Abushakra Susan, Porsteinsson Anton P, Sabbagh Marwan, Watson David, Power Aidan, Liang Earvin, MacSweeney Emer, Boada Merce, Flint Susan, McLaine Rosalind, Kesslak J Patrick, Hey John A, Tolar Martin
Alzheon, Inc. Framingham Massachusetts USA.
Alzheimer's Disease Care, Research & Education Program, Department of Psychiatry University of Rochester Rochester New York USA.
Alzheimers Dement (N Y). 2024 Aug 13;10(3):e12498. doi: 10.1002/trc2.12498. eCollection 2024 Jul-Sep.
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 () ε4/ε4 homozygotes. ALZ-801/valiltramiprosate, an oral brain-penetrant amyloid beta oligomer inhibitor is being evaluated in ε4/ε4 homozygotes with early AD.
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.
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.
APOLLOE4 is the first disease-modification AD trial focused on ε4/ε4 homozygotes. Oral ALZ-801 has the potential to be the first effective and safe anti-amyloid treatment for the high-risk ε4/ε4 population.
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 () ε4/ε4 genotype.The enrolled early AD population ( = 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 ε4/ε4 AD subjects.
用于早期阿尔茨海默病（AD）的已获批淀粉样蛋白抗体带有黑框警告，提示存在淀粉样蛋白相关成像异常（ARIAs）的风险，在载脂蛋白E（APOE）ε4/ε4纯合子中这种风险最高。ALZ-801/瓦立拉米普罗斯特是一种口服可穿透血脑屏障的淀粉样β寡聚体抑制剂，正在对携带APOEε4/ε4的早期AD纯合子进行评估。
这项3期随机、双盲、安慰剂对照、为期78周的研究，将ALZ-801制成每日2次、每次265mg的片剂，纳入年龄在50至80岁、简易精神状态检查表（MMSE）≥22且临床痴呆评定量表总体评分为0.5或1.0的纯合子。该研究旨在检测在阿尔茨海默病评估量表13项认知子量表这一主要结局上药物与安慰剂之间2.0至2.5的差异，每组纳入150名受试者。关键次要结局为临床痴呆评定量表-总积分盒以及日常生活工具性活动；容积磁共振成像和血液生物标志物为其他结局。
APOLLOE4 3期试验纳入了325名受试者，平均年龄69岁，女性占51%，MMSE为25.6，65%为轻度认知障碍。预计2024年公布初步结果。
APOLLOE4是首个针对APOEε4/ε4纯合子的疾病修饰性AD试验。口服ALZ-801有可能成为首个针对高风险APOEε4/ε4人群的有效且安全的抗淀粉样蛋白治疗药物。
APOLLOE4 3期、安慰剂对照、为期78周的研究旨在评估每日2次、每次265mg的ALZ-801在携带载脂蛋白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。纳入的早期AD人群（n = 325）中女性占51%，平均年龄 = 69岁，平均简易精神状态检查表评分为25.6，大多数为轻度认知障碍受试者，疾病阶段与lecanemab 3期AD试验（Clarity AD）相似。主要结局为阿尔茨海默病认知评估量表13项认知子量表，两项功能指标作为关键次要结局（临床痴呆评定量表-总积分盒、阿姆斯特丹日常生活工具性活动），海马体积和血液生物标志物为其他结局。该研究的独特之处在于允许在基线磁共振成像时存在大量微出血或铁血黄素沉着，这些病变提示合并脑淀粉样血管病（CAA）。基线时，32%的纳入人群至少有1处微出血，24%有1至4处，8%有超过4处微出血；10%至少有1处铁血黄素沉着病变；微出血男性多于女性（63%对37%），铁血黄素沉着也是男性多于女性（68%对32%）。研究结果将于2024年下半年公布，如果结果呈阳性，ALZ-801可能成为首个在APOEε4/ε4 AD受试者中显示出良好获益/风险比的口服药物。
