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

摘要 针对病理性Aβ的免疫治疗仍然是阿尔茨海默病的一种有前途的治疗策略 疾病(AD)预防。已发表的数据表明，抑制阿尔茨海默病风险人群的淀粉样蛋白聚集 可以延缓AD的发病。然而，由于治疗计划和单抗的成本，他们的 被动给药可能不是最好的预防治疗策略。因此，我们假设我们的 基于多TEP平台的通用主动疫苗AV-1959D可能是被动疫苗的廉价替代品 疫苗接种策略。为了进一步推进这个项目，我们的多学科团队制作了一个临床等级 AV-1959D疫苗和完成了全面的IND安全性、有效性和免疫原性研究 阿尔茨海默病的小鼠模型、兔子和猴子。由于这些研究是在NIA的范围内进行的 合作协议(U01 AG048310)，我们生成了为第一阶段AV-IND18953的准备数据 FDA于2020年批准的1959D临床试验，制备了200毫克(225瓶，其中145瓶用于释放 测试和3Y稳定性)cGMP AV-1959D用于未来的第一阶段临床试验，并提交了 临床试验：确定患者递增剂量的AV-1959D的安全性/耐受性和免疫原性 在2019年2月，我们才从NIA获得资金，在两年三年后的2022年 尝试，开始对AV-1959D的第一次人体临床试验。因此，我们不得不调整我们的临床计划，根据 关于本行政副刊概述的新信息和监管建议。更多 具体地说，我们将药物产品的稳定性测试延长至五年，并增加了 基于新冠肺炎首例临床试验获得的新数据的AV-1959D疫苗皮内给药 PharmaJet Tropis®提供的经批准的DNA疫苗。这些修正案需要额外的药品 第一阶段试验的小瓶。因此，这一行政补充计划旨在证明制造 新GMP批次的AV-1959D疫苗尽早启动Y1期试验。

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.