Yanagihara Reiko
Office of New Drug II, Pharmaceuticals and Medical Devices Agency Tokyo Japan.
Alzheimers Dement (N Y). 2025 May 13;11(2):e70100. doi: 10.1002/trc2.70100. eCollection 2025 Apr-Jun.
Lecanemab and donanemab were approved in Japan in September 2023 and September 2024, respectively, for the treatment of patients with mild cognitive impairment and mild dementia due to Alzheimer's disease. Evaluating the efficacy of these drugs requires demonstrating a clinically meaningful delay in symptom progression while ensuring an acceptable safety profile. This paper describes the efficacy assessment in the Pharmaceuticals and Medical Devices Agency's (PMDA) review, focusing on clinical endpoints, biomarker evaluations, and the role of minimal clinically important difference (MCID) in benefit-risk assessment. At present, the Clinical Dementia Rating Sum of Boxes (CDR-SB), which assesses both cognitive and functional decline, is one of the most recommended primary endpoints in confirmatory trials. Time-to-progression analysis should be also conducted to support clinical significance. Biomarker evaluations, particularly amyloid beta (Aβ) reduction, should be included as secondary endpoints to confirm the mechanism of action. Though biomarker assessments showed significant Aβ reduction for both anti-amyloid therapies, no direct correlation with clinical outcomes was observed, limiting their use as surrogate endpoints. Therefore, the MCID for clinical symptom progression suppression cannot be inferred based on Aβ reduction. Safety evaluation focused on amyloid-related imaging abnormalities (ARIAs), a key risk associated with anti-Aβ antibody treatments. Under the condition in which ARIA risk is managed through magnetic resonance imaging monitoring and predefined risk mitigation measures, PMDA considers the benefit-risk balance of these anti-amyloid therapies are favorable. While regulatory approval does not require meeting predefined MCID thresholds, it is based on a comprehensive benefit-risk assessment. For regulatory approval, future drugs will be required to demonstrate a benefit-risk balance equivalent to or more favorable than that of the approved anti-Aβ antibody drugs.
Lecanemab and donanemab were approved in Japan for early Alzheimer's disease in 2023 and 2024, respectively.Drug efficacy was considered clinically meaningful after comprehensive evaluation.Biomarker evaluation, including amyloid beta (Aβ), is crucial to support the intended mechanism of action.Aβ reduction did not correlate with the suppression of clinical symptom progression in individual cases.No biomarker is validated as a surrogate, and minimal clinically important difference cannot be inferred from Aβ reduction.
lecanemab和donanemab分别于2023年9月和2024年9月在日本获批，用于治疗因阿尔茨海默病导致的轻度认知障碍和轻度痴呆患者。评估这些药物的疗效需要证明症状进展有临床意义的延迟，同时确保可接受的安全性。本文描述了药品和医疗器械管理局（PMDA）审查中的疗效评估，重点关注临床终点、生物标志物评估以及最小临床重要差异（MCID）在获益风险评估中的作用。目前，评估认知和功能下降的临床痴呆评定量表总和（CDR - SB）是确证性试验中最推荐的主要终点之一。还应进行进展时间分析以支持临床意义。生物标志物评估，特别是淀粉样β蛋白（Aβ）减少，应作为次要终点纳入以确认作用机制。尽管生物标志物评估显示两种抗淀粉样蛋白疗法均有显著的Aβ减少，但未观察到与临床结果有直接相关性，限制了它们作为替代终点的应用。因此，不能基于Aβ减少来推断临床症状进展抑制的MCID。安全性评估重点关注淀粉样蛋白相关成像异常（ARIAs），这是与抗Aβ抗体治疗相关的关键风险。在通过磁共振成像监测和预定义风险缓解措施管理ARIAs风险的情况下，PMDA认为这些抗淀粉样蛋白疗法的获益风险平衡是有利的。虽然监管批准不要求达到预定义的MCID阈值，但它基于全面的获益风险评估。对于监管批准，未来的药物将需要证明其获益风险平衡等同于或优于已获批的抗Aβ抗体药物。
lecanemab和donanemab分别于2023年和2024年在日本获批用于早期阿尔茨海默病。经过全面评估，药物疗效被认为具有临床意义。包括淀粉样β蛋白（Aβ）在内的生物标志物评估对于支持预期的作用机制至关重要。在个体病例中，Aβ减少与临床症状进展抑制无关。没有生物标志物被验证为替代指标，且不能从Aβ减少推断出最小临床重要差异。
