From Genentech, Inc., South San Francisco, CA.
Neurology. 2023 Oct 3;101(14):e1391-e1401. doi: 10.1212/WNL.0000000000207663. Epub 2023 Aug 29.
Accumulation of tau pathology in Alzheimer disease (AD) correlates with cognitive decline. Anti-tau immunotherapies were proposed as potential interventions in AD. While antibodies targeting N-terminal tau failed to demonstrate clinical efficacy in prodromal-to-mild AD, their utility at other disease stages was not evaluated in prior studies. Lauriet is a phase 2 study of an anti-tau monoclonal antibody, semorinemab, in patients with mild-to-moderate AD.
The phase 2 Lauriet study included a randomized, placebo-controlled, double-blind period, during which participants with mild-to-moderate AD received 4,500 mg of IV semorinemab or placebo every 4 weeks for 48 or 60 weeks. Participants who chose to continue in the subsequent optional open-label extension received 4,500 mg of semorinemab every 4 weeks for up to 96 weeks. Coprimary efficacy endpoints were change from baseline to week 49 or 61 on the 11-item version of the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog11) and the Alzheimer's Disease Cooperative Study-Activities of Daily Living (ADCS-ADL) scale. Secondary efficacy endpoints included change from baseline on the Mini-Mental State Examination (MMSE) and Clinical Dementia Rating-Sum of Boxes (CDR-SB). Safety, pharmacokinetics, and pharmacodynamic effects were also evaluated.
Between December 3, 2018, and February 27, 2020, 624 individuals were screened, 272 participants were randomized, and 238 were included in the modified intent-to-treat population (received ≥1 dose(s) of study medication and underwent baseline and ≥1 postbaseline assessment(s)). Baseline characteristics were well balanced. At week 49, the semorinemab arm demonstrated a 42.2% reduction (-2.89 points, 95% CI -4.56 to -1.21, = 0.0008) in decline on the ADAS-Cog11 (coprimary endpoint) relative to the placebo arm. However, no treatment effects were observed on the ADCS-ADL scale (coprimary endpoint; absolute difference between the 2 treatment arms in the ADCS-ADL score change from baseline of -0.83 points, 95% CI -3.39 to 1.72, = 0.52) or on the MMSE or CDR-SB (secondary endpoints). Semorinemab was safe and well tolerated.
Based on the results of the prespecified coprimary endpoints, this study was negative. While semorinemab had a significant effect on cognition measured by the ADAS-Cog11, this effect did not extend to improved functional or global outcomes. These results may warrant further exploration of semorinemab or other anti-tau therapies in mild-to-moderate AD.
This study provides Class I evidence that semorinemab does not slow functional decline in patients with mild-to-moderate AD.
The Lauriet study is registered on ClinicalTrials.gov, NCT03828747, and EudraCT 2018-003398-87.
阿尔茨海默病（AD）中tau 病理学的积累与认知能力下降相关。抗 tau 免疫疗法被认为是 AD 的潜在干预措施。虽然针对 N 端 tau 的抗体在前驱期至轻度 AD 中未能显示出临床疗效，但之前的研究并未评估其在其他疾病阶段的应用。Lauriet 是一项针对轻度至中度 AD 患者的抗 tau 单克隆抗体 semorinemab 的 2 期研究。
2 期 Lauriet 研究包括一项随机、安慰剂对照、双盲的研究期，在此期间，轻度至中度 AD 患者每 4 周接受 4500mg IV semorinemab 或安慰剂，共 48 或 60 周。选择继续进入后续可选开放标签扩展的患者每 4 周接受 4500mg semorinemab，最多 96 周。主要疗效终点是在第 11 项阿尔茨海默病评估量表认知子量表（ADAS-Cog11）和阿尔茨海默病合作研究日常生活活动量表（ADCS-ADL）基线至第 49 或 61 周的变化。次要疗效终点包括从基线开始在迷你精神状态检查（MMSE）和临床痴呆评定总和量表（CDR-SB）上的变化。还评估了安全性、药代动力学和药效学效应。
2018 年 12 月 3 日至 2020 年 2 月 27 日期间，共有 624 人接受了筛选，272 人被随机分配，238 人被纳入改良意向治疗人群（接受了至少 1 剂研究药物，并进行了基线和至少 1 次基线后评估）。基线特征平衡良好。在第 49 周，与安慰剂组相比，semorinemab 组在 ADAS-Cog11 上的下降幅度减少了 42.2%（-2.89 分，95%CI-4.56 至-1.21， = 0.0008）（主要终点）。然而，在 ADCS-ADL 量表（主要终点；2 个治疗组在 ADCS-ADL 评分从基线的变化中的绝对差异为-0.83 分，95%CI-3.39 至 1.72， = 0.52）或 MMSE 或 CDR-SB（次要终点）上未观察到治疗效果。Semorinemab 安全且耐受良好。
根据预先规定的主要终点结果，本研究为阴性。虽然 semorinemab 对 ADAS-Cog11 测量的认知有显著影响，但这种影响并未扩展到改善功能或总体结果。这些结果可能需要进一步探索 semorinemab 或其他抗 tau 疗法在轻度至中度 AD 中的应用。
这项研究提供了 I 级证据，表明 semorinemab 不能减缓轻度至中度 AD 患者的功能下降。
Lauriet 研究在 ClinicalTrials.gov 上注册，NCT03828747 和 EudraCT 2018-003398-87。
Zotero 插件
