From University College London (UCL) Huntington's Disease Centre, Department of Neurodegenerative Disease, Queen Square Institute of Neurology, UCL, and the U.K. Dementia Research Institute at UCL, London (S.J.T., E.J.W.), the Department of Clinical Neuroscience, Addenbrooke's Hospital, University of Cambridge, Cambridge (R.A.B., N.F.B.), Manchester Centre for Genomic Medicine, St. Mary's Hospital, Manchester University NHS Foundation Trust, and the Division of Evolution and Genomic Sciences, School of Biological Sciences, Faculty of Biology, Medicine, and Health, University of Manchester, Manchester Academic Health Science Centre, Manchester (D.C.), the University of Edinburgh and the U.K. Dementia Research Institute, Edinburgh (J.P.), the Institute of Clinical Sciences, College of Medical and Dental Sciences, University Hospital Birmingham, Birmingham (H.R.), and the Cardiff University Brain Repair Group, Brain Repair and Intracranial Neurotherapeutics Unit, Neuroscience and Mental Health Research Institute and School of Biosciences, Cardiff (A.R.) - all in the United Kingdom; the Centre for Huntington's Disease, Department of Medical Genetics, and the Division of Neurology, Department of Medicine, University of British Columbia, and the Centre for Molecular Medicine and Therapeutics, B.C. Children's Hospital, Vancouver, Canada (B.R.L.); the Department of Neurology, Ulm University, Huntington's Disease Centre, Ulm (G.B.L.), the Department of Neurology, Huntington Center North Rhine-Westphalia, Ruhr University Bochum, St. Josef-Hospital, Bochum (C.S.), and the Department of Neuropsychiatry, Charité-Universitätsmedizin Berlin, Deutsches Zentrum für Neurodegenerative Erkrankungen, Berlin (J.P.) - all in Germany; Ionis Pharmaceuticals, Carlsbad, CA (H.B.K., E.E.S., D.A.N., T.B., E.P., A.V.S., C.F.B., R.M.L.); and F. Hoffmann-La Roche, Basel, Switzerland (C.C., I.G., S.A.S.).
N Engl J Med. 2019 Jun 13;380(24):2307-2316. doi: 10.1056/NEJMoa1900907. Epub 2019 May 6.
Huntington's disease is an autosomal-dominant neurodegenerative disease caused by CAG trinucleotide repeat expansion in , resulting in a mutant huntingtin protein. IONIS-HTT (hereafter, HTT) is an antisense oligonucleotide designed to inhibit messenger RNA and thereby reduce concentrations of mutant huntingtin.
We conducted a randomized, double-blind, multiple-ascending-dose, phase 1-2a trial involving adults with early Huntington's disease. Patients were randomly assigned in a 3:1 ratio to receive HTT or placebo as a bolus intrathecal administration every 4 weeks for four doses. Dose selection was guided by a preclinical model in mice and nonhuman primates that related dose level to reduction in the concentration of huntingtin. The primary end point was safety. The secondary end point was HTT pharmacokinetics in cerebrospinal fluid (CSF). Prespecified exploratory end points included the concentration of mutant huntingtin in CSF.
Of the 46 patients who were enrolled in the trial, 34 were randomly assigned to receive HTT (at ascending dose levels of 10 to 120 mg) and 12 were randomly assigned to receive placebo. Each patient received all four doses and completed the trial. Adverse events, all of grade 1 or 2, were reported in 98% of the patients. No serious adverse events were seen in HTT-treated patients. There were no clinically relevant adverse changes in laboratory variables. Predose (trough) concentrations of HTT in CSF showed dose dependence up to doses of 60 mg. HTT treatment resulted in a dose-dependent reduction in the concentration of mutant huntingtin in CSF (mean percentage change from baseline, 10% in the placebo group and -20%, -25%, -28%, -42%, and -38% in the HTT 10-mg, 30-mg, 60-mg, 90-mg, and 120-mg dose groups, respectively).
Intrathecal administration of HTT to patients with early Huntington's disease was not accompanied by serious adverse events. We observed dose-dependent reductions in concentrations of mutant huntingtin. (Funded by Ionis Pharmaceuticals and F. Hoffmann-La Roche; ClinicalTrials.gov number, NCT02519036.).
亨廷顿病是一种常染色体显性神经退行性疾病，由 CAG 三核苷酸重复扩展引起 ，导致突变亨廷顿蛋白。IONIS-HTT（以下简称 HTT）是一种反义寡核苷酸，旨在抑制 信使 RNA，从而降低突变型亨廷顿蛋白的浓度。
我们进行了一项随机、双盲、多剂量递增、1-2a 期临床试验，纳入了早期亨廷顿病患者。患者以 3:1 的比例随机分配接受 HTT 或安慰剂作为鞘内推注，每 4 周一次，共 4 次。剂量选择由在小鼠和非人灵长类动物中进行的临床前模型指导，该模型将剂量水平与亨廷顿蛋白浓度的降低相关联。主要终点是安全性。次要终点是 HTT 在脑脊液（CSF）中的药代动力学。预先指定的探索性终点包括 CSF 中突变型亨廷顿蛋白的浓度。
在参加试验的 46 名患者中，34 名被随机分配接受 HTT（递增剂量水平为 10 至 120mg），12 名被随机分配接受安慰剂。每位患者均接受了全部 4 次剂量并完成了试验。98%的患者报告了不良反应，均为 1 级或 2 级。HTT 治疗的患者未出现严重不良事件。实验室变量无临床相关不良变化。CSF 中 HTT 的预剂量（谷浓度）显示出剂量依赖性，最高剂量可达 60mg。HTT 治疗导致 CSF 中突变型亨廷顿蛋白浓度呈剂量依赖性降低（与基线相比的平均百分比变化，安慰剂组为 10%，HTT 10mg、30mg、60mg、90mg 和 120mg 剂量组分别为-20%、-25%、-28%、-42%和-38%）。
鞘内给予早期亨廷顿病患者 HTT 不伴有严重不良事件。我们观察到浓度的剂量依赖性降低 突变型亨廷顿蛋白。（由 Ionis 制药公司和 F. Hoffmann-La Roche 资助；ClinicalTrials.gov 编号，NCT02519036.）。
