Data_Sheet_1_A Phase II Study to Evaluate the Safety and Efficacy of Prasinezumab in Early Parkinson's Disease (PASADENA): Rationale, Design, and Baseline Data.docx

Background: Currently available treatments for Parkinson's disease (PD) do not slow clinical progression nor target alpha-synuclein, a key protein associated with the disease.
Objective: The study objective was to evaluate the efficacy and safety of prasinezumab, a humanized monoclonal antibody that binds aggregated alpha-synuclein, in individuals with early PD.
Methods: The PASADENA study is a multicenter, randomized, double-blind, placebo-controlled treatment study. Individuals with early PD, recruited across the US and Europe, received monthly intravenous doses of prasinezumab (1,500 or 4,500 mg) or placebo for a 52-week period (Part 1), followed by a 52-week extension (Part 2) in which all participants received active treatment. Key inclusion criteria were: aged 40–80 years; Hoehn & Yahr (H&Y) Stage I or II; time from diagnosis ≤2 years; having bradykinesia plus one other cardinal sign of PD (e.g., resting tremor, rigidity); DAT-SPECT imaging consistent with PD; and either treatment naïve or on a stable monoamine oxidase B (MAO-B) inhibitor dose. Study design assumptions for sample size and study duration were built using a patient cohort from the Parkinson's Progression Marker Initiative (PPMI). In this report, baseline characteristics are compared between the treatment-naïve and MAO-B inhibitor-treated PASADENA cohorts and between the PASADENA and PPMI populations.
Results: Of the 443 patients screened, 316 were enrolled into the PASADENA study between June 2017 and November 2018, with an average age of 59.9 years and 67.4% being male. Mean time from diagnosis at baseline was 10.11 months, with 75.3% in H&Y Stage II. Baseline motor and non-motor symptoms (assessed using Movement Disorder Society—Unified Parkinson's Disease Rating Scale [MDS-UPDRS]) were similar in severity between the MAO-B inhibitor-treated and treatment-naïve PASADENA cohorts (MDS-UPDRS sum of Parts I + II + III [standard deviation (SD)]; 30.21 [11.96], 32.10 [13.20], respectively). The overall PASADENA population (63.6% treatment naïve and 36.4% on MAO-B inhibitor) showed a similar severity in MDS-UPDRS scores (e.g., MDS-UPDRS sum of Parts I + II + III [SD]; 31.41 [12.78], 32.63 [13.04], respectively) to the PPMI cohort (all treatment naïve).
Conclusions: The PASADENA study population is suitable to investigate the potential of prasinezumab to slow disease progression in individuals with early PD.
Trial Registration: NCT03100149.

背景：目前临床可用的帕金森病（PD）治疗手段既无法延缓疾病的临床进展，也不能靶向结合与该病密切相关的关键蛋白α-突触核蛋白（alpha-synuclein）。
研究目的：本研究旨在评估普拉奈珠单抗（prasinezumab，一种可结合聚集型α-突触核蛋白（alpha-synuclein）的人源化单克隆抗体）用于早期帕金森病患者的疗效与安全性。
研究方法：PASADENA研究为一项多中心、随机、双盲、安慰剂对照的治疗性研究。招募自美国与欧洲的早期帕金森病患者，在为期52周的第一阶段（Part 1）中接受每月一次的静脉输注普拉奈珠单抗（1500mg或4500mg）或安慰剂，随后进入为期52周的扩展阶段（Part 2），所有受试者在此阶段均接受活性药物治疗。核心入组标准包括：年龄40~80岁；霍恩-亚尔（Hoehn & Yahr, H&Y）分期I期或II期；确诊时长≤2年；存在运动迟缓合并至少1项帕金森病其他核心体征（如静止性震颤、肌强直）；DAT-SPECT成像结果符合帕金森病表现；且为初治患者或接受稳定剂量单胺氧化酶B（MAO-B）抑制剂治疗。本研究的样本量与研究时长设计假设，基于帕金森病进展标志物倡议（PPMI）的患者队列构建。本报告中，将对初治与接受MAO-B抑制剂治疗的PASADENA研究队列，以及PASADENA研究人群与PPMI人群的基线特征进行对比分析。
研究结果：在443例筛查患者中，共316例于2017年6月至2018年11月期间入组PASADENA研究，受试者平均年龄为59.9岁，其中男性占比67.4%。基线时确诊时长的平均值为10.11个月，75.3%的受试者处于霍恩-亚尔分期II期。采用运动障碍学会-统一帕金森病评定量表（MDS-UPDRS）评估的基线运动与非运动症状严重程度，在接受MAO-B抑制剂治疗与初治的PASADENA队列中无显著差异（MDS-UPDRS I+II+III部分总分[标准差（SD）]分别为30.21[11.96]、32.10[13.20]）。整体PASADENA研究人群（63.6%为初治患者，36.4%接受MAO-B抑制剂治疗）的MDS-UPDRS评分严重程度（如MDS-UPDRS I+II+III部分总分[SD]分别为31.41[12.78]、32.63[13.04]）与全部为初治患者的PPMI队列相似。
研究结论：PASADENA研究人群适合用于评估普拉奈珠单抗延缓早期帕金森病患者疾病进展的潜力。
试验注册：NCT03100149。