Volc Dieter, Poewe Werner, Kutzelnigg Alexandra, Lührs Petra, Thun-Hohenstein Caroline, Schneeberger Achim, Galabova Gergana, Majbour Nour, Vaikath Nishant, El-Agnaf Omar, Winter Dorian, Mihailovska Eva, Mairhofer Andreas, Schwenke Carsten, Staffler Günther, Medori Rossella
Confraternitaet-Privatklinik Josefstadt, Vienna, Austria.
Department of Neurology, Medical University Innsbruck, Innsbruck, Austria.
Lancet Neurol. 2020 Jul;19(7):591-600. doi: 10.1016/S1474-4422(20)30136-8.
Robust evidence supports the role of α-synuclein pathology as a driver of neuronal dysfunction in Parkinson's disease. PD01A is a specific active immunotherapy with a short peptide formulation targeted against oligomeric α-synuclein. This phase 1 study assessed the safety and tolerability of the PD01A immunotherapeutic in patients with Parkinson's disease.
We did a first-in-human, randomised, phase 1 study of immunisations with PD01A, followed by three consecutive study extensions. Patients aged 45-65 years with a clinical diagnosis of Parkinson's disease (≤4 years since diagnosis and Hoehn and Yahr Stage 1 to 2), imaging results (dopamine transporter single photon emission CT and MRI) consistent with their Parkinson's disease diagnosis, and on stable doses of Parkinson's disease medications for at least 3 months were recruited at a single private clinic in Vienna, Austria. Patients were randomly assigned (1:1), using a computer-generated sequence with varying block size, to receive four subcutaneous immunisations with either 15 μg or 75 μg PD01A injected into the upper arms and followed up initially for 52 weeks, followed by a further 39 weeks' follow-up. Patients were then randomly assigned (1:1) again to receive the first booster immunisation at 15 μg or 75 μg and were followed up for 24 weeks. All patients received a second booster immunisation of 75 μg and were followed up for an additional 52 weeks. Patients were masked to dose allocation. Primary (safety) analyses included all treated patients. These four studies were registered with EU Clinical Trials Register, EudraCT numbers 2011-002650-31, 2013-001774-20, 2014-002489-54, and 2015-004854-16.
32 patients were recruited between Feb 14, 2012, and Feb 6, 2013, and 24 were deemed eligible and randomly assigned to receive four PD01A priming immunisations. One patient had a diagnosis change to multiple system atrophy and was withdrawn and two patients withdrew consent during the studies. 21 (87%) of 24 patients received all six immunisations and completed 221-259 weeks in-study (two patients in the 15 μg dose group and one patient in the 75 μg dose group discontinued). All patients experienced at least one adverse event, but most of them were considered unrelated to study treatment (except for transient local injection site reactions, which affected all but one patient). Serial MRI assessments also ruled out inflammatory processes. Systemic treatment-related adverse events were fatigue (n=4), headache (n=3), myalgia (n=3), muscle rigidity (n=2), and tremor (n=2). The geometric group mean titre of antibodies against the immunising peptide PD01 increased from 1:46 at baseline to 1:3580 at week 12 in the 15 μg dose group, and from 1:76 to 1:2462 at week 12 in the 75 μg dose group. Antibody titres returned to baseline over 2 years, but could be rapidly reactivated after booster immunisation from week 116 onwards, reaching geometric group mean titres up to 1:20218.
Repeated administrations of PD01A were safe and well tolerated over an extended period. Specific active immunotherapy resulted in a substantial humoral immune response with target engagement. Phase 2 studies are needed to further assess the safety and efficacy of PD01A for the treatment of Parkinson's disease.
AFFiRiS, Michael J Fox Foundation.
有力证据支持α-突触核蛋白病理改变在帕金森病中作为神经元功能障碍驱动因素的作用。PD01A是一种针对寡聚α-突触核蛋白的短肽制剂的特异性主动免疫疗法。这项1期研究评估了PD01A免疫疗法在帕金森病患者中的安全性和耐受性。
我们开展了一项关于PD01A免疫接种的首次人体随机1期研究，随后进行了三次连续的研究扩展。年龄在45 - 65岁、临床诊断为帕金森病（诊断后≤4年且霍恩和雅尔分期为1至2期）、影像学结果（多巴胺转运体单光子发射计算机断层扫描和磁共振成像）与其帕金森病诊断相符且服用帕金森病药物稳定剂量至少3个月的患者，在奥地利维也纳的一家私立诊所招募。患者使用计算机生成的不同区组大小的序列随机分配（1:1），接受上臂皮下注射15μg或75μg PD01A的四次免疫接种，最初随访52周，随后再随访39周。然后患者再次随机分配（1:1）接受15μg或75μg的首次加强免疫接种，并随访24周。所有患者接受75μg的第二次加强免疫接种，并额外随访52周。患者对剂量分配不知情。主要（安全性）分析包括所有接受治疗的患者。这四项研究已在欧盟临床试验注册中心注册，欧盟临床试验编号分别为2011 - 002650 - 31、2013 - 001774 - 20、2014 - 002489 - 54和2015 - 004854 - 16。
2012年2月14日至2013年2月6日期间招募了32名患者，其中24名被认为符合条件并随机分配接受四次PD01A初始免疫接种。一名患者诊断变更为多系统萎缩并退出研究，两名患者在研究期间撤回同意。24名患者中的21名（87%）接受了全部六次免疫接种，并在研究中完成了221 - 259周（15μg剂量组的两名患者和75μg剂量组的一名患者中断治疗）。所有患者均经历了至少一次不良事件，但大多数被认为与研究治疗无关（除了短暂的局部注射部位反应，除一名患者外所有患者均有此反应）。系列磁共振成像评估也排除了炎症过程。与治疗相关的全身性不良事件有疲劳（n = 4）、头痛（n = 3）、肌痛（n = 3）、肌肉僵硬（n = 2）和震颤（n = 2）。15μg剂量组中针对免疫肽PD01的抗体几何组平均滴度从基线时的1:46增加到第12周时的1:3580，75μg剂量组从基线时的1:76增加到第12周时的1:2462。抗体滴度在2年内恢复到基线水平，但从第116周起加强免疫接种后可迅速重新激活，几何组平均滴度高达1:20218。
长期重复给予PD01A是安全且耐受性良好的。特异性主动免疫疗法引发了显著的体液免疫反应并实现了靶点结合。需要开展2期研究以进一步评估PD01A治疗帕金森病的安全性和有效性。
AFFiRiS，迈克尔·J·福克斯基金会。
