Therapeutic Agent for Rapid Reversal of Methamphetamine Intoxication

项目摘要 这一努力解决了对安全的快速作用逆转剂的迫切需要， 冰毒甲基苯丙胺（冰毒）是美国增长最快的滥用药物， 这是医疗保健系统的一个重大负担，占20多万次急诊室就诊和近 每年有一万人死亡。到目前为止，还没有现有的治疗方法可用于治疗冰毒中毒。长期 目的是获得FDA批准销售和销售CS-1103，一种小分子螯合剂，用于 治疗急性冰毒中毒CS-1103选择性地结合血液中的冰毒，并显着加速其 通过清除进入尿液从体内清除，代表了逆转药物作用的新方法： 消除原因，消除后果。CS-1103耐受性良好，可提供快速持久的 在啮齿动物和非人灵长类动物（NHP）的临床前试验研究中逆转急性甲基中毒。 此处建议完成所有必要的临床前研究以及化学、生产和控制 (CMC)要求获得FDA的研究性新药（IND）批准，然后完成 CS-1103的首次人体I期临床试验。FDA批准过程中的这些重要里程碑将 通过完成以下目标来实现：目标1将建立一个化学过程， 根据现行药品生产质量管理规范（cGMP）生产CS-1103。一批cGMP 将生产用于临床前和临床试验的材料。将开发一种注射制剂， 表征了目的2将确定CS-1103逆转 临床前IND使能研究中的甲基苯丙胺中毒。标准毒理学， 将按照FDA要求进行药代动力学和药效学研究。详细剂量- 将在NHP中进行范围研究，以确定安全的初始人体剂量;终点将是 最大安全/良好耐受剂量。将与FDA举行IND前会议，以制定方案和要求。 目标3将为CS-1103的首次人体I期临床试验制定方案。议定书 将包括：受试者数量估计;安全性排除和入选标准描述;描述 给药计划，包括持续时间、剂量、剂量递增和时间表;对安全性至关重要的所有细节;给药 递增规则和停止标准;以及讨论预期剂量、持续时间、时间表和 给药途径。预期结果是向FDA提交完整的IND包装。目标4将建立 CS-1103在FDA I期试验中的安全性和剂量水平。这项研究将在健康， 没有吸毒经验的志愿者预期结果是，CS-1103在预期有效剂量下将是安全的， 急性甲基苯丙胺中毒的逆转

PROJECT SUMMARY This effort addresses the urgent need for a safe rapidly acting reversal agent for methamphetamine. Methamphetamine (meth) is the fastest growing drug of abuse in the US and has become a significant burden on the health care system, accounting for over 200,000 emergency room visits and nearly 10,000 deaths annually. As yet, no current therapeutics are available to treat meth intoxication. The long-term objective is to obtain FDA approval for sale and marketing of CS-1103, a small-molecule sequestrant, for treatment of acute meth intoxication. CS-1103 selectively binds meth in blood and dramatically accelerates its removal from the body by clearance into the urine, representing a new approach to reversal of drug effect: remove the cause and remove the effect. CS-1103 was well-tolerated and provided rapid long-lasting reversal of acute meth intoxication in pilot pre-clinical studies in rodent and non-human primate (NHP). It is proposed here to complete all necessary preclinical studies and Chemistry, Manufacturing and Controls (CMC) requirements to obtain Investigational New Drug (IND) approval from the FDA and then complete the first-in-human Phase I clinical trial for CS-1103. These significant milestones on the path to FDA approval will be achieved via completion of the following Aims: Aim 1 will establish a chemical process to manufacture CS-1103 under Current Good Manufacturing Practices (cGMP). A batch of cGMP material will be produced for pre-clinical and clinical trials. An injectable formulation will be developed and characterized. Aim 2 will establish the safety and efficacy profile of CS-1103 for reversal of methamphetamine intoxication in pre-clinical IND-enabling studies. Standard toxicology, pharmacokinetics, and pharmacodynamics studies will be conducted per FDA requirements. A detailed dose- ranging study in NHP will be performed to establish a safe initial human dose; the end-point will be the maximum safe/well tolerated dose. A pre-IND meeting will be held with FDA to set protocols and requirements. Aim 3 will establish a protocol for the first-in-human Phase I clinical trial of CS-1103. The protocol will include: estimate of number of subjects; description of safety exclusions and inclusion criteria; description of dosing plan including duration, dose, dose escalation, and schedule; all details critical to safety; dosing escalation rules and stopping criteria; and discussion of rationale for intended dose, duration, schedule, and route of administration. Expected outcome is filing of complete IND package with FDA. Aim 4 will establish the safety and dose level of CS-1103 in an FDA Phase I trial. This study will be conducted on healthy, drug-naive volunteers. Expected outcome is that CS-1103 will be safe at doses anticipated to be effective for reversal of acute methamphetamine intoxication.