Clinical evaluation of medicines for patients with mild cognitive impairment and mild dementia due to Alzheimer's disease in Japan

IF 4.9 Q1 CLINICAL NEUROLOGY

Alzheimer''s and Dementia: Translational Research and Clinical Interventions Pub Date : 2025-05-13 DOI:10.1002/trc2.70100

Reiko Yanagihara

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引用次数: 0

Abstract

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.

Highlights

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.

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日本阿尔茨海默病所致轻度认知障碍和轻度痴呆患者用药的临床评价

Lecanemab和donanemab分别于2023年9月和2024年9月在日本获批，用于治疗阿尔茨海默病引起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在确保可接受的安全性的同时证明有临床意义的症状进展延迟。本文介绍了美国药品和医疗器械管理局（PMDA）审查中的疗效评估，重点介绍了临床终点、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，评估认知和功能衰退的临床痴呆评分盒之和（CDR-SB）是验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β淀粉样蛋白（Aβ）还原，应该作为次要终点来确认作用机制。尽管生物标志物评估显示两种抗淀粉样蛋白疗法均显著降低了Aβ，但没有观察到与临床结果的直接相关性，限制了它们作为替代终点的使用。因此，抑制临床症状进展的MCID不能根据Aβ还原来推断。安全性评估侧重于淀粉样蛋白相关成像异常（ARIAs），这是与抗a β抗体治疗相关的关键风险。在通过磁共振成像监测和预先确定的风险缓解措施来管理ARIA风险的情况下，PMDA认为这些抗淀粉样蛋白疗法的收益-风险平衡是有利的。虽然监管部门的批准不需要满足预定义的MCID门槛，但它是基于全面的利益风险评估。为了获得监管机构的批准，未来的药物将被要求证明与已批准的抗a β抗体药物相当或更有利的利益-风险平衡。Lecanemab和donanemab分别于2023年和2024年在日本被批准用于早期阿尔茨海默病。综合评价后认为药物疗效具有临床意义。包括β淀粉样蛋白（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。在个别病例中，Aβ减少与临床症状进展的抑制无关。没有生物标志物被证实为替代品，从a β还原中不能推断出最小的临床重要差异。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Alzheimer''s and Dementia: Translational Research and Clinical Interventions Medicine-Psychiatry and Mental Health

CiteScore

10.10

自引率

2.10%

发文量

134

审稿时长

10 weeks

期刊介绍： Alzheimer''s & Dementia: Translational Research & Clinical Interventions (TRCI) is a peer-reviewed, open access,journal from the Alzheimer''s Association®. The journal seeks to bridge the full scope of explorations between basic research on drug discovery and clinical studies, validating putative therapies for aging-related chronic brain conditions that affect cognition, motor functions, and other behavioral or clinical symptoms associated with all forms dementia and Alzheimer''s disease. The journal will publish findings from diverse domains of research and disciplines to accelerate the conversion of abstract facts into practical knowledge: specifically, to translate what is learned at the bench into bedside applications. The journal seeks to publish articles that go beyond a singular emphasis on either basic drug discovery research or clinical research. Rather, an important theme of articles will be the linkages between and among the various discrete steps in the complex continuum of therapy development. For rapid communication among a multidisciplinary research audience involving the range of therapeutic interventions, TRCI will consider only original contributions that include feature length research articles, systematic reviews, meta-analyses, brief reports, narrative reviews, commentaries, letters, perspectives, and research news that would advance wide range of interventions to ameliorate symptoms or alter the progression of chronic neurocognitive disorders such as dementia and Alzheimer''s disease. The journal will publish on topics related to medicine, geriatrics, neuroscience, neurophysiology, neurology, psychiatry, clinical psychology, bioinformatics, pharmaco-genetics, regulatory issues, health economics, pharmacoeconomics, and public health policy as these apply to preclinical and clinical research on therapeutics.