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

 描述（由申请人提供）：甲基苯丙胺（METH）滥用在美国和世界范围内造成严重的医疗，社会和经济危害。然而，迄今为止，没有药物被批准用于治疗METH成瘾。该转化项目的主要目标是对METH成瘾的新药进行安全性研究，这是一种称为ch-mAb 7 F9的新型抗METH单克隆抗体（mAb），以支持在METH使用者中启动第一项临床研究。来自在非使用METH的健康受试者中进行的ch-mAb 7 F9的1a期研究的结果表明，该抗体对于人类施用是安全的。Ch-mAb 7 F9的产生是为了选择性和快速地结合血液中的甲基，并防止它进入大脑和其他组织，在那里它会导致多种健康问题，包括成瘾。通过这样做，抗METH ch-mAb 7 F9将通过提供第一种可以长时间降低METH的增强特性的药物来改变成瘾的临床治疗。与使用甲氧苯丙胺有关的累犯率很高。通过使用长效抗体拮抗剂提供全天候保护，使患者不受METH影响，患者对METH使用的复发的脆弱性大大降低，从而显著提高了康复的机会。抗药物mAb药物对于成瘾治疗具有主要优势，因为即使在免疫受损的患者中也可以容易地实现稳态浓度和精确控制剂量，并且因为它们不会与其他药物相互作用。此外，mAb药物对大多数患者人群是安全的。对于研究和测试计划，将在大鼠中测试ch-mAb 7 F9与高、暴食样剂量的METH组合的安全性。此外，将在大鼠中进行METH自我给药研究，以回答FDA关于使用者克服抗体刺激物阻断作用的动机和能力的具体问题。一个经验丰富、跨学科的学术和行业团队将实现以下具体目标：1）完成必要的监管工作，为1b期研究做准备; 3）进行非临床试验以确定大鼠中ch-mAb 7 F9和METH之间相互作用的安全性，和4）在METH自我给药研究中测试ch-mAb 7 F9以检查药物使用的动机方面。这些研究对于在METH使用者中进行1b期研究是必要的，该研究对于确定确定最佳人类给药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-mAb 7 F9疗效是主要终点。治疗愿景是，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矫正计划结合使用，以显着改善患者的预后。

 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.