Susan Abushakra, MD, Alzheon, Inc., 111 Speen Street, Suite 306, Framingham, MA 01701, USA, Phone: 508.861.7709, Fax: 508.861.1500,
J Prev Alzheimers Dis. 2017;4(3):149-156. doi: 10.14283/jpad.2017.26.
Alzheimer's Disease (AD) patients homozygous for the APOE4 allele (APOE4/4) have a distinct clinical and biological phenotype with high levels of beta amyloid (Aβ) pathology and toxic Aβ oligomers. Tramiprosate, an oral agent that inhibits Aβ monomer aggregation into toxic oligomers, was evaluated in two Phase 3 Mild to Moderate AD studies which did not show efficacy in the overall population. Re-analyses of these trials showed the most consistent clinical benefits in APOE4/4 patients. We analyzed efficacy in the APOE4/4 patients with Mild disease.
To determine the optimal stage of AD for future trials in APOE4/4 homozygotes.
Two randomized, double-blind, placebo-controlled parallel-arm multi-center studies of 78-weeks duration.
Academic Alzheimer's disease centers, community-based memory clinics, and neuropsychiatric research sites.
Participants included 2,025 AD patients with MMSE 16-26. Approximately 13-15% had APOE4/4 genotype (N= 147 and 110 per study), mean age 71.1 years, 56% females. Almost all were on stable symptomatic drugs.
Randomized subjects received oral placebo, 100mg BID, or 150mg BID of tramiprosate.
Co-primary outcomes were change from baseline in the ADAS-cog11 and CDR-SB. Disability assessment for dementia (DAD) was a secondary outcome.
In APOE4/4 homozygotes receiving 150mg BID tramiprosate, efficacy in the traditional Mild AD patients (MMSE 20-26) was higher than the overall group (MMSE 16-26) and efficacy in the Mild patients (MMSE 22-26) was highest. Tramiprosate benefits compared to placebo on ADAS-cog, CDR-SB, and DAD were 125%, 81% and 71%, respectively (p<0.02). The Mild subgroup (MMSE 22-26) showed cognitive stabilization with no decline over 78 weeks, both ADAS-cog and DAD effects increased over time. Tramiprosate safety in APOE4/4 patients was favorable. Most common adverse events were nausea, vomiting, depression and decreased weight.
The Mild subgroup of APOE4/4 AD patients (MMSE 22-26) showed larger benefits on the high dose of tramiprosate than the overall Mild and Moderate group. Consistent with its preclinical effects on Aβ oligomers, tramiprosate seemed to stabilize cognitive performance, supporting its disease modification potential. Confirmatory studies using ALZ-801, an improved pro-drug formulation of tramiprosate, will target APOE4/4 patients with Mild AD.
载脂蛋白 E4 纯合子（APOE4/4）的阿尔茨海默病（AD）患者具有独特的临床和生物学表型，β淀粉样蛋白（Aβ）病理学和毒性 Aβ 寡聚体水平较高。曲美普罗斯是一种口服药物，可抑制 Aβ单体聚集成毒性寡聚体，在两项轻度至中度 AD 的 3 期研究中进行了评估，但在总体人群中没有显示出疗效。对这些试验的重新分析显示，APOE4/4 患者最一致的临床获益。我们分析了轻度疾病的 APOE4/4 患者的疗效。
确定未来 APOE4/4 纯合子试验的最佳 AD 阶段。
两项为期 78 周的随机、双盲、安慰剂对照平行臂多中心研究。
学术 AD 中心、社区记忆诊所和神经精神病学研究场所。
包括 2025 名 MMSE 为 16-26 的 AD 患者。大约 13-15%的患者具有 APOE4/4 基因型（每个研究 147 和 110 名，N=147 和 110），平均年龄为 71.1 岁，56%为女性。几乎所有人都在服用稳定的对症药物。
随机受试者接受口服安慰剂、100mg 每日两次或 150mg 每日两次的曲美普罗斯治疗。
主要终点是 ADAS-cog11 和 CDR-SB 从基线的变化。痴呆残疾评估（DAD）是次要终点。
在接受 150mg 每日两次曲美普罗斯的 APOE4/4 纯合子中，传统轻度 AD 患者（MMSE 20-26）的疗效高于总体组（MMSE 16-26），而轻度患者（MMSE 22-26）的疗效最高。与安慰剂相比，曲美普罗斯在 ADAS-cog、CDR-SB 和 DAD 上的获益分别为 125%、81%和 71%（p<0.02）。轻度亚组（MMSE 22-26）在 78 周内没有认知能力下降，表现出认知稳定，ADAS-cog 和 DAD 的效果随着时间的推移而增加。曲美普罗斯在 APOE4/4 患者中的安全性良好。最常见的不良事件是恶心、呕吐、抑郁和体重减轻。
APOE4/4 AD 患者的轻度亚组（MMSE 22-26）在高剂量曲美普罗斯治疗下的获益大于总体轻度和中度组。与它在 Aβ 寡聚体上的临床前作用一致，曲美普罗斯似乎稳定了认知表现，支持其疾病修饰潜力。使用 tramiprosate 的改良前药制剂 ALZ-801 的验证性研究将针对轻度 AD 的 APOE4/4 患者。
