Amyloid-Beta Oligomer Selective Immunotherapy for Prodromal or Mild

用于前驱或轻度的淀粉样蛋白-β寡聚物选择性免疫疗法

基本信息

批准号：
9529831
负责人：
Jeffrey L Ives
金额：
$ 9.01万
依托单位：
ACUMEN PHARMACEUTICALS, INC.
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-15 至 2021-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9529831
关键词：
Acute Adverse effects Affinity Alzheimer&apos s Disease Alzheimer&apos s disease risk Amyloid beta-Protein Animals Antibodies Behavioral Binding Binding Proteins Biochemical Biodistribution Biological Assay Biological Markers Blood - brain barrier anatomy Brain Cause of Death Cell Line Chronic Clinical Clinical Chemistry Clinical Trials Cognitive Cognitive deficits Complex Contracts Controlled Study Cyclic GMP Data Development Disease Disease Progression Dose Double-Blind Method Drug Kinetics Engineering Exhibits Formulation Functional disorder Generations Human IgG1 IgG2 Immunotherapy In Vitro Individual Intellectual Property Investigational Drugs Legal Macaca fascicularis Macaca mulatta Magnetic Resonance Imaging Manufacturer Name Measures Molecular Monoclonal Antibodies Mus Neurotoxins Patients Penetration Pharmaceutical Preparations Pharmacodynamics Pharmacologic Substance Phase Placebo Control Placebos Plasma Process Production Property Randomized Rattus Recovery Reference Standards Research Rights Risk Role Safety Testing Tg2576 Therapeutic Therapeutic antibodies Tissues Toxic effect Toxicology Transgenic Organisms United States United States Food and Drug Administration Viral abeta oligomer aged analytical method base cGMP production cell bank clinical development cross reactivity drug production human tissue in vivo man manufacturing process method development monomer mouse model phase 1 study pre-clinical preclinical study prevent programs progressive neurodegeneration research clinical testing safety study stable cell line trial comparing validation studies

项目摘要

In 2015 in the United States 5.3 million people were estimated to suffer from Alzheimer’s disease, which is also the 6th leading cause of death and lacks treatments to prevent or alter its progression. Recent advances in understanding of the underlying molecular mechanisms of the disease reinforce the role of soluble amyloid-beta (Aβ) oligomers as primary neurotoxins responsible for the acute cognitive deficits and progressive neurodegeneration of Alzheimer’s disease. However, current Aβ immunotherapies in clinical development primarily target Aβ monomers or fibrillic Aβ species; none have selectivity for soluble Aβ oligomers. Although solanezumab and aducanumab have shown some evidence of therapeutic benefit in prodromal and/or mild Alzheimer’s disease patients, therapeutic benefit remains to be confirmed, and on the whole results for Aβ immunotherapies in clinical testing have been disappointing, and indicate they target the wrong Aβ species. Moreover, all Aβ immunotherapies in an IgG1 framework that bind fibrillic Aβ have displayed ARIA-E adverse effects in clinical trials. We propose an Aβ immunotherapy targeting soluble Aβ oligomers that would be expected to display superior efficacy and better safety than Aβ immunotherapies currently in development. ACU193 is a proprietary, affinity matured, humanized, IgG2 monoclonal antibody that has high selectivity for soluble Aβ oligomers versus monomeric and fibrillic Aβ, and shows potent in vitro and in vivo efficacy. ACU193 has demonstrated in vivo biochemical and behavioral efficacy in Alzheimer’s disease mouse models, crosses the blood-brain barrier, and forms complexes with soluble Aβ oligomers in the brain. ACU193 has excellent pharmacokinetics, biodistribution and brain penetration properties in four animal species. Exploratory toxicity studies in rhesus monkeys and in vitro protein binding studies reveal an excellent safety profile for ACU193. A high producing, stable cell line is suitable for production of ACU193. ACU193 is a highly promising IND-track Aβ immunotherapy that is expected to provide acute cognitive benefits, slow disease progression, and be safe and well tolerated in Alzheimer’s disease patients. The aims of this application are to complete pre-clinical chemistry, manufacturing and control studies, toxicology and pharmacokinetic studies, submit an IND dossier to the FDA, and then conduct first in human clinical safety trials for ACU193. Human trials of ACU193 will represent the first test of the hypothesis that soluble Aβ oligomers are the primary molecular cause of Alzheimer’s disease, the results of which may dramatically expand understanding of the pathophysiology of Alzheimer’s disease. The proposed clinical testing of ACU193 consists of Phase 1a/1b and /2a studies of the safety, tolerability, pharmacokinetics, pharmacodynamics and cognitive effects of ACU193 in patients with prodromal or mild Alzheimer disease.

2015年，美国估计有530万人患有阿尔茨海默病，也是第六大死亡原因，并且缺乏预防或改变其进展的治疗方法。了解疾病的潜在分子机制加强了可溶性淀粉样蛋白-β的作用 (Aβ) 寡聚物作为主要神经毒素，导致急性认知缺陷和进行性认知缺陷然而，目前 Aβ 免疫疗法仍在临床开发中。主要针对 Aβ 单体或原纤维 Aβ 物质；没有一个对可溶性 Aβ 寡聚体具有选择性。 solanezumab 和 aducanumab 已显示出对前驱症状和/或轻度症状有治疗益处的一些证据阿尔茨海默氏病患者的治疗效果仍有待证实，Aβ的总体结果临床测试中的免疫疗法令人失望，表明它们针对的是错误的 Aβ 种类。此外，所有在 IgG1 框架中结合原纤维 Aβ 的 Aβ 免疫疗法都表现出 ARIA-E 不良反应。我们提出了一种针对可溶性 Aβ 寡聚体的 Aβ 免疫疗法。预计将比目前正在开发的 Aβ 免疫疗法表现出更优异的疗效和更好的安全性。 ACU193 是一种专有的、亲和力成熟的人源化 IgG2 单克隆抗体，对可溶性 Aβ 寡聚物与单体和原纤维 Aβ 相比，在体外和体内均表现出强大的功效。 ACU193 已在阿尔茨海默病小鼠模型中证明了体内生化和行为功效，穿过血脑屏障，并与大脑中的可溶性 Aβ 寡聚物形成复合物。在四种动物中具有优异的药代动力学、生物分布和脑渗透特性。恒河猴的探索性毒性研究和体外蛋白质结合研究表明其具有极好的安全性 ACU193 的高产、稳定细胞系适合生产 ACU193。有前景的 IND 追踪 Aβ 免疫疗法有望提供急性认知益处、减缓疾病进展，并且对阿尔茨海默病患者安全且耐受性良好。该应用程序的目的是完成临床前化学、制造和控制研究，毒理学和药代动力学研究，向 FDA 提交 IND 档案，然后首先在人体中进行 ACU193 的临床安全性试验将代表对以下假设的首次检验。可溶性 Aβ 寡聚体是阿尔茨海默病的主要分子原因，其结果可能是极大地扩展了对阿尔茨海默氏病病理生理学的理解。 ACU19 的测试包括安全性、耐受性、药代动力学、 ACU193 对前驱或轻度阿尔茨海默病患者的药效学和认知作用。