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Abstract：
BACKGROUND: Donanemab, a monoclonal antibody directed against an insoluble, modified, N-terminal truncated form of amyloid beta, demonstrated efficacy and safety in patients with early, symptomatic Alzheimer\'s disease (AD) in the phase 3 TRAILBLAZER-ALZ 2 trial. Here, we report clinical outcomes, biomarkers, and safety results for the Japanese subpopulation.
METHODS: TRAILBLAZER-ALZ 2 (N = 1736) was conducted in eight countries, including Japan (enrollment June 2020-November 2021; database lock April 2023). Participants (60-85 years) with early, symptomatic AD (mild cognitive impairment/mild dementia), Mini-Mental State Examination score 20-28, and confirmed amyloid and tau pathology were randomized 1:1 (stratified by tau status) to intravenous donanemab (700 mg for three doses, then 1400 mg/dose) or placebo every 4 weeks for 72 weeks. Primary outcome was change from baseline to week 76 in integrated Alzheimer\'s Disease Rating Scale (iADRS) score. Other outcomes included clinical measures of cognitive and functional impairment, biomarkers, and safety.
RESULTS: Of 88 Japanese participants (43 placebo, 45 donanemab), 7 in each group discontinued. Least-squares mean (LSM) change from baseline in iADRS score at week 76 was smaller with donanemab than with placebo in the combined (low-medium tau and high tau) and low-medium tau (N = 76) subpopulations (LSM change difference: 4.43 and 3.99, representing 38.8% and 40.2% slowing of disease progression, respectively). Slowing of AD progression with donanemab was also observed for other clinical outcomes. Marked decreases in amyloid plaque and plasma phosphorylated tau 217 were observed; amyloid clearance (< 24.1 Centiloids) was observed in 83.3% of the combined donanemab and 0% of the combined placebo groups. Amyloid-related imaging abnormalities of edema/effusions occurred in ten (22.2%) donanemab-treated participants (one [2.2%] symptomatic) and one (2.3%) placebo-treated participant.
CONCLUSIONS: The overall efficacy and safety of donanemab in Japanese participants were similar to the global TRAILBLAZER-ALZ 2 population.
BACKGROUND: ClinicalTrials.gov identifier: NCT04437511.
METHODS: TRAILBLAZER-ALZ 2 (N = 1736) was conducted in eight countries, including Japan (enrollment June 2020-November 2021; database lock April 2023). Participants (60-85 years) with early, symptomatic AD (mild cognitive impairment/mild dementia), Mini-Mental State Examination score 20-28, and confirmed amyloid and tau pathology were randomized 1:1 (stratified by tau status) to intravenous donanemab (700 mg for three doses, then 1400 mg/dose) or placebo every 4 weeks for 72 weeks. Primary outcome was change from baseline to week 76 in integrated Alzheimer\'s Disease Rating Scale (iADRS) score. Other outcomes included clinical measures of cognitive and functional impairment, biomarkers, and safety.
RESULTS: Of 88 Japanese participants (43 placebo, 45 donanemab), 7 in each group discontinued. Least-squares mean (LSM) change from baseline in iADRS score at week 76 was smaller with donanemab than with placebo in the combined (low-medium tau and high tau) and low-medium tau (N = 76) subpopulations (LSM change difference: 4.43 and 3.99, representing 38.8% and 40.2% slowing of disease progression, respectively). Slowing of AD progression with donanemab was also observed for other clinical outcomes. Marked decreases in amyloid plaque and plasma phosphorylated tau 217 were observed; amyloid clearance (< 24.1 Centiloids) was observed in 83.3% of the combined donanemab and 0% of the combined placebo groups. Amyloid-related imaging abnormalities of edema/effusions occurred in ten (22.2%) donanemab-treated participants (one [2.2%] symptomatic) and one (2.3%) placebo-treated participant.
CONCLUSIONS: The overall efficacy and safety of donanemab in Japanese participants were similar to the global TRAILBLAZER-ALZ 2 population.
BACKGROUND: ClinicalTrials.gov identifier: NCT04437511.
摘要：
背景：多纳尼玛，一种针对不溶性的单克隆抗体，已修改,β淀粉样蛋白的N末端截短形式，在早期患者中证明了疗效和安全性，3期TRAILBLAZER-ALZ2试验中的症状性阿尔茨海默病（AD）。这里,我们报告临床结果，生物标志物，以及日本亚群的安全性结果。
方法：TRAILBLAZER-ALZ2（N=1736）在八个国家进行，包括日本（2020年6月至2021年11月入学；2023年4月数据库锁定）。参与者（60-85岁）与早期，症状性AD（轻度认知障碍/轻度痴呆），迷你精神状态检查评分20-28，并确认淀粉样蛋白和tau病理以1：1（按tau状态分层）随机分为静脉donanemab（700mg，三个剂量，然后1400毫克/剂）或安慰剂每4周72周。主要结果是阿尔茨海默病综合评定量表（iADRS）评分从基线到第76周的变化。其他结果包括认知和功能障碍的临床测量，生物标志物，和安全。
结果：88名日本参与者（43名安慰剂，45donanemab)，每组7人停药。在联合（低-中tau和高tau）和低-中tau（N=76）亚群中，donanemab在第76周的iADRS评分从基线的最小二乘平均值（LSM）变化小于安慰剂（LSM变化差异：4.43和3.99，代表38.8%和40.2%的疾病进展减缓，分别)。对于其他临床结果，还观察到donanemab的AD进展减慢。观察到淀粉样蛋白斑块和血浆磷酸化tau217的明显减少；在83.3％的组合donanemab和0％的组合安慰剂组中观察到淀粉样蛋白清除（<24.1centeriloid）。水肿/积液的淀粉样蛋白相关成像异常发生在10名（22.2％）donanemab治疗的参与者（1名[2.2％]有症状）和1名（2.3％）安慰剂治疗的参与者中。
结论：donanemab在日本参与者中的总体疗效和安全性与全球TRAILBLAZER-ALZ2人群相似。
背景：ClinicalTrials.gov标识符：NCT04437511。
方法：TRAILBLAZER-ALZ2（N=1736）在八个国家进行，包括日本（2020年6月至2021年11月入学；2023年4月数据库锁定）。参与者（60-85岁）与早期，症状性AD（轻度认知障碍/轻度痴呆），迷你精神状态检查评分20-28，并确认淀粉样蛋白和tau病理以1：1（按tau状态分层）随机分为静脉donanemab（700mg，三个剂量，然后1400毫克/剂）或安慰剂每4周72周。主要结果是阿尔茨海默病综合评定量表（iADRS）评分从基线到第76周的变化。其他结果包括认知和功能障碍的临床测量，生物标志物，和安全。
结果：88名日本参与者（43名安慰剂，45donanemab)，每组7人停药。在联合（低-中tau和高tau）和低-中tau（N=76）亚群中，donanemab在第76周的iADRS评分从基线的最小二乘平均值（LSM）变化小于安慰剂（LSM变化差异：4.43和3.99，代表38.8%和40.2%的疾病进展减缓，分别)。对于其他临床结果，还观察到donanemab的AD进展减慢。观察到淀粉样蛋白斑块和血浆磷酸化tau217的明显减少；在83.3％的组合donanemab和0％的组合安慰剂组中观察到淀粉样蛋白清除（<24.1centeriloid）。水肿/积液的淀粉样蛋白相关成像异常发生在10名（22.2％）donanemab治疗的参与者（1名[2.2％]有症状）和1名（2.3％）安慰剂治疗的参与者中。
结论：donanemab在日本参与者中的总体疗效和安全性与全球TRAILBLAZER-ALZ2人群相似。
背景：ClinicalTrials.gov标识符：NCT04437511。
