背景:批准的用于早期阿尔茨海默病(AD)的淀粉样蛋白抗体带有关于淀粉样蛋白相关成像异常(ARIA)的风险的黑框警告,该异常在载脂蛋白E(APOE)ε4/ε4纯合子中最高。ALZ-801/瓦利曲米,正在对患有早期AD的APOEε4/ε4纯合子中的口服脑渗透淀粉样β寡聚体抑制剂进行评估。
方法:这是第三阶段随机,双盲,安慰剂对照,ALZ-801的78周研究,每天两次服用265毫克片剂,纳入50至80岁的纯合子,其简易精神状态检查(MMSE)≥22,临床痴呆评分-整体评分0.5或1.0。该研究有能力在150名受试者/臂的阿尔茨海默病评估量表13项认知亚量表主要结果上检测2.0至2.5的药物-安慰剂差异。关键的次要结果是临床痴呆评级-盒子和日常生活的仪器活动的总和;体积磁共振成像和流体生物标志物是额外的结果。
结果:APOLLOE43期试验招募了325名受试者,平均年龄69岁,51%女性,MMSE25.6,和65%轻度认知障碍。顶线结果预计在2024年。
结论:APOLLOE4是第一个针对APOEε4/ε4纯合子的疾病修饰AD试验。口服ALZ-801有可能成为高危APOEε4/ε4人群的第一个有效和安全的抗淀粉样蛋白治疗方法。
■APOLLOE4阶段3,安慰剂对照,为期78周的研究旨在评估ALZ-801265mg每天两次在具有载脂蛋白E(APOE)ε4/ε4基因型的早期阿尔茨海默病(AD)受试者中的疗效和安全性。登记的早期AD人群(N=325)有51%的女性,平均年龄=69岁,平均迷你精神状态检查=25.6,大多数是轻度认知障碍受试者,与lecanemab3期AD试验(ClarityAD)相似的疾病阶段。主要结果是认知阿尔茨海默病评估量表13项认知子量表,以两种功能测量为关键次要结果(临床痴呆评级-方框和,阿姆斯特丹-日常生活的器乐活动),海马体积和液体生物标志物作为额外的结果。该研究的独特之处在于,在基线磁共振成像时允许大量微出血或铁质沉着,表明伴随脑淀粉样血管病(CAA)的病变。在基线,32%的登记人群至少有1次微出血,24%的患者有1至4,8%的患者有>4的微出血;10%的患者有至少1个铁质沉着病变;男性多于女性的微出血(63%vs.37%)和铁质沉着症(68%vs.32%)。研究结果将于2024年下半年公布,如果是积极的,ALZ-801可能成为在APOEε4/ε4AD受试者中表现出有利益处/风险特征的第一种口服药物。
BACKGROUND: The approved amyloid antibodies for early Alzheimer\'s disease (AD) carry a boxed warning about the risk of amyloid-related imaging abnormalities (ARIAs) that are highest in apolipoprotein E (APOE) ε4/ε4 homozygotes. ALZ-801/valiltramiprosate, an oral brain-penetrant amyloid beta oligomer inhibitor is being evaluated in APOE ε4/ε4 homozygotes with early AD.
METHODS: This Phase 3 randomized, double-blind, placebo-controlled, 78-week study of ALZ-801 administered as 265 mg twice per day tablets, enrolled 50- to 80-year-old homozygotes with Mini-Mental State Examination (MMSE) ≥ 22 and Clinical Dementia Rating-Global Score 0.5 or 1.0. The study is powered to detect a 2.0 to 2.5 drug-placebo difference on the Alzheimer\'s Disease Assessment Scale 13-item Cognitive subscale primary outcome with 150 subjects/arm. The key secondary outcomes are Clinical Dementia Rating-Sum of Boxes and Instrumental Activities of Daily Living; volumetric magnetic resonance imaging and fluid biomarkers are additional outcomes.
RESULTS: The APOLLOE4 Phase 3 trial enrolled 325 subjects with a mean age of 69 years, 51% female, MMSE 25.6, and 65% mild cognitive impairment. Topline results are expected in 2024.
CONCLUSIONS: APOLLOE4 is the first disease-modification AD trial focused on APOE ε4/ε4 homozygotes. Oral ALZ-801 has the potential to be the first effective and safe anti-amyloid treatment for the high-risk APOE ε4/ε4 population.
UNASSIGNED: The APOLLOE4 Phase 3, placebo-controlled, 78-week study is designed to evaluate the efficacy and safety of ALZ-801 265 mg twice per day in early Alzheimer\'s disease (AD) subjects with the apolipoprotein E (APOE) ε4/ε4 genotype.The enrolled early AD population (N = 325) has 51% females, a mean age = 69 years, and a mean Mini-Mental State Examination = 25.6, with the majority being mild cognitive impairment subjects, a similar disease stage to the lecanemab Phase 3 AD trial (Clarity AD).The primary outcome is the cognitive Alzheimer\'s Disease Assessment Scale 13-item Cognitive subscale, with two functional measures as key secondary outcomes (Clinical Dementia Rating-Sum of Boxes, Amsterdam-Instrumental Activities of Daily Living), and with hippocampal volume and fluid biomarkers as additional outcomes.The study is unique in allowing a large number of microhemorrhages or siderosis at baseline magnetic resonance imaging, lesions that indicate concomitant cerebral amyloid angiopathy (CAA).At baseline, 32% of the enrolled population had at least 1 microhemorrhage, 24% had 1 to 4, and 8% had > 4 microhemorrhages; 10% had at least 1 siderosis lesion; with more males than females having microhemorrhages (63% vs. 37%) and siderosis (68% vs. 32%).Study results will become available in the second half of 2024 and, if positive, ALZ-801 may become the first oral drug to demonstrate a favorable benefit/risk profile in APOE ε4/ε4 AD subjects.