Therapeutic Agent for Rapid Reversal of Methamphetamine Intoxication

快速逆转甲基苯丙胺中毒的治疗剂

• 批准号: 10267771
• 负责人: Xinhua Li
• 金额: $ 394.18万
• 依托单位: CLEAR SCIENTIFIC, LLC
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-30 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10267771
• 关键词: Accident and Emergency department; Accounting; Acute; Address; Adrenergic Agents; Agitation; Agonist; Behavior; Behavioral; Benchmarking; Binding; Blood; Blood Chemical Analysis; Cardiovascular system; Cessation of life; Chemicals; Chemistry; Clinical Trials; Cross-Over Studies; Data; Dose; Drug Metabolic Detoxication; Emergency department visit; Excision; Exclusion Criteria; Filtration; Food and Drug Administration Drug Approval; Formulation; Half-Life; Healthcare Systems; Hospitalization; Hospitals; Human; Hypertension; Increased sweating; Injectable; Intoxication; Investigational Drugs; Investigational New Drug Application; Kidney; Marketing; Metabolism; Methamphetamine; Monitor; Mydriasis; Naloxone; Neuraxis; Opioid Receptor; Outcome; Patient-Focused Outcomes; Pharmaceutical Preparations; Phase I Clinical Trials; Physiological; Placebos; Plasma; Process; Protocols documentation; Resources; Rodent; Route; Safety; Sales; Saline; Schedule; Serum; Site; Sympathetic Nervous System; Tachycardia; Therapeutic; Therapeutic Agents; Toxicology; United States Food and Drug Administration; Urine; Work; drug clearance; drug of abuse; first-in-human; hemodynamics; improved; inclusion criteria; manufacturing process; meetings; methamphetamine effect; mortality; new technology; nonhuman primate; novel; novel strategies; pharmacokinetics and pharmacodynamics; phase I trial; pre-clinical; preclinical study; preclinical trial; receptor; scale up; small molecule; standard of care; symptom treatment; volunteer

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.

项目摘要 这项努力解决了对安全迅速行动的逆转代理的迫切需求 甲基苯丙胺。甲基苯丙胺（甲基苯丙胺）是美国增长最快的滥用药物，已经成为 医疗保健系统的重大负担，占200,000多个急诊室访问，几乎是 每年10,000人死亡。到目前为止，目前尚无治疗方法来治疗中毒。长期 目的是获得FDA批准出售和销售CS-1113（一种小分子封存），用于 治疗急性甲基毒化。 CS-11103在血液中有选择地结合METH，并急剧加速其 通过清除到尿液中从身体中移除，代表了一种逆转药物作用的新方法： 删除原因并删除效果。 CS-11103耐受良好，并提供了快速持久的 在啮齿动物和非人类灵长类动物（NHP）的临床前研究中，急性甲基毒化的逆转。 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）获得FDA的研究新药（IND）批准的要求，然后完成 CS-11103的第一阶段I期临床试验。在FDA批准之路上的这些重要里程碑将 通过完成以下目的来实现：AIM 1将建立化学过程 在当前良好的制造实践（CGMP）下制造CS-11103。一批CGMP 材料将用于临床前和临床试验。将开发一个可注射的配方，并 特征。 AIM 2将确定CS-11103的安全性和功效概况 甲基苯丙胺的中毒在临床前的辅助研究中。标准毒理学， 根据FDA的要求将进行药代动力学和药效学研究。详细的剂量 - 将进行NHP的范围研究以建立安全的初始人类剂量；终点将是 最大安全/耐受剂量。将与FDA举行预先会议，以设定协议和要求。 AIM 3将为CS-11103的第一阶段I期临床试验建立一项方案。协议 将包括：受试者数量的估计；安全排除和纳入标准的描述；描述 剂量计划包括持续时间，剂量，剂量升级和时间表；所有对安全至关重要的细节；给药 升级规则和停止标准；并讨论预期剂量，持续时间，时间表和 管理途径。预期的结果是用FDA提交完整的IND包。 AIM 4将建立 在FDA I期试验中，CS-11103的安全性和剂量水平。这项研究将针对健康， 毒品志愿者。预期的结果是，CS-11103将以预期有效的剂量安全 急性甲基苯丙胺中毒的逆转。