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.

项目总结/摘要 这一努力解决了对芬太尼的安全快速作用逆转剂的迫切需求， 其类似物（F/FA）的作用机制不同于μ-阿片受体（莫尔） 拮抗剂包括纳洛酮。F/FA的滥用现在是每年都在增加的主要死亡原因。 疾病控制和预防中心的数据显示，在2013年至2020年期间， 增加了10倍;与芬太尼有关的死亡人数现在是海洛因造成的死亡人数的两倍。纳洛酮，目前 标准治疗逆转阿片类药物过量引起的呼吸抑制，对海洛因非常有效 和许多来自天然产物的阿片类药物，但对F/FA的效果要差得多。长期目标 是获得FDA批准销售和销售CS-1103，一种小分子螯合剂， 肌内注射，作为急救药物治疗F/FA毒性，在常见的紧急情况下 多种F/FA的混合物和F/FA与兴奋剂的共同使用的情景。CS-1103耐受性良好，选择性 结合血液中的F/FA，并通过清除进入尿液显著加速其从体内的清除， 代表了一种新的逆转药物作用的方法：消除原因和消除效果。是 本文建议继续开发CS-1103作为紧急情况下治疗阿片类药物毒性的急救药物 场景将优化用于IM给药的CS-1103制剂，并且将提供安全有效的IM剂量， 将确定在这些情况下阿片类药物的生理作用的快速逆转。这些重大 FDA批准过程中的里程碑将通过完成以下目标来实现：目标1将 优化CS-1103的稳定制剂，适用于IM注射，在 血浆室将调整制剂以使稳定性、耐受性和给药速度最大化。 血浆中CS-1103的外观，并在大鼠和犬中进行评价。预期成果是制定 适用于人体研究。目的2将确立CS-1103治疗IM的疗效特征 在临床前研究中，在现实世界中注射F/FA逆转中毒。三 场景：1）多种F/FA，2）存在兴奋剂的芬太尼，以及3）与纳洛酮联合使用， 将被评估。将在大鼠和犬中进行详细的剂量范围研究，以确定有效剂量。 终点是恢复充分通气和阿片样物质从血浆清除到尿液中。预计 结果是用于逆转毒性作用和快速阿片类药物清除的CS-1103剂量。目标3将建立 临床前研究性新药申请中CS-1103 IM注射的安全性特征 （IND）-赋能研究。标准药物非临床研究质量管理规范（GLP）毒理学和药代动力学研究 根据FDA要求，将在大鼠和犬中进行，以确定安全的初始人体剂量;终点 是最大安全剂量将与FDA举行IND前会议。成功完成 预期目标1-3将产生可用于进一步IND使能临床前研究的候选药物。