Novel Therapeutic Agents to Reverse Opioid Overdose

项目摘要/摘要 这一努力满足了对安全、快速起效的芬太尼和 其类似物(F/FA)的作用机制与µ-阿片受体(MOR)不同 包括纳洛酮在内的拮抗剂。滥用F/FA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至2020年间，与芬太尼有关的死亡人数 增加了10倍；与芬太尼有关的死亡人数现在是海洛因死亡人数的两倍。纳洛酮，目前是 标准护理逆转阿片类药物过量导致的呼吸抑制，对海洛因非常有效 许多阿片类药物来自天然产品，但对F/FA的效果要差得多。长期目标 将获得FDA批准CS-1103的销售和营销，CS-1103是一种小分子隔离剂，为 肌肉注射作为抢救药物抢救常见F/FA中毒 多种F/FA混合和F/FA与兴奋剂联合使用的场景。CS-1103具有良好的耐受性，具有选择性 将F/FA结合在血液中，并通过清除到尿液中极大地加速其从体内的清除， 代表了一种逆转药物效应的新方法：去掉原因，消除影响。它是 建议继续开发CS-1103作为急诊阿片类药物中毒的抢救药物 场景。用于肌注的CS-1103的配方将得到优化，安全有效的肌注剂量 将确定阿片类药物在这些情况下的快速逆转生理影响。这些意义重大 将通过完成以下目标来实现FDA批准道路上的里程碑：目标1将 筛选出一种稳定的注射用CS-1103处方，可快速用于肌注。 血浆舱。配方将进行调整，以最大限度地提高稳定性、耐受性和速度 CS-1103在血浆中的出现，并在大鼠和犬身上进行了评价。预期结果是一个公式 适合在人体研究中使用。目标2将建立CS-1103对IM的疗效 在临床前研究中，在真实世界的情况下，注射用于逆转F/FA中毒。三 场景：1)多个F/FA，2)芬太尼在兴奋剂存在下，以及3)与纳洛酮联合使用， 将会被评估。将在大鼠和狗身上进行详细的剂量范围研究，以确定有效剂量。 终点是恢复足够的通风和将阿片类药物从血浆中清除到尿液中。预期 结果是CS-1103剂量可逆转毒性作用并快速清除阿片类药物。目标3将建立 肌注CS-1103在新药临床前研究中的安全性 (IND)-使研究成为可能。标准良好实验室规范(GLP)毒理学和药代动力学研究 根据FDA的要求，将在大鼠和犬身上进行试验，以确定安全的初始人类剂量；终点 将是最大安全剂量。将与FDA举行IND前会议。成功完成 AIMS 1-3预计将产生一种候选药物，为进一步的IND临床前研究做好准备。

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.