medical Center (P.D.G.), New York; University College London-National Amyloidosis Centre, London (C.W.); Penn Presbyterian Medical Center, University of Pennsylvania Health System, Philadelphia (B.M.D.); Centre Hospitaliere Universitaire Bicêtre, AP-HP, Unité 1195, INSERM, Université Paris-Sud, Paris (D.A.); Oregon Health and Science University, Portland (S.B.H.); Centro Hospitalar Lisboa Norte-Hospital de Santa Maria, Lisbon (I.C.), and Centro Hospitalar do Porto, Porto (T.C.) - both in Portugal; Universitätsklinikum Münster, Münster, Germany (H.H.S.); Hospital Clínic, Universitat de Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (J.M.C.), and Hospital Universitari Vall d'Hebron (J.G.), Barcelona; Auckland City Hospital, Auckland, New Zealand (E.G.); and Ionis Pharmaceuticals, Carlsbad, CA (B.P.M., S.G.H., T.J.K., B.W.M., S.W.J., B.F.B., E.J.A.).
出版信息
N Engl J Med. 2018 Jul 5;379(1):22-31. doi: 10.1056/NEJMoa1716793.
BACKGROUND
Hereditary transthyretin amyloidosis is caused by pathogenic single-nucleotide variants in the gene encoding transthyretin ( TTR) that induce transthyretin misfolding and systemic deposition of amyloid. Progressive amyloid accumulation leads to multiorgan dysfunction and death. Inotersen, a 2'- O-methoxyethyl-modified antisense oligonucleotide, inhibits hepatic production of transthyretin.
METHODS
We conducted an international, randomized, double-blind, placebo-controlled, 15-month, phase 3 trial of inotersen in adults with stage 1 (patient is ambulatory) or stage 2 (patient is ambulatory with assistance) hereditary transthyretin amyloidosis with polyneuropathy. Patients were randomly assigned, in a 2:1 ratio, to receive weekly subcutaneous injections of inotersen (300 mg) or placebo. The primary end points were the change in the modified Neuropathy Impairment Score+7 (mNIS+7; range, -22.3 to 346.3, with higher scores indicating poorer function; minimal clinically meaningful change, 2 points) and the change in the score on the patient-reported Norfolk Quality of Life-Diabetic Neuropathy (QOL-DN) questionnaire (range, -4 to 136, with higher scores indicating poorer quality of life). A decrease in scores indicated improvement.
RESULTS
A total of 172 patients (112 in the inotersen group and 60 in the placebo group) received at least one dose of a trial regimen, and 139 (81%) completed the intervention period. Both primary efficacy assessments favored inotersen: the difference in the least-squares mean change from baseline to week 66 between the two groups (inotersen minus placebo) was -19.7 points (95% confidence interval [CI], -26.4 to -13.0; P<0.001) for the mNIS+7 and -11.7 points (95% CI, -18.3 to -5.1; P<0.001) for the Norfolk QOL-DN score. These improvements were independent of disease stage, mutation type, or the presence of cardiomyopathy. There were five deaths in the inotersen group and none in the placebo group. The most frequent serious adverse events in the inotersen group were glomerulonephritis (in 3 patients [3%]) and thrombocytopenia (in 3 patients [3%]), with one death associated with one of the cases of grade 4 thrombocytopenia. Thereafter, all patients received enhanced monitoring.
CONCLUSIONS
Inotersen improved the course of neurologic disease and quality of life in patients with hereditary transthyretin amyloidosis. Thrombocytopenia and glomerulonephritis were managed with enhanced monitoring. (Funded by Ionis Pharmaceuticals; NEURO-TTR ClinicalTrials.gov number, NCT01737398 .).
背景
遗传性转甲状腺素蛋白淀粉样变性是由编码转甲状腺素蛋白（TTR）的基因中的致病性单核苷酸变异引起的，这些变异导致转甲状腺素蛋白错误折叠和全身性淀粉样沉积。进行性淀粉样物质积累导致多器官功能障碍和死亡。Inotersen 是一种 2'-O-甲氧基乙基修饰的反义寡核苷酸，可抑制肝脏转甲状腺素蛋白的产生。
方法
我们进行了一项国际性、随机、双盲、安慰剂对照、为期 15 个月的 3 期临床试验，评估了 inotersen 对有周围神经病变的 1 期（患者可走动）或 2 期（患者可走动但需要辅助）遗传性转甲状腺素蛋白淀粉样变性的成年患者的疗效。患者以 2:1 的比例随机分配，每周接受皮下注射 inotersen（300mg）或安慰剂。主要终点是改良神经病损评分+7（mNIS+7；范围-22.3 至 346.3，得分越高表示功能越差；最小临床意义变化为 2 分）和患者报告的诺福克生活质量-糖尿病神经病变问卷（QOL-DN）评分的变化（范围-4 至 136，得分越高表示生活质量越差）。分数下降表示改善。
结果
共有 172 名患者（inotersen 组 112 名，安慰剂组 60 名）接受了至少一剂试验方案，其中 139 名（81%）完成了干预期。两种主要疗效评估均支持 inotersen：两组之间从基线到第 66 周的最小二乘均值变化差异（inotersen 减去安慰剂）在 mNIS+7 为-19.7 分（95%置信区间[CI]：-26.4 至-13.0；P<0.001），在 Norfolk QOL-DN 评分中为-11.7 分（95%CI：-18.3 至-5.1；P<0.001）。这些改善与疾病阶段、突变类型或是否存在心肌病无关。inotersen 组有 5 例死亡，安慰剂组无死亡。inotersen 组最常见的严重不良事件是肾小球肾炎（3 例[3%]）和血小板减少症（3 例[3%]），其中 1 例死亡与 1 例 4 级血小板减少症有关。此后，所有患者均接受了强化监测。
结论
Inotersen 改善了遗传性转甲状腺素蛋白淀粉样变性患者的神经病变和生活质量。用强化监测治疗血小板减少症和肾小球肾炎。（由 Ionis 制药公司资助；NEURO-TTR ClinicalTrials.gov 编号，NCT01737398）。
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