Transition to Human Phase 1b Trials: Nonclinical Studies of an Anti-METH mAb

 描述(申请人提供)：甲基苯丙胺(冰毒)滥用在美国和世界造成严重的医疗、社会和经济危害。然而，到目前为止，还没有药物被批准用于治疗冰毒成瘾。这个翻译项目的主要目标是对一种治疗冰毒成瘾的新药进行安全性研究，一种名为ch-mAb7F9的新型抗冰毒单抗(MAb)，以支持在冰毒使用者中启动第一项临床研究。在未使用冰毒的健康受试者中对ch-mAb7F9进行1a期研究的结果表明，该抗体在人体内注射是安全的。CH-mAb7F9是为了选择性地快速结合血液中的冰毒，并防止它进入大脑和其他组织，在那里它会导致包括成瘾在内的多种健康问题。通过这样做，抗冰毒单抗Ab7F9将改变成瘾的临床治疗，提供第一种可以长时间减少冰毒增强特性的药物。与使用冰毒相关的再犯罪率很高。通过使用长效抗体拮抗剂来提供24小时不受冰毒影响的保护，患者将不太容易再次使用冰毒，从而大大提高康复的机会。抗药物单抗药物在成瘾治疗中具有重大优势，因为即使在免疫功能低下的患者中，也很容易实现稳定的浓度和精确的剂量控制，而且因为它们不会与其他药物相互作用。此外，单抗药物对大多数患者群体是安全的。在这项研究和测试计划中，ch-mAb7F9将在大鼠身上进行安全性测试，与大剂量的大剂量冰毒相结合。此外，还将在大鼠身上进行冰毒自我给药研究，以回答FDA提出的有关使用者克服抗体刺激剂阻断效应的动机和能力的具体问题。一支经验丰富的跨学科学术和行业团队将实现以下具体目标：1)完成基本的监管工作，为1b期研究做准备；2)为必要的非临床和未来临床研究制造ch-mAb7F9；3)进行非临床测试，以确定ch-mAb7F9与冰毒相互作用的安全性；以及4)在冰毒自我给药研究中测试ch-mAb7F9，以检查药物使用的激励方面。这些研究对于准备在冰毒使用者中进行1b期研究是必要的，这对于确定决定最佳人体剂量方案的因素至关重要，并将允许有效设计未来的临床研究，其中ch-mAb7F9疗效是主要终点。治疗的愿景是，这种可用于启动和继续药物治疗的药物将与高质量的行为调整计划结合使用，以显著改善患者的结果。

 DESCRIPTION (provided by applicant): Methamphetamine (METH) abuse causes serious medical, social, and economic harm in the USA and the world. However, to date, no medications are approved to treat METH addiction. The primary goal of this translational project is to conduct safety studies of a new medicine for METH addiction, a novel anti- METH monoclonal antibody (mAb) called ch-mAb7F9, to support the initiation of a first clinical study in METH users. Results from a Phase 1a study of ch-mAb7F9 in non-METH-using healthy subjects indicate that the antibody is safe for administration in humans. Ch-mAb7F9 was created to selectively and quickly bind METH in the blood and prevent it from entering the brain and other tissues where it causes multiple health problems, including addiction. By so doing, anti-METH ch-mAb7F9 will transform the clinical treatment of addiction by providing the first medication that can reduce METH's reinforcing properties for prolonged periods of time. There is a high rate of recidivism associated with METH use. By using a long-acting antibody antagonist to provide around-the-clock protection from METH effects, patients will be much less vulnerable to relapse to METH use and thereby have significantly improved chances for recovery. Anti-drug mAb medications have major advantages for addiction therapy since steady-state concentrations and precise control of dosing are readily achievable even in immune compromised patients, and because they will not interact with other medicines. Furthermore, mAb medications are safe for most patient populations. For the research and testing program, ch-mAb7F9 will be tested in rats for safety in combination with high, binge-like doses of METH. Additionally, METH self-administration studies in rats will be performed to answer specific questions from the FDA concerning the motivation and ability of users to overcome the antibody's stimulant blocking effects. A highly experienced, trans disciplinary academic and industry team will accomplish the following Specific Aims: 1) complete essential regulatory work in preparation for a Phase 1b study; 2) manufacture ch-mAb7F9 for necessary nonclinical and future clinical studies, 3) conduct nonclinical testing to determine safety of the interaction between ch-mAb7F9 and METH in rats, and 4) test ch-mAb7F9 in METH self-administration studies to examine the motivational aspect of drug use. These studies are necessary to prepare for a Phase 1b study in METH users that will be crucial for identifying factors that determine optimal human dosing regimens and will allow for the effective design of future clinical studies where ch-mAb7F9 efficacy is the primary endpoint. The therapeutic vision is that this medication, which can be used to initiate and continue pharmacologic treatment, will be used in combination with high quality behavioral modification programs to dramatically improve patient outcomes.