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项目概要 2.迫切需要一种治疗剂，可以快速灭活并去除芬太尼。 三是身体。正如诺拉科罗夫博士所述，“尽管纳洛酮和过量使用， 4需要多次纳洛酮剂量。这是一个全国性的危机，每年有超过73，000例过量死亡， 5超过300万人患有阿片类药物使用障碍。纳洛酮短时间阻断μ阿片受体 6而不影响体内芬太尼的水平，这可能导致再麻醉。单剂量治疗 需要立即恢复呼吸并尽可能最大限度地将芬太尼从体内清除 8率，即肾小球滤过率（GFR），排除了再结节化的可能性。 9我们的治疗剂CS-1103与纳洛酮的作用不同，可以满足这一需求。后 注射后，CS-1103与血流中的芬太尼结合，迅速逆转其作用， 11芬太尼清除到尿液中的速率接近GFR。在小型和大型动物模型中，我们 12证明CS-1103对合成阿片类药物有效，从芬太尼到卡芬太尼， 13呼吸在2-3分钟内，扭转肌肉强直在1分钟内，防止再神经化后，致死剂量的 14卡芬太尼，并迅速降低体内阿片类药物的水平。此外，CS-1103引起较温和的阿片类药物 15戒断相比，纳洛酮，并不干扰纳洛酮的活性。 16我们目前正在开发静脉注射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要求的非临床研究，并预计完成第一个- 于二零二三年年中进行18项人体1a期临床试验。根据迄今为止的结果，我们认为第1a阶段具有很高的 成功概率为19，因为CS-1103：（1）是一次性药物;（2）在GLP研究中具有出色的安全性 20只大鼠和犬，在剂量为预期人体治疗剂量的500倍时快速清除，与 螯合剂BRIDION®和Captisol®;和（3）在非人灵长类动物（NHP）中高度有效和安全。 22我们在这项工作中的主要目标是开发CS-1103的IV制剂用于治疗芬太尼中毒 23、获得FDA批准。这将通过完成具体目标1-5（UG 3）和6-9（UH 3）来实现： 24 Aim 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 图25在芬太尼存在下IV CS-1103在大鼠中的分布。目标3将证明IV CS-1103降低了 26芬太尼的剂量依赖性的方式，在大鼠。Aim 4将提交IV CS-1103的IND。目标5将建立 在1b期临床试验中，在芬太尼存在下IV CS-1103的安全性/剂量水平。目标6将决定 28有效临床剂量的CS-1103在2a期临床试验中治疗芬太尼中毒。Aim 7将展示 29 IV CS-1103在降低芬太尼水平和恢复呼吸方面的疗效，在关键的2b期试验中。目的 30 8将提交IV CS-1103的NDA。Aim 9将对适用于IM的CS-1103进行IND使能研究 31注射和/或IN施用。目标9将使用我们自己的资金完成，以扩大使用到外地设置。