Randomized, Double-Blind, Placebo-Controlled, Phase 3 Study

随机、双盲、安慰剂对照、3 期研究

基本信息

批准号：
10653118
负责人：
Susan Abushakra
金额：
$ 650万
依托单位：
ALZHEON, INC.
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-08-15 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10653118
关键词：
Aducanumab Adverse event Alleles Alzheimer&apos s Disease Alzheimer&apos s disease patient Alzheimer&apos s disease risk Alzheimer’s disease biomarker Amyloid Amyloid beta-Protein Antibodies Apolipoprotein E Atrophic Automobile Driving Biological Availability Biological Markers Blood Vessels Brain Characteristics Clinical Clinical Data Clinical Investigator Clinical Research Clinical Trials Cognition Cognitive Data Data Set Delayed Memory Dementia Disease Disease Outcome Dose Double-Blind Method Drug Approval Drug Kinetics Elderly Enrollment Formulation Future Genes Genotype Goals Hippocampus Homozygote Image Impaired cognition Incidence Light Magnetic Resonance Imaging Medical Economics Memory Microglia Modification Nausea and Vomiting Nerve Degeneration Oral Outcome Pathology Patients Pharmaceutical Preparations Phase Phase III Clinical Trials Placebo Control Placebos Plasma Population Positron-Emission Tomography Prodrugs Production Property Protocols documentation Quality of life Randomized Risk Role Safety Sample Size Signal Transduction Specific qualifier value Sum Synapses Tablets Testing abeta oligomer apolipoprotein E-4 beta-site APP cleaving enzyme 1 cerebral atrophy clinical efficacy disease phenotype drug candidate drug testing efficacy evaluation efficacy outcomes experience functional outcomes gastrointestinal high risk imaging biomarker improved indexing inhibitor insight mental state monomer neurofilament neurogranin neuropsychiatric symptom participant enrollment phase 1 study phase 2 study phase 3 study phase III trial pre-clinical small molecule socioeconomics study population tau Proteins tau-1 trial design vasogenic edema β-amyloid burden

项目摘要

Project Summary There is an urgent need for agents that slow or arrest the progressive course of AD. BAN2401 and aducanumab, antibodies partially targeting soluble Aβ oligomers, have shown efficacy in late-stage clinical trials, validating amyloid targeting in AD. ALZ-801, an oral agent that selectively inhibits the formation of Aβ oligomers, is an improved prodrug formulation of tramiprosate. ALZ-801 and its active agent, tramiprosate, showed favorable preclinical and clinical safety that supports a regulatory submission. Alzheon is developing ALZ-801 as a disease-modifying treatment for AD patients who are homozygous for the ε4 allele of the apolipoprotein E gene (APOE4). Tramiprosate was evaluated in two placebo-controlled 78-week Phase 3 trials, which enrolled 2025 patients with Mild to Moderate AD (Mini-Mental State Examination, MMSE, scores of 16-26). Co-primary efficacy outcomes in both trials were: Alzheimer’s Disease Assessment Scale-Cognitive Subscale (ADAS-cog) and Clinical Dementia Rating-Sum of Boxes (CDR-SB). In the completed Phase 3 trial, efficacy outcomes did not achieve significance in the overall study population of 1052 subjects. In a protocol-specified analysis, there was clinically meaningful efficacy in APOE4 carriers (approximately 60% of all subjects). Additional analyses revealed a gene dose effect, with APOE4/4 homozygotes showing most benefit versus placebo (ADAS-cog ~3.0 points, nominal p<0.05) on top of symptomatic therapy. This benefit was greater in the Mild APOE4/4 patients (MMSE 22-26) who showed dose dependent efficacy, with the high dose group showing 5.5 points improvement on ADAS-cog, nominal p = 0.0003. The strong efficacy of tramiprosate/ALZ-801 in APOE4/4 patients can be explained by their high rate of amyloid positivity (98%) on amyloid PET imaging versus 60% in noncarriers. APOE4/4 AD patients have also been shown to have a higher burden of Aβ oligomers than noncarriers. APOE4/4 patients therefore represent an AD phenotype that is enriched with Aβ oligomers and most likely to benefit from the anti-oligomer effect of ALZ-801. Tramiprosate showed favorable long-term safety in ~1600 AD patients; the most common adverse events were mild to moderate nausea and vomiting. In healthy elderly and AD subjects, ALZ-801 showed improved gastrointestinal tolerability and improved pharmacokinetics compared to tramiprosate. We plan to conduct a Phase 3 clinical trial to evaluate the efficacy of ALZ-801 in APOE4/4 patients with Early AD (MMSE 22-30) using ADAS-cog as the primary clinical outcome. We will also evaluate the effects on an MRI imaging biomarker (hippocampal volume), on plasma and CSF biomarkers of neurodegeneration, and the correlations of biomarkers with clinical outcomes. These results can confirm the efficacy of ALZ-801 as a disease-modifying drug by stabilizing cognition, and potentially decreasing brain atrophy in this population. ALZ-801 has received FDA Fast Track status, and positive data can support submission for regulatory approval and inform future AD trial designs.

项目概要迫切需要减缓或阻止 AD 进展的药物。部分靶向可溶性 Aβ 寡聚体的抗体已在后期临床试验中显示出功效，验证了 AD 中的淀粉样蛋白靶向药物 ALZ-801 是一种选择性抑制 Aβ 寡聚体形成的口服药物。 ALZ-801 及其活性剂曲米酸的改进前药配方显示出良好的效果。 Alzheon 正在开发 ALZ-801 作为一种支持监管提交的临床前和临床安全性。针对载脂蛋白 E ε4 等位基因纯合的 AD 患者的疾病缓解治疗基因（APOE4）。两项为期 78 周的安慰剂对照 3 期试验对曲米前列腺进行了评估，该试验纳入了 2025 名患有以下疾病的患者：轻度至中度 AD（简易精神状态检查，MMSE，共同主要疗效结果为 16-26）。两项试验的内容为：阿尔茨海默病评估量表-认知子量表 (ADAS-cog) 和临床痴呆症评级总和 (CDR-SB) 在已完成的 3 期试验中，未达到疗效结果。在 1052 名受试者的总体研究人群中具有显着性。对 APOE4 携带者（约占所有受试者的 60%）具有有意义的功效其他分析揭示了一个基因。剂量效应，APOE4/4 纯合子与安慰剂相比显示出最大的益处（ADAS-cog ~3.0 分，名义值 p<0.05) 在对症治疗的基础上，这种益处在轻度 APOE4/4 患者 (MMSE 22-26) 中更大。显示出剂量依赖性功效，高剂量组在 ADAS-cog 上显示出 5.5 分的改善，名义 p = 0.0003。曲米酸/ALZ-801 对 APOE4/4 患者的强大疗效可以通过其疗效来解释。淀粉样蛋白 PET 成像的淀粉样蛋白阳性率较高 (98%)，而非 APOE4/4 AD 患者的淀粉样蛋白阳性率为 60%。因此，与非 APOE4/4 携带者相比，Aβ 寡聚体的负担也更高。代表富含 Aβ 寡聚物且最有可能受益于抗寡聚物的 AD 表型 ALZ-801 的效果。曲米前列腺素在约 1600 名 AD 患者中表现出良好的长期安全性，最常见的不良事件是 ALZ-801 在健康老年人和 AD 受试者中显示出轻度至中度恶心和呕吐的改善。与曲米酸相比，胃肠道耐受性和药代动力学有所改善，我们计划进行一项研究。评估 ALZ-801 对早期 AD (MMSE 22-30) APOE4/4 患者疗效的 3 期临床试验 ADAS-cog 作为主要临床结果，我们还将评估其对 MRI 成像生物标志物的影响。（海马体积），神经退行性变的血浆和脑脊液生物标志物，以及生物标志物的相关性这些结果可以证实 ALZ-801 作为疾病缓解药物的功效。 ALZ-801 具有稳定认知功能，并可能减少该人群的脑萎缩，已获得 FDA 快速批准。跟踪状态和积极的数据可以支持提交监管审批并为未来的 AD 试验设计提供信息。