Novel Therapeutic Agents to Reverse Opioid Overdose

逆转阿片类药物过量的新型治疗药物

• 批准号: 10390959
• 负责人: Xinhua Li
• 金额: $ 128.37万
• 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 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10390959
• 关键词: Address; Anesthetics; Appearance; Binding; Bioavailable; Biodistribution; Blood; Brain; Canis familiaris; Cause of Death; Centers for Disease Control and Prevention (U.S.); Cessation of life; Characteristics; Chest wall structure; Cocaine; Data; Development; Dose; Drug Kinetics; Effectiveness; Emergency Situation; Excision; Exhibits; Fatty acid glycerol esters; Fentanyl; Filtration; Formulation; Heroin; Human; In Vitro; Injections; Intoxication; Intramuscular; Intramuscular Injections; Investigational New Drug Application; Kidney; Lead; Link; Marketing; Methamphetamine; Naloxone; Natural Products; Neuraxis; Opioid; Osmolalities; Outcome; Overdose; Patient-Focused Outcomes; Pharmaceutical Preparations; Physiological; Plasma; Prevention; Rattus; Risk; Safety; Sales; Seizures; Site; Speed; Techniques; Therapeutic Agents; Tissues; Toxic effect; Toxicology; Urine; Ventilatory Depression; Work; analog; carfentanil; club drug; drug candidate; drug clearance; good laboratory practice; improved; in vivo; meetings; mu opioid receptors; nonhuman primate; novel; novel strategies; novel therapeutics; opioid overdose; opioid user; pharmacokinetics and pharmacodynamics; pre-clinical; preclinical study; prevent; restoration; small molecule; standard of care; synthetic opioid; treatment comparison; ventilation

Project Summary/Abstract This effort addresses the urgent need for a safe rapidly acting reversal agent for fentanyl and its analogues (F/FA) with a mechanism of action that differs from the µ-opioid receptor (MOR) antagonists including naloxone. Abuse of F/FA is now a major cause of death that is increasing yearly. Centers for Disease Control and Prevention data show that between 2013 and 2020 fentanyl-linked deaths have increased 10-fold; fentanyl related deaths now are double those caused by heroin. Naloxone, currently the standard of care to reverse respiratory depression caused by opioid overdose, is highly effective against heroin and many opioids derived from natural products, but is far less effective against F/FA. The long-term objective is to obtain FDA approval for sale and marketing of CS-1103, a small-molecule sequestrant, formulated for intramuscular injection, as a rescue drug to treat F/FA toxicity in the commonly encountered emergency scenarios of mixtures of multiple F/FA and co-use of F/FA with stimulants. CS-1103 is well tolerated, selectively binds F/FA 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. It is proposed here to continue development of CS-1103 as a rescue drug to treat opioid toxicity in emergency scenarios. Formulation of CS-1103 for IM administration will be optimized and a safe and effective IM dose that rapidly reverses physiological effects of opioids in these scenarios will be determined. These significant milestones on the path to FDA approval will be achieved via completion of the following Aims: Aim 1 will optimize a stable formulation of CS-1103 suitable for IM injection with rapid appearance in the plasma compartment. The formulation will be adjusted to maximize stability, tolerability, and speed of appearance of CS-1103 in plasma, and evaluated in rat and canine. Expected outcome is a formulation appropriate for use in human studies. Aim 2 will establish the efficacy profile of CS-1103 for IM injection for reversal of F/FA intoxication in real-world scenarios, in pre-clinical studies. Three scenarios: 1) multiple F/FA, 2) fentanyl in the presence of stimulants, and 3) use in conjunction with naloxone, will be evaluated. A detailed dose-ranging study in rat and canine will be conducted to establish an effective dose. Endpoints are restoration of adequate ventilation and clearance of opioid from plasma into urine. Expected outcome is CS-1103 dose for reversal of toxic effects and rapid opioid clearance. Aim 3 will establish the safety profile of CS-1103 for IM injection in pre-clinical Investigational New Drug Application (IND)-enabling studies. Standard Good Laboratory Practice (GLP) toxicology and pharmacokinetic studies per FDA requirements will be performed in rat and canine to establish a safe initial human dose; the endpoint will be the maximum safe dose. A pre-IND meeting will be conducted with the FDA. Successful completion of Aims 1-3 is anticipated to yield a drug candidate ready for further IND-enabling pre-clinical studies.

项目摘要/摘要 这项努力迫切需要对芬太尼和 它的类似物（f/fa）具有与阿片受体不同的作用机理（MOR） 包括纳洛酮在内的拮抗剂。滥用F/FA现在是每年增加的主要死亡原因。 疾病控制与预防中心数据显示，2013年至2020年之间的芬太尼连接死亡中有 增加了10倍；芬太尼相关的死亡现在是海洛因引起的两倍。纳洛酮，目前 护理标准以逆转阿片类药物过量引起的呼吸抑郁症，对海洛因非常有效 许多阿片类药物来自天然产物，但针对F/FA的有效性要差得多。长期目标 是为了获得FDA批准出售和销售CS-1113，这是一种小型隔离剂，适用于 肌肉注射，作为一种救援药物，可治疗常见的紧急情况下F/FA毒性 多种f/fa的混合物和f/fa与兴奋剂共同使用的场景。 CS-11103的耐受性良好，有选择性 结合血液中的f/fa，并通过间隙向尿液中的尿液中大幅加速其从身体中的去除， 代表一种逆转药物效应的新方法：删除原因并删除效果。这是 在这里提议继续开发CS-11103作为一种救援药物，以治疗紧急情况下的阿片类药物毒性 方案。将优化用于IM管理的CS-11103的配方，并可以安全有效 在这些情况下，将迅速逆转阿片类药物的物理作用。这些重要 通过完成以下目标，将实现FDA批准之路的里程碑：AIM 1将 优化适用于IM注射的CS-1113的稳定公式，在 等离子体室。该公式将进行调整以最大化稳定性，耐受性和速度 血浆中CS-1113的出现，并在大鼠和犬类中进行评估。预期结果是一个公式 适用于人类研究。 AIM 2将确定IM CS-11103的效率概况 在现实世界中，在临床前研究中注射了f/fa肠毒性的逆转。三 方案：1）多个f/fa，2）在存在兴奋剂的情况下芬太尼，3）与纳洛酮结合使用， 将进行评估。将在大鼠和犬类中进行详细的剂量范围研究以建立有效的剂量。 终点是恢复足够的通风和阿片类药物从血浆中清除到尿液中。预期的 结果是CS-11103剂量，用于逆转有毒作用和快速阿片类药物清除率。 AIM 3将确定 CS-11103的安全性在临床前调查新药应用中注射IM注射 （IND） - 增强研究。标准良好实验室实践（GLP）毒理学和药代动力学研究 每fda要求将在大鼠和犬类中执行以建立安全的初始人剂量；端点 将是最大安全剂量。 FDA将举行预定会议。成功完成 AIMS 1-3预计会产生候选药物，准备进一步促进临床前研究。