甘特纳珠单抗可减少前驱期至中度阿尔茨海默病患者的淀粉样蛋白-β斑块：一项 PET 亚研究中期分析。
Gantenerumab reduces amyloid-β plaques in patients with prodromal to moderate Alzheimer's disease: a PET substudy interim analysis.
机构信息
Roche Pharma Research and Early Development, Basel, Switzerland.
Roche/Genentech Product Development, Neuroscience, Basel, Switzerland.
出版信息
Alzheimers Res Ther. 2019 Dec 12;11(1):101. doi: 10.1186/s13195-019-0559-z.
BACKGROUND
We previously investigated low doses (105 or 225 mg) of gantenerumab, a fully human monoclonal antibody that binds and removes aggregated amyloid-β 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-β 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-β 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-β plaque levels below the amyloid-β 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-β plaque removal at 2 years. PET amyloid levels were consistent with sparse-to-no neuritic amyloid-β 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.
TRIAL REGISTRATION
ClinicalTrials.gov, NCT01224106 (SCarlet RoAD) and NCT02051608 (Marguerite RoAD).
背景
我们之前研究了低剂量（105 或 225mg）的甘露特纳单抗，这是一种完全人源的单克隆抗体，通过 Fc 受体介导的吞噬作用结合并清除聚集的淀粉样-β。在 SCarlet RoAD（SR）和 Marguerite RoAD（MR）的 3 期试验中。有几条证据表明，可能需要更高的剂量才能达到临床疗效。因此，我们设计了一项正电子发射断层扫描（PET）子研究，以评估甘露特纳单抗在剂量增加至 1200mg 每 4 周时对淀粉样-β斑块的影响，该研究使用氟比他滨 PET 评估了有前驱至中度阿尔茨海默病（AD）的患者。
方法
该子研究纳入了 SR 和 MR 研究中随后进入开放标签扩展（OLE）的部分患者。患者年龄在 50 至 90 岁之间，临床诊断为前驱至中度 AD，且根据双盲期的原始筛查扫描的视觉阅读结果纳入。患者被分配到 5 个滴定方案中的 1 个（持续 2 至 10 个月），目标甘露特纳单抗剂量为每 4 周 1200mg。该子研究的主要终点是从 OLE 基线到第 52 周和第 104 周，使用氟比他滨 PET 评估淀粉样-β斑块负担的变化。氟比他滨的全球皮质信号使用预先指定的标准摄取值比值法计算，并转换为 Centiloid 标度。
结果
截至 2018 年 8 月 15 日，最初纳入的 89 名患者中有 67 名至少有 1 次随访扫描。第一年平均淀粉样水平降低了 39 个 Centiloids，第二年降低了 59 个 Centiloids，这是 SR 中 225mg 治疗 2 年后的 3.5 倍。在第 1 年和第 2 年，分别有 37%和 51%的患者淀粉样-β斑块水平低于淀粉样-β阳性阈值。
结论
这项 PET 子研究的探索性中期分析结果表明，高达 1200mg 的甘露特纳单抗剂量在 2 年内可有效清除淀粉样-β斑块。在 2 年的治疗后，51%的患者的 PET 淀粉样蛋白水平与稀疏至无神经原纤维淀粉样蛋白斑块一致。淀粉样蛋白的减少与其他安慰剂对照研究一致，这些研究表明可能具有临床益处。
试验注册
ClinicalTrials.gov，NCT01224106（SCarlet RoAD）和 NCT02051608（Marguerite RoAD）。
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