随机、Ⅱ期研究 Semorinemab 在轻度至中度阿尔茨海默病患者中的安全性和疗效：Lauriet.

Randomized Phase II Study of the Safety and Efficacy of Semorinemab in Participants With Mild-to-Moderate Alzheimer Disease: Lauriet.

机构信息

From Genentech, Inc., South San Francisco, CA.

出版信息

Neurology. 2023 Oct 3;101(14):e1391-e1401. doi: 10.1212/WNL.0000000000207663. Epub 2023 Aug 29.

DOI:10.1212/WNL.0000000000207663

PMID:37643887

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10573141/

Abstract

BACKGROUND AND OBJECTIVES

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.

METHODS

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.

RESULTS

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.

DISCUSSION

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.

CLASSIFICATION OF EVIDENCE

This study provides Class I evidence that semorinemab does not slow functional decline in patients with mild-to-moderate AD.

TRIAL REGISTRATION INFORMATION

The Lauriet study is registered on ClinicalTrials.gov, NCT03828747, and EudraCT 2018-003398-87.

摘要

背景与目的

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。

方法

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。

结果

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。