Gantenerumab reduces amyloid-β plaques in patients with prodromal to moderate Alzheimer's disease: a PET substudy interim analysis
Gantenerumab reduces amyloid-β plaques in patients with prodromal to moderate Alzheimer's disease: a PET substudy interim analysis
复制标题
DOI：
10.1186/s13195-019-0559-z
复制
发表时间：
2019-12-12
影响因子：
9
通讯作者：
Doody, Rachelle
中科院分区：
文献类型：
--
作者：
Klein, Gregory;Delmar, Paul;Doody, Rachelle
背景我们先前在猩红路(SR)和玛格丽特路(MR)3期试验中研究了低剂量(105或225 mg)的Gantenerumab，这是一种完全的人类单抗，通过Fc受体介导的吞噬作用结合和去除聚集的淀粉样β蛋白。一些证据表明，为了达到临床疗效，可能需要更高的剂量。因此，我们设计了一项正电子发射断层扫描(PET)子研究，以评估每4周升至1200 mg的Gantenerumab对先兆至中度阿尔茨海默病(AD)患者的Florbetapir PET测量的淀粉样β斑块的影响。方法在SR和MR研究中登记的患者的子集随后进入开放标签扩展(OLE)。这些患者年龄在50岁到90岁之间，临床诊断为可能的前驱症状到中度AD，并根据双盲阶段的原始筛查扫描的视觉读数纳入其中。患者被分配到5个滴定方案中的1个(从2到10个月不等)，目标加替纳单抗剂量为每4周1200毫克。这项子研究的主要终点是由OLE基线到52周和104周的淀粉样β斑块负荷的变化，使用FLOBETAPIR PET进行评估。用预先指定的标准摄取值比率法计算florbetapir的整体皮质信号，该方法转换为Centiloid标度。结果截至2018年8月15日，在最初登记的89名患者中，有67名患者进行了1次随访扫描。平均淀粉样蛋白水平在第一年减少了39 Centiloid，到第二年减少了59 Centiloid，比两年后SR中225毫克的降低幅度要大3.5倍。在第1年和第2年，分别有37%和51%的患者的淀粉样β斑块水平低于淀粉样β阳性阈值。结论：PET亚研究的这一探索性中期分析结果表明，剂量达1200 mg的Gantenerumab在2年内可有效清除淀粉样β蛋白斑块。在治疗2年后，51%的患者的PET淀粉样蛋白水平与稀疏到无神经性淀粉样β蛋白斑块是一致的。淀粉样蛋白的减少与其他安慰剂对照研究中观察到的相似，这些研究表明了潜在的临床益处。
Background We previously investigated low doses (105 or 225 mg) of gantenerumab, a fully human monoclonal antibody that binds and removes aggregated amyloid-beta by Fc receptor-mediated phagocytosis, in the SCarlet RoAD (SR) and Marguerite RoAD (MR) phase 3 trials. Several lines of evidence suggested that higher doses may be necessary to achieve clinical efficacy. We therefore designed a positron emission tomography (PET) substudy to evaluate the effect of gantenerumab uptitrated to 1200 mg every 4 weeks on amyloid-beta plaques as measured using florbetapir PET in patients with prodromal to moderate Alzheimer's disease (AD). Methods A subset of patients enrolled in the SR and MR studies who subsequently entered the open-label extensions (OLEs) were included in this substudy. Patients were aged 50 to 90 years with a clinical diagnosis of probable prodromal to moderate AD and were included based on a visual read of the original screening scan in the double-blind phase. Patients were assigned to 1 of 5 titration schedules (ranging from 2 to 10 months) with a target gantenerumab dose of 1200 mg every 4 weeks. The main endpoint of this substudy was change in amyloid-beta plaque burden from OLE baseline to week 52 and week 104, assessed using florbetapir PET. Florbetapir global cortical signal was calculated using a prespecified standard uptake value ratio method converted to the Centiloid scale. Results Sixty-seven of the 89 patients initially enrolled had >= 1 follow-up scan by August 15, 2018. Mean amyloid levels were reduced by 39 Centiloids by the first year and 59 Centiloids by year 2, a 3.5-times greater reduction than was seen after 2 years at 225 mg in SR. At years 1 and 2, 37% and 51% of patients, respectively, had amyloid-beta plaque levels below the amyloid-beta positivity threshold. Conclusion Results from this exploratory interim analysis of the PET substudy suggest that gantenerumab doses up to 1200 mg resulted in robust amyloid-beta plaque removal at 2 years. PET amyloid levels were consistent with sparse-to-no neuritic amyloid-beta plaques in 51% of patients after 2 years of therapy. Amyloid reductions were similar to those observed in other placebo-controlled studies that have suggested potential clinical benefit.