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首页> 外文期刊>JAMA neurology >Safety and Tolerability of Multiple Ascending Doses of PRX002/RG7935, an Anti–α-Synuclein Monoclonal Antibody, in Patients With Parkinson DiseaseA Randomized Clinical Trial
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Safety and Tolerability of Multiple Ascending Doses of PRX002/RG7935, an Anti–α-Synuclein Monoclonal Antibody, in Patients With Parkinson DiseaseA Randomized Clinical Trial

机译：帕金森·斯内西亚患者随机临床试验，抗α-突触核蛋白单克隆抗体，抗α-突触核蛋白单克隆抗体，抗α-突触核蛋白单克隆抗体的安全性和耐受性。

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Importance Aggregated α-synuclein is believed to be central to the pathogenesis of Parkinson disease (PD). PRX002/RG7935 (PRX002) is a humanized monoclonal antibody designed to target aggregated forms of α-synuclein, thereby inhibiting neuron-to-neuron transfer of presumed pathogenic forms of α-synuclein, potentially resulting in neuronal protection and slowing disease progression.Objective To evaluate the safety and tolerability of multiple intravenous infusions of PRX002 in patients with idiopathic PD.Design, Setting, and Participants Multicenter, randomized, double-blind, placebo-controlled, multiple ascending-dose trial at 8 US study centers from July 2014 to September 2016. Eligible participants were aged 40 to 80 years with mild to moderate idiopathic PD (Hoehn and Yahr stages 1-3).Interventions Participants were enrolled into 6 ascending-dose cohorts and randomly assigned to receive PRX002 (0.3 mg/kg, 1.0 mg/kg, 3.0 mg/kg, 10 mg/kg, 30 mg/kg, or 60 mg/kg) or placebo. Participants received 3 intravenous infusions every 4 weeks of PRX002 or placebo and were monitored during a 24-week observational period.Main Outcomes and Measures Safety and tolerability assessments included physical and neurological examinations, laboratory tests, vital signs, and adverse events. Pharmacokinetic parameters included maximum PRX002 concentration, area under the curve, and half-life.Results Of the 80 participants, most were white (97.5%; n = 78) and male (80%; n = 64); median (SD) age was 58 (8.4) years. PRX002 was generally safe and well tolerated; no serious or severe PRX002-related treatment-emergent adverse events (TEAEs) were reported. The TEAEs experienced by at least 5% of patients receiving PRX002, irrespective of relatedness to study drug, were constipation (9.1%; n = 5), infusion reaction (7.3%; n = 4), diarrhea (5.5%; n = 3), headache (5.5%; n = 3), peripheral edema (5.5%; n = 3), post–lumbar puncture syndrome (5.5%; n = 3), and upper respiratory tract infection (5.5%; n = 3). No antidrug antibodies were detected. Serum PRX002 levels increased in an approximately dose-proportional manner; mean terminal elimination half-life was similar across all doses (10.2 days). Rapid dose- and time-dependent mean reductions from baseline vs placebo in free serum α-synuclein levels of up to 97% were seen after a single infusion at the highest dose (F78,284 = 1.66; P = .002), with similar reductions after 2 additional infusions. Mean cerebrospinal fluid PRX002 concentration increased with PRX002 dose and was approximately 0.3% relative to serum across all dose cohorts.Conclusions and Relevance Single and multiple doses of PRX002 were generally safe and well tolerated and resulted in robust binding of peripheral α-synuclein and dose-dependent increases of PRX002 in cerebrospinal fluid, reaching cerebrospinal fluid concentrations that may be expected to engage extracellular aggregated α-synuclein in the brain. Findings support the design of an ongoing phase 2 clinical study (NCT03100149).Trial Registration ClinicalTrials.gov Identifier: NCT02157714.
机译：重要的聚集α-突触核蛋白被认为是帕金森病的发病机制（PD）的核心。 PRX002 / RG7935（PRX002）是一种人源化单克隆抗体，设计用于靶向α-突触核蛋白的聚集形式，从而抑制α-突触核蛋白的预测致病形式的神经元至神经元转移，可能导致神经元保护和疾病减缓进展。目的评估患有特性，设定和参与者多中心，随机，双盲，安慰剂控制，8美国学习中心的多中心，随机，双盲，安慰剂控制的多中心，随机，双盲，安慰剂对照，从2014年7月至9月2016年，符合条件的参与者年龄40至80岁，患有轻度至中度特发性PD（Hoehn和Yahr Stages 1-3）.Interventions参与者已注册到6个上升剂量队列中并随机分配接收PRX002（0.3 mg / kg，1.0 mg。 / kg，3.0 mg / kg，10 mg / kg，30 mg / kg或60 mg / kg）或安慰剂。参与者每4周接受3个静脉注射的PRX002或安慰剂，并在24周的观察期内监测。此期间的结果和措施安全性和耐受性评估包括物理和神经检查，实验室测试，生命体征和不良事件。药代动力学参数包括最大PRX002浓度，曲线下的区域，半衰期。80名参与者的方法，大多数是白色（97.5％; n = 78）和雄性（80％; n = 64）;中位数（SD）年龄为58（8.4）年。 PRX002通常是安全和耐受性的;报告了没有严重或严重的PRX002相关治疗紧急不良事件（茶）。茶叶经过至少5％的患者接受PRX002，无论有相关性研究药物，都是便秘的（9.1％; n = 5），输注反应（7.3％; n = 4），腹泻（5.5％; n = 3 ），头痛（5.5％; n = 3），外周水肿（5.5％; n = 3），后腰椎穿刺综合征（5.5％; n = 3）和上呼吸道感染（5.5％; n = 3） 。没有检测到抗体抗体。血清PRX002水平以近似剂量比例的方式增加;平均终端消除半衰期在所有剂量上相似（10.2天）。在最高剂量的单一输注后，在单次输注后，从基线VS安慰剂的快速剂量和时间依赖性平均减少高达97％（F78,284 = 1.66; P = .002），具有相似的减少2次额外输注后。平均脑脊液PRX002浓度随pRX002剂量增加，相对于所有剂量族的血清约为0.3％。结论和相关性单剂量和多剂量PRX002通常是安全的，并且导致外周α-突触核蛋白和剂量的鲁棒结合。脑脊液中PRX002的依赖性增加，达到脑脊液浓度，可能预期接合大脑中的细胞外聚集α-突触核蛋白。调查结果支持持续阶段2临床研究的设计（NCT03100149）.trial注册ClinicalTrials.gov标识符：NCT02157714。

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