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

• 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
• 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

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个项目摘要 2迫切需要一种迅速停用并从中取出芬太尼的治疗性 3身体。正如Nora Volkow博士所说，“芬太尼的死亡尽管有纳洛酮，并且过量 4需要多种纳洛酮剂量。 5超过300万人患有阿片类药物使用障碍。纳洛酮在短时 6不影响体内芬太尼的水平，这可能导致肾脏化。单剂量疗法 需要7立即恢复呼吸，并以最大的可能 8速率，肾小球过滤率（GFR），消除了肾脏化的可能性。 9我们的治疗剂CS-11103的作用与纳洛酮的作用不同，它满足了这一需求。后 10注射CS-11103与芬太尼在血液中结合，迅速逆转其作用，并大大增加 11芬太尼清除尿液的速率是在GFR附近。在大小动物模型中，我们有 12证明CS-11103对合成阿片类药物有效，范围从芬太尼到carfentanil，恢复 在2-3分钟内呼吸13，在1分钟内逆转肌肉刚度 14 Carfentanil，并迅速降低体内阿片类药物水平。此外，CS-11103导致米勒阿片类药物 与纳洛酮相比，15戒断，不干扰纳洛酮的活性。 16我们目前正在开发IV CS-11103，以治疗由滥用药物引起的急性中毒 17甲基苯丙胺。我们已经完成了所有必需的非临床研究，并预计完成了第一项 在2023年中期的18阶段1A临床试验。基于迄今为止的结果，我们认为1A阶段有很高 19成功的概率，如CS-11103：（1）是一种使用药物； （2）在GLP研究中具有出色的安全性 20大鼠和犬的快速清除率，剂量为500倍，预期的人类治疗剂量类似于 21固剂Bridion®和Captisol®; （3）在非人类灵长类动物（NHP）中是非常有效且安全的。 22这项工作的主要目标是开发CS-11103的IV公式用于治疗芬太尼中毒 23并获得FDA批准。这将通过完成特定目标1-5（UG3）和6-9（UH3）来实现： 24 AIM 1将完成与FDA的IV CS-11103之前的预定会议。 AIM 2将建立安全/毒理学 25在大鼠存在芬太尼的情况下IV CS-11103的曲线。 AIM 3将证明IV CS-11103降低了水平 大鼠以剂量依赖性方式的芬太尼26。 AIM 4将向IV CS-11103提交IND。 AIM 5将确定 27在1B期临床试验中，在存在芬太尼的情况下，IV CS-11103的安全/剂量水平。 AIM 6将确定 28在2A期临床试验中，有效的CS-11103临床剂量以治疗芬太尼中毒。 AIM 7将证明 在一项关键的2B期试验中，29 IV CS-11103在降低芬太尼水平和恢复呼吸方面的效率。目的 30 8将向IV CS-11103提交NDA。 AIM 9将对适合IM的CS-11103进行辅助研究 31注射和/或管理。 AIM 9将使用我们自己的资金完成，以扩展到现场设置。