Alzheimer's Therapeutic Research Institute, Keck School of Medicine, University of Southern California, San Diego, San Diego.
AC Immune SA, Lausanne, Switzerland.
JAMA Neurol. 2022 Jun 1;79(6):565-574. doi: 10.1001/jamaneurol.2022.0983.
Individuals with Down syndrome (DS) are at high risk of developing Alzheimer disease due to an increased dose of the amyloid precursor protein gene, APP, which leads to increased levels of full-length APP and its products, including amyloid-β (Aβ). The liposome-based antiamyloid ACI-24 vaccine is intended to treat neurological disorders caused by misfolded Aβ pathological protein. However, the safety, tolerability, and immunogenicity of the ACI-24 vaccine among adults with DS have not been fully examined.
To assess the safety and tolerability of the ACI-24 vaccine among adults with DS as well as its ability to induce immunogenicity measured by anti-Aβ immunoglobulin G titers.
DESIGN, SETTING, AND PARTICIPANTS: This multicenter double-blind placebo-controlled dose-escalation phase 1b randomized clinical trial was conducted at 3 US academic medical centers with affiliated Down syndrome clinics between March 30, 2016, and June 29, 2020. A total of 20 adults with DS were screened; of those, 16 adults were eligible to participate. Eligibility criteria included men or women aged 25 to 45 years with cytogenetic diagnosis of either trisomy 21 or complete unbalanced translocation of chromosome 21. Between April 27, 2016, and July 2, 2018, participants were randomized 3:1 into 2 dose-level cohorts (8 participants per cohort, with 6 participants receiving the ACI-24 vaccine and 2 receiving placebo) in a 96-week study. Participants received 48 weeks of treatment followed by an additional 48 weeks of safety follow-up.
Participants were randomized to receive 7 subcutaneous injections of ACI-24, 300 μg or 1000 μg, or placebo.
Primary outcomes were measures of safety and tolerability as well as antibody titers.
Among 16 enrolled participants, the mean (SD) age was 32.6 (4.4) years; 9 participants were women, and 7 were men. All participants were White, and 1 participant had Hispanic or Latino ethnicity. Treatment adherence was 100%. There were no cases of meningoencephalitis, death, or other serious adverse events (AEs) and no withdrawals as a result of AEs. Most treatment-emergent AEs were of mild intensity (110 of 132 events [83.3%]) and unrelated or unlikely to be related to the ACI-24 vaccine (113 of 132 events [85.6%]). No amyloid-related imaging abnormalities with edema or cerebral microhemorrhage and no evidence of central nervous system inflammation were observed on magnetic resonance imaging scans. Increases in anti-Aβ immunoglobulin G titers were observed in 4 of 12 participants (33.3%) receiving ACI-24 (2 receiving 300 μg and 2 receiving 1000 μg) compared with 0 participants receiving placebo. In addition, a greater increase was observed in plasma Aβ1-40 and Aβ1-42 levels among individuals receiving ACI-24.
In this study, the ACI-24 vaccine was safe and well tolerated in adults with DS. Evidence of immunogenicity along with pharmacodynamic and target engagement were observed, and anti-Aβ antibody titers were not associated with any adverse findings. These results support progression to clinical trials using an optimized formulation of the ACI-24 vaccine among individuals with DS.
ClinicalTrials.gov Identifier: NCT02738450.
由于淀粉样前体蛋白基因（APP）的剂量增加，导致全长 APP 及其产物（包括淀粉样蛋白-β[Abeta]）的水平增加，唐氏综合征（DS）患者发生阿尔茨海默病的风险很高。载脂蛋白 ACI-24 的脂基抗淀粉样蛋白疫苗旨在治疗由错误折叠 Abeta 病理蛋白引起的神经紊乱。然而，载脂蛋白 ACI-24 疫苗在 DS 成人中的安全性、耐受性和免疫原性尚未得到充分研究。
评估载脂蛋白 ACI-24 疫苗在 DS 成人中的安全性和耐受性，以及其诱导 Abeta 免疫球蛋白 G 滴度的能力。
设计、地点和参与者：这是一项在美国 3 所学术医疗中心及其附属唐氏综合征诊所进行的多中心、双盲、安慰剂对照、剂量递增 1b 期随机临床试验，于 2016 年 3 月 30 日至 2020 年 6 月 29 日进行。共有 20 名 DS 成人接受了筛查；其中 16 名成人有资格参加。入选标准包括 25 至 45 岁的男性或女性，细胞遗传学诊断为 21 三体或 21 号染色体完全不平衡易位。2016 年 4 月 27 日至 2018 年 7 月 2 日，参与者以 3:1 的比例随机分为 2 个剂量水平队列（每组 8 名参与者，6 名接受 ACI-24 疫苗，2 名接受安慰剂），研究时间为 96 周。参与者接受 48 周的治疗，随后进行 48 周的安全性随访。
参与者随机接受 7 次皮下注射 ACI-24，剂量为 300μg 或 1000μg，或安慰剂。
主要结局是安全性和耐受性以及抗体滴度的衡量标准。
在 16 名入组的参与者中，平均（SD）年龄为 32.6（4.4）岁；9 名为女性，7 名为男性。所有参与者均为白人，1 名为西班牙裔或拉丁裔。治疗依从性为 100%。无脑膜炎、死亡或其他严重不良事件（AE），也无因 AE 而退出。大多数治疗相关的 AE 为轻度（132 项事件中的 110 项[83.3%]），且与 ACI-24 疫苗无关或不太可能相关（132 项事件中的 113 项[85.6%]）。磁共振成像扫描未观察到与淀粉样蛋白相关的水肿或脑微出血的异常影像和中枢神经系统炎症的证据。与接受安慰剂的参与者相比，接受 ACI-24 治疗的 12 名参与者中有 4 名（33.3%）的 Abeta 免疫球蛋白 G 滴度升高（2 名接受 300μg，2 名接受 1000μg）。此外，接受 ACI-24 治疗的个体的血浆 Abeta1-40 和 Abeta1-42 水平升高。
在这项研究中，ACI-24 疫苗在 DS 成人中是安全且耐受良好的。观察到了免疫原性的证据以及药效学和靶标结合，并且 Abeta 抗体滴度与任何不良发现无关。这些结果支持在 DS 患者中使用 ACI-24 疫苗的优化制剂进行临床试验。
ClinicalTrials.gov 标识符：NCT02738450。
