A Therapeutic Agent to Lower the Level of Synthetic Opioids in the Body

降低体内合成阿片类药物水平的治疗剂

基本信息

批准号：
10759091
负责人：
Xinhua Li
金额：
$ 303.59万
依托单位：
CLEAR SCIENTIFIC, LLC
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-01 至 2025-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10759091
关键词：
Acceleration Acute Address Affect Animal Model Antidotes Binding Blood Circulation Brain Canis familiaris Central Nervous System Cessation of life Clinical Clinical Trials Complex Cyclic GMP Data Dose Drug Interactions Drug Metabolic Detoxication Drug usage Epidemic Excretory function Fentanyl Formulation Funding Glomerular Filtration Rate Goals Half-Life Hospitals Human Human body Induction of neuromuscular blockade Injections Intoxication Intramuscular Intramuscular Injections Intranasal Administration Intravenous Kidney Metabolic Clearance Rate Methamphetamine Modeling Muscle Rigidity Naloxone Opioid Organ Overdose Patient-Focused Outcomes Performance Persons Pharmaceutical Preparations Phase Phase Ia Clinical Trial Phase Ib Clinical Trial Plasma Probability Rattus Resources Respiration Route Safety Site Therapeutic Therapeutic Agents Time Tissues Toxicology Urine Withdrawal Work carfentanil drug of abuse fentanyl overdose first-in-human improved intravenous injection medication for opioid use disorder mouse model mu opioid receptors nonhuman primate opioid overdose opioid use disorder opioid withdrawal overdose death pre-Investigational New Drug meeting prevent standard of care success synthetic opioid

项目摘要

1 PROJECT SUMMARY 2 There is an urgent need for a therapeutic that rapidly deactivates and removes fentanyl from 3 the body. As stated by Dr. Nora Volkow, “Deaths from fentanyl are increasing in spite of naloxone, and overdose 4 requires multiple naloxone doses.” This is a nationwide crisis, with over 73,000 overdose deaths annually, and 5 over 3M people living with opioid use disorder. Naloxone blocks mu-opioid receptors for a short period of time 6 without affecting the level of fentanyl in the body, which can result in renarcotization. A single-dose therapeutic 7 is needed that restores respiration immediately and removes fentanyl from the body at the maximum possible 8 rate, the glomerular filtration rate (GFR), eliminating the possibility of renarcotization. 9 Our therapeutic agent, CS-1103, which works differently than naloxone, meets this need. After 10 injection, CS-1103 binds to fentanyl in the bloodstream, rapidly reversing its effects, and dramatically increases 11 the rate of fentanyl clearance into urine to near the GFR. In small and large animal models, we have 12 demonstrated that CS-1103 is effective against synthetic opioids, ranging from fentanyl to carfentanil, restoring 13 respiration in 2-3 min, reversing muscle rigidity in 1 min, preventing renarcotization after a lethal dose of 14 carfentanil, and rapidly lowering opioid levels in the body. Furthermore, CS-1103 causes milder opioid 15 withdrawal compared to naloxone, and does not interfere with the activity of naloxone. 16 We are currently developing IV CS-1103 to treat acute intoxication caused by drugs of abuse including 17 methamphetamine. We have completed all required nonclinical studies and anticipate completion of the First- 18 in-Human Phase 1a clinical trial in mid-2023. Based on results to date, we believe that Phase 1a has a high 19 probability of success, as CS-1103: (1) is a single use drug; (2) has an excellent safety profile in GLP studies in 20 rat and canine with rapid clearance, at doses 500x the expected human therapeutic dose, similar to the 21 sequestrants BRIDION® and Captisol®; and (3) is highly effective and safe in non-human primates (NHP). 22 Our primary goal in this effort is to develop an IV formulation of CS-1103 for treatment of fentanyl intoxication 23 and obtain FDA approval. This will be achieved via completion of Specific Aims 1-5 (UG3) and 6-9 (UH3): 24 Aim 1 will complete a pre-IND meeting with FDA for IV CS-1103. Aim 2 will establish the safety/toxicology 25 profile of IV CS-1103 in the presence of fentanyl, in rat. Aim 3 will demonstrate that IV CS-1103 lowers the level 26 of fentanyl in a dose-dependent manner, in rat. Aim 4 will submit IND for IV CS-1103. Aim 5 will establish the 27 safety/dose level of IV CS-1103, in the presence of fentanyl, in a Phase 1b clinical trial. Aim 6 will determine 28 effective clinical dose of CS-1103 to treat fentanyl intoxication in a Phase 2a clinical trial. Aim 7 will demonstrate 29 efficacy of IV CS-1103 in lowering the level of fentanyl and restoring respiration, in a pivotal Phase 2b trial. Aim 30 8 will submit NDA for IV CS-1103. Aim 9 will perform IND-enabling studies for CS-1103 suitable for IM 31 injection and/or IN administration. Aim 9 will be completed using our own funds, to expand use to field settings.

1 项目概要 2 迫切需要一种能够快速灭活并去除芬太尼的治疗方法 3 身体。正如诺拉·沃尔科 (Nora Volkow) 博士所说，“尽管有纳洛酮，而且服用过量，芬太尼导致的死亡仍在增加。 4 需要多次服用纳洛酮。这是一场全国性的危机，每年有超过 73,000 人因服药过量死亡，并且超过 300 万人患有阿片类药物使用障碍，纳洛酮会在短时间内阻断 mu-阿片类药物受体。 6 不影响体内芬太尼的水平，这会导致重新麻醉 A 单剂量治疗。需要7立即恢复呼吸并最大限度地从体内清除芬太尼 8率，肾小球滤过率（GFR），消除再麻醉的可能性。 9 我们的治疗剂 CS-1103 的作用与纳洛酮不同，可以满足这一需求。注射 10 次后，CS-1103 与血液中的芬太尼结合，迅速逆转其作用，并显着增加 11 在小型和大型动物模型中，芬太尼进入尿液的清除率接近 GFR。 12 证明 CS-1103 可有效对抗合成阿片类药物（从芬太尼到卡芬太尼），恢复 13 2-3 分钟内呼吸，1 分钟内逆转肌肉僵硬，防止致命剂量后重新麻醉 14 卡芬太尼，并迅速降低体内阿片类药物水平此外，CS-1103 会导致较温和的阿片类药物。 15.与纳洛酮相比戒断效果好，且不干扰纳洛酮的活性。 16 我们目前正在开发 IV CS-1103，用于治疗滥用药物引起的急性中毒，包括 17 甲基苯丙胺我们已经完成了所有必需的非临床研究，并预计完成第一个- 2023 年中期进行 18 项人体 1a 期临床试验根据迄今为止的结果，我们认为 1a 期具有较高的临床试验效果。 19 成功的可能性，因为 CS-1103：(1) 是一种一次性药物；(2) 在 GLP 研究中具有出色的安全性。 20只大鼠和犬可快速清除，剂量为预期人类治疗剂量的500倍，类似于 21 种螯合剂 BRIDION® 和 Captisol®；以及 (3) 对非人类灵长类动物 (NHP) 非常有效且安全。 22 我们这项工作的主要目标是开发用于治疗芬太尼中毒的 CS-1103 静脉注射制剂 23 并获得 FDA 批准这将通过完成具体目标 1-5 (UG3) 和 6-9 (UH3) 来实现： 24 目标 1 将与 FDA 完成 IV CS-1103 的 IND 前会议，目标 2 将确定安全性/毒理学。目标 3 中存在芬太尼的情况下 IV CS-1103 在大鼠中的 25 个曲线将证明 IV CS-1103 降低了水平。 26 芬太尼以剂量依赖性方式在大鼠中进行，目标 4 将提交 IV CS-1103 的 IND。 27 在存在芬太尼的情况下，IV CS-1103 的安全性/剂量水平将在 1b 期临床试验中确定，目标 6。 2a 期临床试验将证明 CS-1103 治疗芬太尼中毒的 28 个有效临床剂量。 29 在一项关键的 2b 期 Aim 试验中，IV CS-1103 在降低芬太尼水平和恢复呼吸方面的功效。 30 8 将提交 IV CS-1103 的新药申请 (NDA)，目标 9 将进行适用于 IM 的 CS-1103 IND 启用研究。 31 注射和/或 IN 管理将使用我们自己的资金完成，以扩大使用范围。