Patisiran 治疗转甲状腺素蛋白心脏淀粉样变心肌病患者。

Patisiran Treatment in Patients with Transthyretin Cardiac Amyloidosis.

机构信息

From Columbia University Irving Medical Center (M.S.M.) and Grossman School of Medicine, NYU Langone (A.G.-D.) - both in New York; the Center for Advanced Heart and Lung Disease, Baylor University Medical Center (P.K., R.L.G.), Baylor Scott & White Research Institute, and Texas A&M Health Science Center, Dallas (R.L.G.), and TCU School of Medicine, Fort Worth (R.L.G.) - all in Texas; the National Amyloidosis Centre, UCL, Division of Medicine, Royal Free Hospital, London (M.F., J.D.G.); Boston University School of Medicine (J.L.B.), the Cardiovascular Division, Brigham and Women's Hospital (S.D.S., M.D.C.), and the Division of Nuclear Medicine and Molecular Imaging, Brigham and Women's Hospital, Harvard Medical School (M.D.C.), Boston, and Alnylam Pharmaceuticals, Cambridge (P.B., M.T.W., J.C., E.Y., M.T.S., P.Y.J., P.P.G., J.V.) - all in Massachusetts; the Department of Cardiovascular Diseases, Mayo Clinic College of Medicine, Rochester, MN (M.G.); the Department of Cardiology, Rigshospitalet, University of Copenhagen, Copenhagen (F.G.), and the Department of Cardiology, Aarhus University Hospital, Aarhus (S.H.P.) - both in Denmark; the Division of Cardiovascular Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville (R.R.H.); the Cardiology Department and French National Reference Center for Cardiac Amyloidosis, GRC Amyloid Research Institute and Clinical Investigation Centre 1430 at Hôpitaux Universitaires Henri-Mondor Assistance Publique-Hôpitaux de Paris, and IMRB, INSERM, Université Paris Est Creteil, Creteil (T.D.), and INSERM, LTSI UMR 1099, Centre Hospitalier Universitaire de Rennes, Rennes (E.D.) - both in France; Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, México City (A.G.-D.); the Department of Medicine, University of Chicago, Chicago (N.S.); the Department of Medicine (Neurology and Rheumatology), Shinshu University School of Medicine, Matsumoto (Y.S.), the Division of Cardiovascular Medicine, Department of Medicine, Kurume University School of Medicine, Kurume (N.T.), and the Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kumamoto University, Kumamoto (K.T.) - all in Japan; Westmead Amyloidosis Service, Westmead Hospital, Sydney (M.S.T.); the Department of Cardiology, Institute for Clinical and Experimental Medicine (M.K.), and the 2nd Department of Medicine, Department of Cardiovascular Medicine, First Faculty of Medicine, Charles University in Prague and General University Hospital in Prague (T.P.) - both in Prague, Czech Republic; the Heart Vascular and Thoracic Institute, Cleveland Clinic, Cleveland (W.H.W.T.); Taipei Veterans General Hospital and National Yang Ming Chiao Tung University, Taipei, Taiwan (W.-C.Y.); Amyloidosis Research & Treatment Center, Fondazione IRCCS Policlinico San Matteo di Pavia, Pavia (L.O.), the Department of Medical and Surgical Sciences, University of Bologna, and the Cardiology Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna (I.D.), and the Department of Clinical and Experimental Medicine, Careggi University Hospital, Florence (F.P.) - all in Italy; and Unidade de Pesquisa Clínica-UPC, Hospital Das Clinicas da Faculdade de Medicina de Ribeirão Preto-USP (M.S.), and Instituto do Coração-HCFMUSP (F.F.) - both in São Paulo.

出版信息

N Engl J Med. 2023 Oct 26;389(17):1553-1565. doi: 10.1056/NEJMoa2300757.

DOI:10.1056/NEJMoa2300757

PMID:37888916

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10757426/

Abstract

BACKGROUND

Transthyretin amyloidosis, also called ATTR amyloidosis, is associated with accumulation of ATTR amyloid deposits in the heart and commonly manifests as progressive cardiomyopathy. Patisiran, an RNA interference therapeutic agent, inhibits the production of hepatic transthyretin.

METHODS

In this phase 3, double-blind, randomized trial, we assigned patients with hereditary, also known as variant, or wild-type ATTR cardiac amyloidosis, in a 1:1 ratio, to receive patisiran (0.3 mg per kilogram of body weight) or placebo once every 3 weeks for 12 months. A hierarchical procedure was used to test the primary and three secondary end points. The primary end point was the change from baseline in the distance covered on the 6-minute walk test at 12 months. The first secondary end point was the change from baseline to month 12 in the Kansas City Cardiomyopathy Questionnaire-Overall Summary (KCCQ-OS) score (with higher scores indicating better health status). The second secondary end point was a composite of death from any cause, cardiovascular events, and change from baseline in the 6-minute walk test distance over 12 months. The third secondary end point was a composite of death from any cause, hospitalizations for any cause, and urgent heart failure visits over 12 months.

RESULTS

A total of 360 patients were randomly assigned to receive patisiran (181 patients) or placebo (179 patients). At month 12, the decline in the 6-minute walk distance was lower in the patisiran group than in the placebo group (Hodges-Lehmann estimate of median difference, 14.69 m; 95% confidence interval [CI], 0.69 to 28.69; P = 0.02); the KCCQ-OS score increased in the patisiran group and declined in the placebo group (least-squares mean difference, 3.7 points; 95% CI, 0.2 to 7.2; P = 0.04). Significant benefits were not observed for the second secondary end point. Infusion-related reactions, arthralgia, and muscle spasms occurred more often among patients in the patisiran group than among those in the placebo group.

CONCLUSIONS

In this trial, administration of patisiran over a period of 12 months resulted in preserved functional capacity in patients with ATTR cardiac amyloidosis. (Funded by Alnylam Pharmaceuticals; APOLLO-B ClinicalTrials.gov number, NCT03997383.).

摘要

背景

转甲状腺素蛋白淀粉样变性病，也称为ATTR 淀粉样变性病，与心脏中 ATTR 淀粉样沉积物的积累有关，通常表现为进行性心肌病。Patisiran 是一种 RNA 干扰治疗药物，可抑制肝转甲状腺素的产生。

方法

在这项 3 期、双盲、随机试验中，我们按照 1:1 的比例将遗传性（也称变异型或野生型）ATTR 心脏淀粉样变性病患者分配至接受 patisiran（0.3mg/公斤体重）或安慰剂组，每 3 周给药一次，共 12 个月。采用分层程序检验主要终点和三个次要终点。主要终点为 12 个月时 6 分钟步行试验距离自基线的变化。第一个次要终点为 12 个月时堪萨斯城心肌病问卷总概括评分（KCCQ-OS）自基线的变化（评分越高表示健康状况越好）。第二个次要终点为全因死亡、心血管事件以及 12 个月时 6 分钟步行试验距离自基线的变化组成的复合终点。第三个次要终点为全因死亡、因任何原因住院和 12 个月内紧急心力衰竭就诊组成的复合终点。

结果

共 360 例患者被随机分配至 patisiran 组（181 例）或安慰剂组（179 例）。在 12 个月时，patisiran 组的 6 分钟步行距离下降幅度低于安慰剂组（Hodges-Lehmann 估计的中位数差值为 14.69m；95%CI，0.69 至 28.69；P=0.02）；patisiran 组的 KCCQ-OS 评分升高，安慰剂组下降（最小二乘均数差值为 3.7 分；95%CI，0.2 至 7.2；P=0.04）。次要终点 2 未观察到显著益处。与安慰剂组相比，patisiran 组更常发生输注相关反应、关节痛和肌肉痉挛。