IND-enabling program for a long-acting anti-methamphetamine monoclonal antibody for treating methamphetamine use disorder

用于治疗甲基苯丙胺使用障碍的长效抗甲基苯丙胺单克隆抗体的 IND 项目

基本信息

批准号：
10476678
负责人：
Misty Ward Stevens
金额：
$ 124.89万
依托单位：
INTERVEXION THERAPEUTICS, LLC
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-30 至 2025-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10476678
关键词：
Adherence Affinity Animals Antibodies Antibody Therapy Behavior Therapy Behavioral Binding Biological Assay Brain Cell Line Chronic Clinic Clinical Clinical Protocols Clinical Research Clinical Trials Clone Cells Cognitive Data Development Diagnosis Dose Drug Kinetics FDA approved Fab Immunoglobulins Frequencies Goals Grant Half-Life Health Health Care Costs Healthcare Home Human Immunoglobulin G In Vitro Infusion procedures Length Methamphetamine Methamphetamine overdose Methamphetamine use disorder Modeling Modification Monoclonal Antibodies Motor Activity Mutation Outcome Participant Patient-Focused Outcomes Patients Persons Pharmaceutical Preparations Population Preclinical Testing Preparation Production Rattus Recovery Relapse Research Research Design Risk Rodent Running Safety Step Tests Stimulant Testing Time Toxicokinetics Toxicology Treatment Cost Vaccines Visit Work Writing antagonist base cell bank clinical development compliance behavior contingency management cost design disability efficacy study first-in-human healthy volunteer humanized monoclonal antibodies immunogenicity improved lead candidate manufacturing process medication compliance meetings methamphetamine effect methamphetamine use nonhuman primate phase 1 study programs response stable cell line

项目摘要

PROJECT ABSTRACT Nearly 1 million people in the US were diagnosed with a methamphetamine (METH) use disorder (MUD) in 2017. Once established, MUD can last a long time and is very difficult to treat. Yet there are still no FDA-approved medications indicated specifically for MUD. Anti-METH antibodies have been tested preclinically in efficacy models and have shown the ability to reduce METH’s stimulant effects in rodents. In humans, these same antibodies alter METH PK by reducing volume of distribution and likely decreasing distribution to the brain. Current antibodies would be dosed once a month; longer-acting agents would increase compliance due to less frequent dosing. The goal of this application is to identify a follow-on anti-METH monoclonal antibody with an extended half-life and conduct IND-enabling development and toxicology studies so that at the end of the project it is ready for a first-in-human clinical trial. In addition to increased compliance, the benefits of a long-acting antibody for treating MUD may include lower cost of treatment and overall better clinical outcomes. The identified antibody will also be fully humanized, which may lower the risk of antigenicity upon chronic dosing. The project will be accomplished through four Specific Aims. Aim 1 is to select the final lead candidate long- acting antibody. A panel of seven previously humanized METH-binding regions will be produced as Fabs and tested in a METH-stimulated locomotor model in rats. The best will be paired with two IgG constant domains that have selected mutations to extend their half-life. The two IgG will be compared in the same efficacy model, along with in vitro characterization, and the final candidate selected. In Aim 2, a clonal cell line and scalable manufacturing process will be developed for the final candidate IgG. A Master Cell Bank will be generated from the cell line and used for manufacture of clinical batches. A 50L run will produce material for development work and testing, then a 250L batch will be made to provide antibody for toxicology testing in Aim 3. Finally, a 500L GMP batch will be manufactured for first-in-human clinical studies. IND-enabling toxicology studies in rats will be conducted under Aim 3. A single-dose study will test IV doses up to 1.5 g/kg. A multiple-dose study will test doses up to 1 g/kg given every other week for six months. Antibody toxicokinetics and immunogenicity will be determined along with typical toxicology outcomes. Aim 4 consists of the development of the regulatory submissions and other preparations for initial clinical trials. A pre-IND meeting will be held with FDA following the completion of Aim 1, then a clinical protocol will be fully developed based on the discussion. As the program develops, the entire IND including quality, nonclinical, and FDA-specific modules will be written and submitted at the end. The expected outcome of this project is a clinic-ready humanized monoclonal antibody to treat MUD that only has to be dosed once every 2-3 months. Such a candidate would deliver improved patient outcomes with lower treatment burden and higher adherence.

项目摘要 2017 年，美国有近 100 万人被诊断患有甲基苯丙胺 (METH) 使用障碍 (MUD)。 MUD 一旦形成，会持续很长时间并且很难治疗，但目前还没有 FDA 批准的治疗方法。专门针对 MUD 的药物已经过临床前疗效测试。模型并显示出减少冰毒对啮齿动物的刺激作用的能力，对人类来说也是如此。抗体通过减少分布体积并可能减少对大脑的分布来改变 METH PK。目前的抗体将每月给药一次；长效药物会因剂量减少而提高依从性。本申请的目的是确定后续抗 METH 单克隆抗体，其具有以下特点：延长半衰期并进行支持 IND 的开发和毒理学研究，以便在项目结束时它已准备好进行首次人体临床试验除了提高依从性外，长效的好处也是如此。用于治疗 MUD 的抗体可能包括更低的治疗成本和更好的总体临床结果。抗体也将完全人源化，这可能会降低长期给药时产生抗原性的风险。该项目将通过四个具体目标来实现，目标 1 是选择最终的主要候选人。一组七个先前人源化的 METH 结合区域将被生产为 Fab 和在 METH 刺激的大鼠运动模型中进行测试，最好的将与两个 IgG 恒定结构域配对。已选择突变以延长其半衰期，这两种 IgG 将在相同的功效模型中进行比较。进行体外表征，并选择最终候选者。在目标 2 中，将为最终候选 IgG A 开发克隆细胞系和可扩展的生产工艺。主细胞库将从细胞系中产生并用于临床批次的生产。生产用于开发工作和测试的材料，然后将生产 250L 批次，为目标 3 中的毒理学测试。最后，将生产 500L GMP 批次用于首次人体临床研究。目标 3 将在大鼠中进行 IND 毒理学研究。单剂量研究将测试静脉注射剂量多剂量研究将测试每两周一次高达 1 g/kg 的抗体剂量，持续六个月。毒代动力学和免疫原性将与典型的毒理学结果一起确定。目标 4 包括制定监管申请和初始临床试验的其他准备工作。目标 1 完成后，将与 FDA 举行 IND 前会议，然后全面制定临床方案随着计划的发展，整个 IND 包括质量、非临床和 FDA 特定模块将在最后编写并提交。该项目的预期成果是一种可用于临床的人源化单克隆抗体，用于治疗 MUD 必须每 2-3 个月给药一次，这样的候选药物可以以更低的成本改善患者的治疗效果。治疗负担和更高的依从性。