Manufacturing of New Batch AV-1959D Drug Product and Placebo for Phase 1 Trial

为 1 期试验生产新批次 AV-1959D 药品和安慰剂

• 批准号: 10732215
• 负责人: Michael G Agadjanyan
• 金额: $ 69.9万
• 依托单位: INSTITUTE FOR MOLECULAR MEDICINE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-15 至 2027-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10732215
• 关键词: Administrative Supplement; Agreement; Alzheimer disease prevention; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease risk; Amendment; Amyloid; Amyloid beta-Protein; Applications Grants; Award; COVID-19; Client; Clinical; Clinical Trials; Critical Pathways; Cyclic GMP; DNA Vaccines; Data; Dose; Funding; Future; Goals; Grant; Human; Immunotherapy; Label; Masks; Monkeys; Monoclonal Antibodies; Onset of illness; Oryctolagus cuniculus; Pathologic; Patients; Pharmaceutical Preparations; Phase; Phase I Clinical Trials; Placebos; Populations at Risk; Preparation; Preventive treatment; Publishing; Randomized; Recommendation; Running; Safety; Shipping; System; Testing; Therapeutic; Time; Treatment Protocols; U-Series Cooperative Agreements; Vaccines; Vial device; clinical research site; cost; drug production; drug testing; first-in-human; immunogenicity; manufacture; mouse model; multidisciplinary; phase I trial; programs; stability testing; treatment strategy; vaccination strategy; vaccine delivery; vaccine development

Abstract Immunotherapy targeting pathological Aβ continues to be a promising therapeutic strategy for Alzheimer's Disease (AD) prevention. Published data suggested that inhibition of amyloid aggregation in people at risk of AD could delay AD onset. However, due to the treatment schedule and the cost of monoclonal antibodies, their passive administration may not be the best preventive treatment strategy. Therefore, we hypothesized that our universal MultiTEP-platform-based active vaccine, AV-1959D, could be an inexpensive alternative to the passive vaccination strategy. To move further with this program, our multidisciplinary team manufactured a clinical grade AV-1959D vaccine and completed comprehensive IND-enabling safety, efficacy, and immunogenicity studies in mouse models of AD, rabbits, and monkeys. As a result of these studies conducted within the scope of an NIA cooperative agreement (U01 AG048310), we generated data for the preparation of IND18953 for Phase 1 AV- 1959D clinical trials that the FDA cleared in 2020, prepared 200 mg (225 vials, 145 of which was used for release test and 3Y stability) cGMP AV-1959D for future phase 1 clinical trial and submitted the grant application for clinical trial "Determine the safety/tolerability and immunogenicity of ascending doses of AV-1959D in patients with early-stage AD" in February of 2019. We received funding from NIA only in 2022, after two years and three attempts, to begin the first human clinical trial of AV-1959D. Hence, we had to adjust our clinical program based on new information and regulatory recommendations outlined in this Administrative Supplement. More specifically, we extended the stability testing of the drug product up to five years and increased doses for the intradermal delivery of the AV-1959D vaccine based on new data obtained in COVID-19 trials with the first approved DNA vaccine delivered by Pharmajet Tropis®. These amendments required additional drug product vials for the Phase 1 trial. Accordingly, this administrative supplement program aims to justify manufacturing a new GMP batch of the AV-1959D vaccine as early as possible to initiate the Phase 1 trial in Y1 of this program.

抽象的 靶向病理Aβ的免疫疗法仍然是阿尔茨海默氏症的有前途的治疗策略 疾病（AD）预防。已发布的数据表明，抑制AD风险的人中淀粉样蛋白聚集 可能会延迟广告发作。但是，由于治疗时间表和单克隆抗体的成本， 被动管理可能不是最好的预防治疗策略。因此，我们假设我们的 基于通用的MultiteP-Platform活性疫苗AV-1959D可能是被动的廉价替代品 疫苗接种策略。为了进一步发展该计划，我们的多学科团队制造了临床等级 AV-1959D疫苗并完成了综合的综合安全性，效率和免疫原性研究 AD，兔子和猴子的小鼠模型。由于这些在NIA范围内进行的研究 合作协议（U01 AG048310），我们生成了用于制备IND18953的数据 1959d FDA于2020年清除，制备了200毫克（225个小瓶，其中145件用于释放 测试和3Y稳定性）CGMP AV-1959D未来1阶段临床试验，并提交了赠款申请 临床试验“确定患者的AV-1959D上升剂量的安全性/耐受性和免疫原性 在2019年2月的早期广告中。我们仅在2022年才从NIA获得资金 尝试开始AV-1959D的第一次人类临床试验。因此，我们必须调整基于临床计划的 根据本行政补充中概述的新信息和监管建议。更多的 具体而言，我们将药物的稳定性测试扩展到了五年，并增加了剂量 基于在COVID-19试验中获得的新数据，对AV-1959D疫苗的皮内输送 由PharmajetTropis®批准的DNA疫苗。这些修订需要其他药物 第1阶段试验的小瓶。据此，该行政补充计划旨在证明制造业合理 AV-1959D疫苗的新GMP批次尽可能尽早启动该计划的Y1阶段试验。