Karolinska Institutet Alzheimer Disease Research Centre and Clinical Trial Unit, Geriatric Clinic, Karolinska University Hospital, Huddinge, Sweden.
Lancet Neurol. 2012 Jul;11(7):597-604. doi: 10.1016/S1474-4422(12)70140-0. Epub 2012 Jun 6.
Immunotherapy targeting the amyloid β (Aβ) peptide is a potential strategy to slow the progression of Alzheimer's disease. We aimed to assess the safety and tolerability of CAD106, a novel active Aβ immunotherapy for patients with Alzheimer's disease, designed to induce N-terminal Aβ-specific antibodies without an Aβ-specific T-cell response.
We did a phase 1, double-blind, placebo-controlled, 52-week study in two centres in Sweden. Participants, aged 50-80 years, with mild-to-moderate Alzheimer's disease were entered into one of two cohorts according to time of study entry and then randomly allocated (by use of a computer-generated randomisation sequence) to receive either CAD106 or placebo (4:1; cohort one received CAD106 50 μg or placebo, cohort two received CAD106 150 μg or placebo). Each patient received three subcutaneous injections. All patients, caregivers, and investigators were masked to treatment allocation throughout the study. Primary objectives were to assess the safety and tolerability of CAD106 and to identify the Aβ-specific antibody response. Safety assessment was done by recording of all adverse events, assessment of MRI scans, physical and neurological examinations, vital signs, electrocardiography, electroencephalography, and laboratory analysis of blood and CSF. Patients with Aβ-IgG serum titres higher than 16 units at least once during the study were classified as responders. This study is registered with ClinicalTrials.gov, number NCT00411580.
Between August, 2005, and March, 2007, we randomly allocated 31 patients into cohort one (24 patients to CAD106 treatment and seven to placebo) and 27 patients into cohort two (22 patients to CAD106 treatment and five to placebo). 56 of 58 patients reported adverse events. In cohort one, nasopharyngitis was the most commonly reported adverse event (10 of 24 CAD106-treated patients). In cohort two, injection site erythema was the most commonly reported adverse event (14 of 22 CAD106-treated patients). Overall, nine patients reported serious adverse events--none was thought to be related to the study drug. We recorded no clinical or subclinical cases of meningoencephalitis. 16 of 24 (67%) CAD106-treated patients in cohort one and 18 of 22 (82%) in cohort two developed Aβ antibody response meeting pre-specified responder threshold. One of 12 placebo-treated patients (8%) had Aβ-IgG concentrations that qualified them as a responder.
Our findings suggest that CAD106 has a favourable safety profile and acceptable antibody response in patients with Alzheimer's disease. Larger trials with additional dose investigations are needed to confirm the safety and establish the efficacy of CAD106.
Novartis Pharma AG.
针对淀粉样蛋白β（Aβ）肽的免疫疗法是减缓阿尔茨海默病进展的一种潜在策略。我们旨在评估 CAD106 的安全性和耐受性，CAD106 是一种新型的针对阿尔茨海默病的活性 Aβ免疫疗法，旨在诱导 N 端 Aβ特异性抗体而不产生 Aβ特异性 T 细胞反应。
我们在瑞典的两个中心进行了一项为期 52 周的、双盲、安慰剂对照的 1 期研究。参与者年龄在 50-80 岁之间，患有轻度至中度阿尔茨海默病，根据研究入组时间进入两个队列之一，然后随机分配（使用计算机生成的随机序列）接受 CAD106 或安慰剂（4:1；队列 1 接受 CAD106 50μg 或安慰剂，队列 2 接受 CAD106 150μg 或安慰剂）。每位患者接受三次皮下注射。在整个研究过程中，所有患者、护理人员和研究人员均对治疗分配进行了盲法。主要目的是评估 CAD106 的安全性和耐受性，并确定 Aβ 特异性抗体反应。通过记录所有不良事件、评估 MRI 扫描、身体和神经系统检查、生命体征、心电图、脑电图以及血液和 CSF 的实验室分析来进行安全性评估。在研究期间至少有一次血清 Aβ-IgG 滴度高于 16 单位的患者被归类为应答者。本研究在 ClinicalTrials.gov 注册，编号为 NCT00411580。
在 2005 年 8 月至 2007 年 3 月期间，我们将 31 名患者随机分配到队列 1（24 名患者接受 CAD106 治疗，7 名患者接受安慰剂）和队列 2（22 名患者接受 CAD106 治疗，5 名患者接受安慰剂）。58 名患者中有 56 名报告了不良事件。在队列 1 中，最常见的不良事件是鼻咽炎（24 名 CAD106 治疗患者中有 10 名）。在队列 2 中，最常见的不良事件是注射部位红斑（22 名 CAD106 治疗患者中有 14 名）。总的来说，有 9 名患者报告了严重不良事件-没有一例被认为与研究药物有关。我们没有记录到任何临床或亚临床脑膜炎的病例。队列 1 中 24 名 CAD106 治疗患者中有 16 名（67%）和队列 2 中 22 名 CAD106 治疗患者中有 18 名（82%）产生了符合预先指定应答者阈值的 Aβ 抗体反应。在接受安慰剂治疗的 12 名患者中，有 1 名（8%）的 Aβ-IgG 浓度符合应答者标准。
我们的研究结果表明，CAD106 在阿尔茨海默病患者中具有良好的安全性和可接受的抗体反应。需要更大规模的试验和额外的剂量研究来确认 CAD106 的安全性并确定其疗效。
诺华制药公司。
