Therapeutic Agent for Rapid Reversal of Methamphetamine Intoxication

快速逆转甲基苯丙胺中毒的治疗剂

基本信息

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
项目类别：
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

项目摘要

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.

项目概要这项工作解决了对安全快速作用逆转剂的迫切需求甲基苯丙胺。甲基苯丙胺 (meth) 是美国滥用增长最快的药物，已成为对医疗保健系统造成了沉重负担，导致急诊室就诊次数超过 200,000 次，近每年有 10,000 人死亡。迄今为止，目前还没有可用于治疗冰毒中毒的疗法。长期来看目标是获得 FDA 批准小分子螯合剂 CS-1103 的销售和营销，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尿液清除体内，代表一种逆转药物作用的新方法：去除因，去除果。 CS-1103 具有良好的耐受性并提供快速、持久的效果在啮齿动物和非人类灵长类动物 (NHP) 的临床前试验研究中逆转急性冰毒中毒。此处建议完成所有必要的临床前研究以及化学、制造和控制 (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 批准之路上的这些重要里程碑将通过完成以下目标来实现：目标 1 将建立化学工艺根据现行良好生产规范 (cGMP) 生产 CS-1103。一批cGMP 将生产用于临床前和临床试验的材料。将开发一种注射剂型并特点。目标 2 将建立 CS-1103 逆转临床前 IND 启用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。详细剂量- 将在 NHP 中进行范围研究，以确定安全的人体初始剂量；终点将是最大安全/耐受良好的剂量。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。协议将包括：科目数量的估计；安全排除和纳入标准的描述；描述给药计划，包括持续时间、剂量、剂量递增和时间表；所有对安全至关重要的细节；剂量升级规则和停止标准；以及对预期剂量、持续时间、时间表的基本原理的讨论给药途径。预期结果是向 FDA 提交完整的 IND 包。目标 4 将建立 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、未接触过药物的志愿者。预期结果是，CS-1103 在预期有效剂量下是安全的逆转急性甲基苯丙胺中毒。