Axon Neuroscience CRM Services SE, Dvorakovo nabrezie 11, 811 02, Bratislava, Slovakia.
Clinical Division of Neurogeriatrics and Division of General Neurology, Department of Neurology, Medical University Graz, Auenbruggerplatz 2, 8036, Graz, Austria.
Alzheimers Res Ther. 2018 Oct 24;10(1):108. doi: 10.1186/s13195-018-0436-1.
Neurofibrillary pathology composed of tau protein is closely correlated with severity and phenotype of cognitive impairment in patients with Alzheimer's disease and non-Alzheimer's tauopathies. Targeting pathological tau proteins via immunotherapy is a promising strategy for disease-modifying treatment of Alzheimer's disease. Previously, we reported a 24-week phase 1 trial on the active vaccine AADvac1 against pathological tau protein; here, we present the results of a further 72 weeks of follow-up on those patients.
We did a phase 1, 72-week, open-label study of AADvac1 in patients with mild to moderate Alzheimer's disease who had completed the preceding phase 1 study. Patients who were previously treated with six doses of AADvac1 at monthly intervals received two booster doses at 24-week intervals. Patients who were previously treated with only three doses received another three doses at monthly intervals, and subsequently two boosters at 24-week intervals. The primary objective was the assessment of long-term safety of AADvac1 treatment. Secondary objectives included assessment of antibody titres, antibody isotype profile, capacity of the antibodies to bind to AD tau and AADvac1, development of titres of AADvac1-induced antibodies over time, and effect of booster doses; cognitive assessment via 11-item Alzheimer's Disease Assessment Scale cognitive assessment (ADAS-Cog), Category Fluency Test and Controlled Oral Word Association Test; assessment of brain atrophy via magnetic resonance imaging (MRI) volumetry; and assessment of lymphocyte populations via flow cytometry.
The study was conducted between 18 March 2014 and 10 August 2016. Twenty-six patients who completed the previous study were enrolled. Five patients withdrew because of adverse events. One patient was withdrawn owing to noncompliance. The most common adverse events were injection site reactions (reported in 13 [50%] of vaccinated patients). No cases of meningoencephalitis or vasogenic oedema were observed. New micro-haemorrhages were observed only in one ApoE4 homozygote. All responders retained an immunoglobulin G (IgG) antibody response against the tau peptide component of AADvac1 over 6 months without administration, with titres regressing to a median 15.8% of titres attained after the initial six-dose vaccination regimen. Booster doses restored previous IgG levels. Hippocampal atrophy rate was lower in patients with high IgG levels; a similar relationship was observed in cognitive assessment.
AADvac1 displayed a benign safety profile. The evolution of IgG titres over vaccination-free periods warrants a more frequent booster dose regimen. The tendency towards slower atrophy in MRI evaluation and less of a decline in cognitive assessment in patients with high titres is encouraging. Further trials are required to expand the safety database and to establish proof of clinical efficacy of AADvac1.
The studies are registered with the EU Clinical Trials Register and ClinicalTrials.gov : the preceding first-in-human study under EudraCT 2012-003916-29 and NCT01850238 (registered on 9 May 2013) and the follow-up study under EudraCT 2013-004499-36 and NCT02031198 (registered 9 Jan 2014), respectively.
由 tau 蛋白组成的神经原纤维病理学与阿尔茨海默病和非阿尔茨海默病 tau 病患者的认知障碍严重程度和表型密切相关。通过免疫疗法靶向病理性 tau 蛋白是一种有希望的疾病修饰治疗阿尔茨海默病的策略。此前，我们报告了一项针对病理性 tau 蛋白的主动疫苗 AADvac1 的 24 周 1 期临床试验；在此，我们介绍了对这些患者进一步随访 72 周的结果。
我们进行了一项为期 72 周、开放标签的 1 期 AADvac1 研究，纳入了先前完成了 1 期研究的轻度至中度阿尔茨海默病患者。先前接受过六剂 AADvac1 每月间隔治疗的患者接受了两次 24 周间隔的加强针。先前仅接受过三剂治疗的患者接受了另外三剂，随后每 4 周接受两次加强针。主要目标是评估 AADvac1 治疗的长期安全性。次要目标包括评估抗体滴度、抗体同种型谱、抗体结合 AD tau 和 AADvac1 的能力、随时间推移 AADvac1 诱导的抗体滴度的发展，以及加强针的效果；通过 11 项阿尔茨海默病评估量表认知评估（ADAS-Cog）、类别流畅性测试和受控口头联想测试进行认知评估；通过磁共振成像（MRI）容积测量评估脑萎缩；通过流式细胞术评估淋巴细胞群。
该研究于 2014 年 3 月 18 日至 2016 年 8 月 10 日进行。26 名完成前一项研究的患者入组。5 名患者因不良事件退出。1 名患者因不遵守规定而退出。最常见的不良事件是注射部位反应（26 名接种疫苗患者中的 13 名[50%]报告）。未观察到脑膜炎或血管源性水肿病例。仅在一名 ApoE4 纯合子中观察到新的微出血。所有应答者在 6 个月内无需给药即可保留针对 AADvac1 tau 肽成分的免疫球蛋白 G（IgG）抗体反应，其滴度回归至最初接受六剂疫苗接种方案后获得的滴度的 15.8%。加强针恢复了先前的 IgG 水平。高 IgG 水平的患者海马萎缩率较低；在认知评估中也观察到类似的关系。
AADvac1 表现出良性的安全性特征。在无疫苗接种期间 IgG 滴度的演变需要更频繁的加强针方案。在 MRI 评估中，高滴度患者的萎缩趋势较慢，认知评估中下降幅度较小，这令人鼓舞。需要进一步的试验来扩大安全性数据库，并证实 AADvac1 的临床疗效。
这些研究在欧盟临床试验注册处和 ClinicalTrials.gov 注册：先前的首次人体研究根据 EudraCT 2012-003916-29 和 NCT01850238（于 2013 年 5 月 9 日注册）进行，随访研究根据 EudraCT 2013-004499-36 和 NCT02031198（于 2014 年 1 月 9 日注册）进行。
