用于遗传性转甲状腺素蛋白淀粉样变性的 RNAi 治疗药物 Patisiran
Patisiran, an RNAi Therapeutic, for Hereditary Transthyretin Amyloidosis.
机构信息
From Assistance Publique-Hôpitaux de Paris (APHP), National Reference Center for Familial Amyloidotic Polyneuropathy, Centre Hospitalier Universitaire (CHU) Bicêtre, INSERM Unité 1195, Université Paris-Sud, Le Kremlin-Bicêtre (D.A.), the Department of Neuromuscular Disorders and ALS, Hôpital de la Timone, Marseille (S.A.), and the Department of Neurology, Amyloid Network, CHU Henri Mondor-APHP, Créteil (V.P.-B.) - all in France; the National Institute of Medical Sciences and Nutrition-Salvador Zubiran, Mexico City (A.G.-D.); the Department of Clinical Research, eStudySite, San Diego, CA (W.D.O.); the Department of Neurology, National Taiwan University Hospital (C.-C.Y.), and the Department of Neurology, Taipei Veterans General Hospital (K.-P.L.), Taipei, Taiwan; Kumamoto University Hospital, Kumamoto (M.U.), and the Department of Medicine (Neurology and Rheumatology), Shinshu University School of Medicine, Matsumoto (Y.S.) - both in Japan; the Department of Cardiology, University of Heidelberg, Heidelberg (A.V.K.), and Medizinische Klinik B für Gastroenterologie und Hepatologie, Universitätsklinikum Münster, Münster (H.H.S.) - both in Germany; University Multiprofile Hospital for Active Treatment, Sofia, Bulgaria (I.T.); Hospital de Santo António, Centro Hospitalar do Porto, Porto, Portugal (T.C.); the Amyloidosis Center, Department of Medicine, Boston Medical Center (J.L.B.), and Harvard Medical School (S.D.S.), Boston; the Department of Clinical and Experimental Medicine, University Hospital of Messina, Messina, Italy (G.V.); the Departments of Neurology and Medicine, Vancouver General Hospital, Vancouver, BC, Canada (M.M.M.); the Department of Nephrology, Hospital Clinic, Barcelona (J.M.C.), and the Balearic Islands Health Research Institute and Hospital Son Llatzer, Palma de Mallorca (J.B.) - all in Spain; the Department of Neurology, Columbia University, College of Physicians and Surgeons, New York (T.H.B.); Samsung Medical Center, Sungkyunkwan University School of Medicine (B.J.K.), and the the Department of Neurology, Konkuk University Medical Center (J.O.), Seoul, South Korea; the Department of Neurology, Istanbul University, Istanbul, Turkey (Y.P.); the Division of Medicine, University College London, London (P.N.H.); Johns Hopkins Bayview Medical Center, Baltimore (M.P.); the Department of Neurology, Mayo Clinic, Rochester, MN (P.J.D.); Alnylam Pharmaceuticals, Cambridge, MA (P.J.G., S.G., J.C., A.L.S., S.V.N., M.T.S., P.P.G., A.K.V., J.A.G.); and the Department of Public Health and Clinical Medicine, Umeå University, Umeå, Sweden (O.B.S.).
出版信息
N Engl J Med. 2018 Jul 5;379(1):11-21. doi: 10.1056/NEJMoa1716153.
BACKGROUND
Patisiran, an investigational RNA interference therapeutic agent, specifically inhibits hepatic synthesis of transthyretin.
METHODS
In this phase 3 trial, we randomly assigned patients with hereditary transthyretin amyloidosis with polyneuropathy, in a 2:1 ratio, to receive intravenous patisiran (0.3 mg per kilogram of body weight) or placebo once every 3 weeks. The primary end point was the change from baseline in the modified Neuropathy Impairment Score+7 (mNIS+7; range, 0 to 304, with higher scores indicating more impairment) at 18 months. Other assessments included the Norfolk Quality of Life-Diabetic Neuropathy (Norfolk QOL-DN) questionnaire (range, -4 to 136, with higher scores indicating worse quality of life), 10-m walk test (with gait speed measured in meters per second), and modified body-mass index (modified BMI, defined as [weight in kilograms divided by square of height in meters]×albumin level in grams per liter; lower values indicated worse nutritional status).
RESULTS
A total of 225 patients underwent randomization (148 to the patisiran group and 77 to the placebo group). The mean (±SD) mNIS+7 at baseline was 80.9±41.5 in the patisiran group and 74.6±37.0 in the placebo group; the least-squares mean (±SE) change from baseline was -6.0±1.7 versus 28.0±2.6 (difference, -34.0 points; P<0.001) at 18 months. The mean (±SD) baseline Norfolk QOL-DN score was 59.6±28.2 in the patisiran group and 55.5±24.3 in the placebo group; the least-squares mean (±SE) change from baseline was -6.7±1.8 versus 14.4±2.7 (difference, -21.1 points; P<0.001) at 18 months. Patisiran also showed an effect on gait speed and modified BMI. At 18 months, the least-squares mean change from baseline in gait speed was 0.08±0.02 m per second with patisiran versus -0.24±0.04 m per second with placebo (difference, 0.31 m per second; P<0.001), and the least-squares mean change from baseline in the modified BMI was -3.7±9.6 versus -119.4±14.5 (difference, 115.7; P<0.001). Approximately 20% of the patients who received patisiran and 10% of those who received placebo had mild or moderate infusion-related reactions; the overall incidence and types of adverse events were similar in the two groups.
CONCLUSIONS
In this trial, patisiran improved multiple clinical manifestations of hereditary transthyretin amyloidosis. (Funded by Alnylam Pharmaceuticals; APOLLO ClinicalTrials.gov number, NCT01960348 .).
背景
Patisiran 是一种正在研究的 RNA 干扰治疗药物，专门抑制肝合成转甲状腺素蛋白。
方法
在这项 3 期试验中，我们以 2:1 的比例随机分配患有遗传性转甲状腺素淀粉样变性伴多发性神经病的患者，分别接受静脉注射 patisiran（0.3mg/每千克体重）或安慰剂，每 3 周一次。主要终点是 18 个月时改良神经病损伤评分+7（mNIS+7；范围 0 至 304，得分越高表示损伤越严重）与基线相比的变化。其他评估包括诺福克生活质量-糖尿病神经病变问卷（Norfolk QOL-DN）（范围-4 至 136，得分越高表示生活质量越差）、10 米步行试验（用米/秒表示步速）和改良体重指数（改良 BMI，定义为[体重/身高平方×克/升白蛋白水平]；较低的值表示较差的营养状态）。
结果
共有 225 名患者接受了随机分组（148 名接受 patisiran 组，77 名接受安慰剂组）。patisiran 组基线时 mNIS+7 的平均值（±SD）为 80.9±41.5，安慰剂组为 74.6±37.0；18 个月时，最小二乘均值（±SE）与基线相比的变化为-6.0±1.7 对 28.0±2.6（差异为-34.0 分；P<0.001）。patisiran 组基线时 Norfolk QOL-DN 评分的平均值（±SD）为 59.6±28.2，安慰剂组为 55.5±24.3；18 个月时，与基线相比的最小二乘均值（±SE）变化为-6.7±1.8 对 14.4±2.7（差异为-21.1 分；P<0.001）。Patisiran 还对步态速度和改良 BMI 有影响。18 个月时，patisiran 组与安慰剂组相比，与基线相比的最小二乘均值（±SE）变化为 0.08±0.02 米/秒，而安慰剂组为-0.24±0.04 米/秒（差异为 0.31 米/秒；P<0.001），改良 BMI 的最小二乘均值（±SE）变化为-3.7±9.6 对-119.4±14.5（差异为 115.7；P<0.001）。约 20%接受 patisiran 治疗的患者和 10%接受安慰剂治疗的患者出现轻度或中度输注相关反应；两组的总体不良事件发生率和类型相似。
结论
在这项试验中，patisiran 改善了遗传性转甲状腺素淀粉样变性的多种临床表现。（由 Alnylam 制药公司资助；APOLLO 临床试验.gov 编号，NCT01960348）。
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