Therapeutic Agent for Rapid Reversal of Methamphetamine Intoxication

项目总结 这一努力解决了对一种安全、快速起作用的逆转剂的迫切需求 冰毒。甲基苯丙胺是美国增长最快的滥用毒品，已成为 对卫生保健系统造成重大负担，急诊室就诊人数超过20万人次，近 每年有一万人死亡。到目前为止，还没有治疗冰毒的现有疗法。长期的 目标是获得FDA批准销售和上市CS-1103，一种小分子隔离剂，用于 急性冰毒中毒的治疗。CS-1103选择性地结合血液中的冰毒并显著加速其 通过清除进入尿液从体内排出，代表了一种逆转药物作用的新方法： 去掉原因，消除后果。CS-1103耐受性好，提供了快速、持久的 在啮齿动物和非人灵长类动物(NHP)的试点临床前研究中逆转急性冰毒中毒。 这里建议完成所有必要的临床前研究和化学、制造和控制 (CMC)要求获得FDA的研究新药(IND)批准，然后完成 CS-1103的首个人类I期临床试验。FDA批准道路上的这些重要里程碑将 将通过完成以下目标来实现：目标1将建立一个化学过程，以 根据现行良好制造规范(CGMP)制造CS-1103。一批cGMP 将为临床前和临床试验制作材料。将开发一种可注射制剂，并 特色化的。目标2将建立CS-1103逆转高血压的安全性和有效性 临床前IND研究中的甲基苯丙胺中毒。标准毒理学， 药代动力学和药效学研究将根据FDA的要求进行。详细的剂量- 将在NHP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/耐受性剂量。IND前会议将与FDA举行，以制定协议和要求。 AIM 3将为CS-1103的第一个人类阶段临床试验建立一个方案。该协议 将包括：受试者数量估计；安全排除和纳入标准说明；说明 剂量计划，包括持续时间、剂量、剂量升级和时间表；对安全至关重要的所有细节；剂量 上报规则和停止标准；以及对预期剂量、持续时间、时间表和 管理路线。预期结果是向FDA提交完整的IND包。目标4将建立 在FDA I期试验中，CS-1103的安全性和剂量水平。这项研究将在健康的， 毒品天真的志愿者。预期结果是CS-1103在预期有效的剂量下将是安全的 急性甲基苯丙胺中毒逆转。

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.