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.

摘要 针对病理性Aβ的免疫治疗仍然是阿尔茨海默氏症的一种有前途的治疗策略 疾病（AD）预防。已发表的数据表明，在有AD风险的人群中抑制淀粉样蛋白聚集 可以延缓AD的发作然而，由于单克隆抗体的治疗时间表和成本， 被动给药可能不是最好的预防性治疗策略。因此，我们假设， 一种通用的基于MultiTEP平台的主动疫苗AV-1959 D可能是被动疫苗的廉价替代品。 疫苗接种战略。为了进一步推动这一计划，我们的多学科团队制造了一种临床级的 AV-1959 D疫苗和已完成的全面IND使能安全性、有效性和免疫原性研究， AD的小鼠模型、兔和猴。由于在NIA范围内进行了这些研究， 合作协议（U 01 AG 048310），我们生成了用于第1阶段AV的IND 18953准备的数据- FDA于2020年批准的1959 D临床试验，制备了200 mg（225瓶，其中145瓶用于放行 试验和3年稳定性）cGMP AV-1959 D用于未来的1期临床试验，并提交了 临床试验“确定患者中AV-1959 D剂量递增的安全性/耐受性和免疫原性 早期AD”的患者我们在2022年才从NIA获得资金， 尝试，开始AV-1959 D的首次人体临床试验。因此，我们不得不调整我们的临床计划， 本行政补充文件中概述的新信息和监管建议。更 具体而言，我们将药物产品的稳定性测试延长至五年，并增加了 根据COVID-19试验获得的新数据， 由Pharmajet Tropis®递送的批准的DNA疫苗。这些修订案需要额外的制剂 用于1期试验。因此，这一行政补充计划的目的是证明制造业的合理性， 尽快获得AV-1959 D疫苗的新GMP批次，以便在该项目的Y1启动I期试验。