一项评估靶向 PCSK9 的免疫治疗药物的安全性、耐受性、免疫原性和降低低密度脂蛋白胆固醇活性的 I 期研究。
A phase I study assessing the safety, tolerability, immunogenicity, and low-density lipoprotein cholesterol-lowering activity of immunotherapeutics targeting PCSK9.
机构信息
Department of Clinical Pharmacology, Medical University of Vienna, Währinger Gürtel 18-20, 1090, Vienna, Austria.
Department of Vascular Surgery, Academic Medical Center, University of Amsterdam, P.O. Box 22660, 1100 DD, Amsterdam, Netherlands.
出版信息
Eur J Clin Pharmacol. 2021 Oct;77(10):1473-1484. doi: 10.1007/s00228-021-03149-2. Epub 2021 May 10.
PURPOSE
AT04A and AT06A are two AFFITOPE® peptide vaccine candidates being developed for the treatment of hypercholesterolemia by inducing proprotein convertase subtilisin/kexin type 9 (PCSK9)-specific antibodies. This study aimed to investigate safety, tolerability, antibody development, and reduction of low-density lipoprotein cholesterol (LDLc) following four subcutaneous immunizations.
METHODS
This phase I, single-blind, randomized, placebo-controlled study was conducted in a total of 72 healthy subjects with a mean fasting LDLc level at baseline of 117.1 mg/dL (range 77-196 mg/dL). Each cohort enrolled 24 subjects to receive three priming immunizations at weeks 0, 4, and 8 and to receive a single booster immunization at week 60 of either AT04A, AT06A, or placebo. In addition to safety (primary objective), the antigenic peptide- and PCSK9-specific antibody response and the impact on LDLc were evaluated over a period of 90 weeks.
RESULTS
The most common systemic treatment-related adverse events (AEs) reported were fatigue, headache, and myalgia in 75% of subjects in the AT06A group and 58% and 46% of subjects in the placebo and AT04A groups, respectively. Injection site reactions (ISR) representing 63% of all treatment-emergent adverse events (TEAEs), were transient and mostly of mild or moderate intensity and rarely severe (3%). Both active treatments triggered a robust, long-lasting antibody response towards the antigenic peptides used for immunization that optimally cross-reacted with the target epitope on PCSK9. In the AT04A group, a reduction in serum LDLc was observed with a mean peak reduction of 11.2% and 13.3% from baseline compared to placebo at week 20 and 70 respectively, and over the whole study period, the mean LDLc reduction for the AT04A group vs. placebo was -7.2% (95% CI [-10.4 to -3.9], P < 0.0001). In this group, PCSK9 target epitope titers above 50 were associated with clinically relevant LDLc reductions with an individual maximal decrease of 39%.
CONCLUSIONS
Although both AT04A and AT06 were safe and immunogenic, only AT04A demonstrated significant LDLc-lowering activity, justifying further development.
TRIAL REGISTRATION
EudraCT: 2015-001719-11. ClinicalTrials.gov Identifier: NCT02508896.
目的
AT04A 和 AT06A 是两种 AFFITOPE® 肽疫苗候选物，通过诱导前蛋白转化酶枯草溶菌素/柯萨奇蛋白酶 9（PCSK9）特异性抗体，用于治疗高胆固醇血症。本研究旨在评估四种皮下免疫接种后的安全性、耐受性、抗体产生情况以及降低低密度脂蛋白胆固醇（LDLc）的效果。
方法
这是一项 I 期、单盲、随机、安慰剂对照研究，共纳入 72 名健康受试者，平均基线空腹 LDLc 水平为 117.1mg/dL（范围为 77-196mg/dL）。每个队列招募 24 名受试者，分别在第 0、4 和 8 周接受三次基础免疫接种，并在第 60 周接受 AT04A、AT06A 或安慰剂的单次加强免疫接种。除安全性（主要目标）外，还评估了抗原肽和 PCSK9 特异性抗体反应以及对 LDLc 的影响，研究持续 90 周。
结果
AT06A 组 75%的受试者报告的最常见全身性治疗相关不良事件（AE）为疲劳、头痛和肌痛，安慰剂和 AT04A 组分别为 58%和 46%。75%的受试者报告的注射部位反应（ISR）占所有治疗后出现的不良事件（TEAE）的 63%，为一过性，且多为轻度或中度，很少为重度（3%）。两种活性治疗均引发了针对免疫用抗原肽的强大、持久的抗体反应，且最佳地与 PCSK9 的靶表位发生交叉反应。在 AT04A 组中，与安慰剂相比，血清 LDLc 在第 20 周和第 70 周分别观察到 11.2%和 13.3%的平均峰值降低，整个研究期间，AT04A 组与安慰剂相比，平均 LDLc 降低 -7.2%（95%CI[-10.4 至-3.9]，P<0.0001）。在该组中，PCSK9 靶表位滴度高于 50 与临床相关的 LDLc 降低相关，个体最大降低 39%。
结论
尽管 AT04A 和 AT06A 均安全且具有免疫原性，但只有 AT04A 显示出显著的 LDLc 降低活性，因此值得进一步开发。
试验注册
EudraCT：2015-001719-11。ClinicalTrials.gov 标识符：NCT02508896。
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