普拉克索尼单抗治疗早期帕金森病的试验。

Trial of Prasinezumab in Early-Stage Parkinson's Disease.

机构信息

From the Neuroscience and Rare Diseases, Discovery and Translational Area (G.P., K.I.T., A. Boulay, A.V., F.G.B., J.D., G.D., H.S., M.B., S.D., Š.H., T.K., G.A.K., D.U., A. Bonni), and Pharmaceutical Sciences (B.R.), Roche Pharma Research and Early Development (pRED), and Roche pRED Informatics (F.L., E.V.-V., M.L.), Roche Innovation Center Basel, and Product Development Neuroscience (S.Z., A.M., N. Pross, P.F., R.D., T.N.) and Product Development Safety (M.M., D.R.), F. Hoffmann-La Roche - all in Basel, Switzerland; University of Exeter Medical School, London (G.P.), Roche Products, Welwyn Garden City (J.A.-C., R.F.), and the Clinical Ageing Research Unit, Newcastle University, Newcastle upon Tyne (N. Pavese) - all in the United Kingdom; the Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago (T.S.); Institute for Neurodegenerative Disorders, New Haven, CT (K.M., D.S.R.); the Department of Neurology, McGill University, and Montreal Neurological Institute, Montreal (R.B.P.); University San Raffaele Roma and the Institute for Research and Medical Care, IRCCS San Raffaele Pisana, Rome (F.S.); Centre Hospitalier de la Timone, Marseille, France (J.-P.A.); Paracelsus-Elena-Klinik, Kassel (B.M.), the Department of Neurology, University Medical Center Göttingen, Göttingen (B.M.), Hertie Institute for Clinical Brain Research, University of Tübingen, and the German Center for Neurodegenerative Diseases, Tübingen (T.G.), the Institute of Neurosciences and Medicine, Brain and Behavior, Research Center Jülich, Jülich (J.D.), the Institute of Systems Neuroscience, Medical Faculty, Heinrich Heine University Düsseldorf, Düsseldorf (J.D.), and Excelya Germany, Freiburg (A.H.) - all in Germany; the Department of Neurology, University Hospital de La Princesa, Madrid (L.L.-M.), and University Clinic of Navarra, Pamplona (M.R.L.) - both in Spain; University of South Florida, Tampa (R.A.H.); University of Vermont Larner College of Medicine, Burlington (J.T.B.); University of Alabama Medical Center, Birmingham (A.P.N.); and the Department of Neurology, Innsbruck Medical University, Innsbruck, Austria (W.P.).

出版信息

N Engl J Med. 2022 Aug 4;387(5):421-432. doi: 10.1056/NEJMoa2202867.

DOI:10.1056/NEJMoa2202867

PMID:35921451

Abstract

BACKGROUND

Aggregated α-synuclein plays an important role in the pathogenesis of Parkinson's disease. The monoclonal antibody prasinezumab, directed at aggregated α-synuclein, is being studied for its effect on Parkinson's disease.

METHODS

In this phase 2 trial, we randomly assigned participants with early-stage Parkinson's disease in a 1:1:1 ratio to receive intravenous placebo or prasinezumab at a dose of 1500 mg or 4500 mg every 4 weeks for 52 weeks. The primary end point was the change from baseline to week 52 in the sum of scores on parts I, II, and III of the Movement Disorder Society-sponsored revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS; range, 0 to 236, with higher scores indicating greater impairment). Secondary end points included the dopamine transporter levels in the putamen of the hemisphere ipsilateral to the clinically more affected side of the body, as measured by I-ioflupane single-photon-emission computed tomography (SPECT).

RESULTS

A total of 316 participants were enrolled; 105 were assigned to receive placebo, 105 to receive 1500 mg of prasinezumab, and 106 to receive 4500 mg of prasinezumab. The baseline mean MDS-UPDRS scores were 32.0 in the placebo group, 31.5 in the 1500-mg group, and 30.8 in the 4500-mg group, and mean (±SE) changes from baseline to 52 weeks were 9.4±1.2 in the placebo group, 7.4±1.2 in the 1500-mg group (difference vs. placebo, -2.0; 80% confidence interval [CI], -4.2 to 0.2; P = 0.24), and 8.8±1.2 in the 4500-mg group (difference vs. placebo, -0.6; 80% CI, -2.8 to 1.6; P = 0.72). There was no substantial difference between the active-treatment groups and the placebo group in dopamine transporter levels on SPECT. The results for most clinical secondary end points were similar in the active-treatment groups and the placebo group. Serious adverse events occurred in 6.7% of the participants in the 1500-mg group and in 7.5% of those in the 4500-mg group; infusion reactions occurred in 19.0% and 34.0%, respectively.

CONCLUSIONS

Prasinezumab therapy had no meaningful effect on global or imaging measures of Parkinson's disease progression as compared with placebo and was associated with infusion reactions. (Funded by F. Hoffmann-La Roche and Prothena Biosciences; PASADENA ClinicalTrials.gov number, NCT03100149.).

摘要

背景

聚集的α-突触核蛋白在帕金森病的发病机制中起重要作用。针对聚集的α-突触核蛋白的单克隆抗体 prasinezumab 正在研究其对帕金森病的影响。

方法

在这项 2 期试验中，我们以 1:1:1 的比例随机分配早期帕金森病患者接受静脉注射安慰剂或 1500mg 或 4500mg 的 prasinezumab，每 4 周一次，共 52 周。主要终点是从基线到第 52 周时运动障碍协会赞助的统一帕金森病评定量表（MDS-UPDRS；范围为 0 至 236，得分越高表示损伤越大）I、II 和 III 部分总和的变化。次要终点包括使用 I-ioflupane 单光子发射计算机断层扫描（SPECT）测量的对侧纹状体的多巴胺转运蛋白水平。

结果

共纳入 316 名参与者；105 名被分配接受安慰剂，105 名接受 1500mg 的 prasinezumab，106 名接受 4500mg 的 prasinezumab。安慰剂组的基线平均 MDS-UPDRS 评分为 32.0，1500mg 组为 31.5，4500mg 组为 30.8，从基线到 52 周的平均（±SE）变化为安慰剂组为 9.4±1.2，1500mg 组为 7.4±1.2（与安慰剂相比的差异，-2.0；80%置信区间[CI]，-4.2 至 0.2；P=0.24），4500mg 组为 8.8±1.2（与安慰剂相比的差异，-0.6；80%CI，-2.8 至 1.6；P=0.72）。SPECT 上多巴胺转运蛋白水平在活性治疗组与安慰剂组之间没有实质性差异。活性治疗组与安慰剂组的大多数临床次要终点结果相似。1500mg 组有 6.7%的参与者发生严重不良事件，4500mg 组有 7.5%的参与者发生严重不良事件；分别有 19.0%和 34.0%的参与者发生输注反应。