抗心肌转甲状腺素蛋白抗体 NI006 用于清除心脏淀粉样变性的 1 期临床试验。
Phase 1 Trial of Antibody NI006 for Depletion of Cardiac Transthyretin Amyloid.
机构信息
From Hospital Universitario Puerta de Hierro Majadahonda, IDIPHISA, CIBERCV, and Centro Nacional de Investigaciones Cardiovasculares, Madrid, and Universidad Francisco de Vitoria, Pozuelo de Alarcón - all in Spain (P.G.-P.); the Department of Cardiology, University Hospital Heidelberg, Heidelberg (F.S.), and Cardiovascular Center Darmstadt, Darmstadt (A.V.K.) - both in Germany; the Department of Cardiology, University of Rennes, Centre Hospitalier Universitaire (CHU) de Rennes, INSERM, LTSI-UMR 1099, Rennes (E.D.), Service de Cardiologie, CHU de Toulouse-Hôpital Rangueil, Toulouse (O.L.), and the Cardiology Department and French National Reference Center for Cardiac Amyloidosis, Hôpitaux Universitaires Henri Mondor, Assistance Publique-Hôpitaux de Paris, and Institut Mondor de Recherche Biomédicale, INSERM, Université Paris Est Créteil, Créteil (T.D.) - all in France; the Department of Cardiology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands (P.M.); Alexion-AstraZeneca Rare Disease, Boston (M.F.M.); and Neurimmune (A.M., R.J.A.F., J.G., R.M.N., C.H., P.C.K.) and the Institute for Regenerative Medicine (R.M.N., C.H.) and the Center for Molecular Cardiology (P.C.K.), University of Zurich - all in Schlieren, Switzerland.
出版信息
N Engl J Med. 2023 Jul 20;389(3):239-250. doi: 10.1056/NEJMoa2303765. Epub 2023 May 20.
BACKGROUND
Transthyretin amyloid (ATTR) cardiomyopathy is a progressive and fatal disease caused by misfolded transthyretin. Despite advances in slowing disease progression, there is no available treatment that depletes ATTR from the heart for the amelioration of cardiac dysfunction. NI006 is a recombinant human anti-ATTR antibody that was developed for the removal of ATTR by phagocytic immune cells.
METHODS
In this phase 1, double-blind trial, we randomly assigned (in a 2:1 ratio) 40 patients with wild-type or variant ATTR cardiomyopathy and chronic heart failure to receive intravenous infusions of either NI006 or placebo every 4 weeks for 4 months. Patients were sequentially enrolled in six cohorts that received ascending doses (ranging from 0.3 to 60 mg per kilogram of body weight). After four infusions, patients were enrolled in an open-label extension phase in which they received eight infusions of NI006 with stepwise increases in the dose. The safety and pharmacokinetic profiles of NI006 were assessed, and cardiac imaging studies were performed.
RESULTS
The use of NI006 was associated with no apparent drug-related serious adverse events. The pharmacokinetic profile of NI006 was consistent with that of an IgG antibody, and no antidrug antibodies were detected. At doses of at least 10 mg per kilogram, cardiac tracer uptake on scintigraphy and extracellular volume on cardiac magnetic resonance imaging, both of which are imaging-based surrogate markers of cardiac amyloid load, appeared to be reduced over a period of 12 months. The median N-terminal pro-B-type natriuretic peptide and troponin T levels also seemed to be reduced.
CONCLUSIONS
In this phase 1 trial of the recombinant human antibody NI006 for the treatment of patients with ATTR cardiomyopathy and heart failure, the use of NI006 was associated with no apparent drug-related serious adverse events. (Funded by Neurimmune; NI006-101 ClinicalTrials.gov number, NCT04360434.).
背景
转甲状腺素蛋白淀粉样变（ATTR）心肌病是一种由错误折叠的转甲状腺素蛋白引起的进行性和致命性疾病。尽管在减缓疾病进展方面取得了进展，但尚无可用的治疗方法可以从心脏中清除 ATTR，以改善心脏功能障碍。NI006 是一种重组人抗-ATTR 抗体，旨在通过吞噬免疫细胞来清除 ATTR。
方法
在这项 1 期、双盲试验中，我们将 40 名野生型或变异型 ATTR 心肌病和慢性心力衰竭患者随机（2:1 比例）分为接受静脉输注 NI006 或安慰剂组，每 4 周输注一次，持续 4 个月。患者按顺序入组 6 个队列，接受递增剂量（0.3 至 60mg/kg 体重）。输注 4 次后，患者入组开放标签扩展阶段，接受 8 次递增剂量的 NI006 输注。评估了 NI006 的安全性和药代动力学特征，并进行了心脏成像研究。
结果
NI006 的使用与无明显药物相关的严重不良事件无关。NI006 的药代动力学特征与 IgG 抗体一致，未检测到抗药物抗体。在至少 10mg/kg 的剂量下，闪烁扫描和心脏磁共振成像上的心脏示踪剂摄取以及细胞外容积（均为心脏淀粉样负荷的基于成像的替代标志物）似乎在 12 个月内有所降低。中位 N 末端脑钠肽前体和肌钙蛋白 T 水平也似乎有所降低。
结论
在这项针对 ATTR 心肌病和心力衰竭患者的重组人抗体 NI006 的 1 期试验中，NI006 的使用与无明显药物相关的严重不良事件无关。（由 Neurimmune 资助；NI006-101 ClinicalTrials.gov 编号，NCT04360434。）
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