IND-enabling development of a long-duration antagonist to treat opioid overdose

能够开发长效拮抗剂来治疗阿片类药物过量的 IND

• 批准号: 10786015
• 负责人: Lawrence J Zana
• 金额: $ 133.08万
• 依托单位: CONSEGNA PHARMA, INC.
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-15 至 2026-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10786015
• 关键词: Acceleration; Acute; Address; Advanced Development; Agitation; American; Animals; Antidotes; Applications Grants; Canis familiaris; Cardiovascular system; Caring; Cessation of life; Chemicals; Clinical; Clinical Research; Complication; Cyclic GMP; Dangerousness; Data; Dehydration; Delirium; Development; Documentation; Dosage Forms; Dose; Drops; Drug Delivery Systems; Drug Kinetics; Drug Packaging; Electrolytes; Emergency medical service; Encapsulated; Excretory function; FDA approved; Fentanyl; Formulation; Future; Goals; Half-Life; Hospitals; Hour; Individual; Intellectual Property; Investigational Drugs; Investigational New Drug Application; Legal patent; Life; Medical; Metabolism; Monitor; Naloxone; Opiate Addiction; Opioid; Opioid Antagonist; Outcome; Overdose; Overdose reduction; Overdose reversal; Patients; Pharmaceutical Preparations; Phase; Poison; Poisoning; Procedures; Process; Production; Public Health; Pulmonary Edema; Regulatory Pathway; Research Design; Residual state; Risk; Sales; Secure; Shapes; Small Business Innovation Research Grant; Symptoms; Temperature; Testing; Therapeutic; Toxicology; United States National Institutes of Health; Ventilatory Depression; Vomiting; Work; Writing; antagonist; canine model; commercialization; design; efficacy study; first responder; in vivo; innovation; manufacture; manufacturing process; manufacturing scale-up; meetings; mortality; mu opioid receptors; nalmefene; novel; opioid overdose; opioid withdrawal; particle; pre-Investigational New Drug meeting; prevent; programs; research and development; rural area; safety study; synthetic opioid; warfighter; weapons

PROJECT SUMMARY / ABSTRACT More than 80,000 Americans died in 2021 from fentanyl and other high-potency opioids. The emergence of illicit, highly potent synthetic opioids such as fentanyl is a key contributing factor to the recent spike in opioid- related mortality, increasing ten-fold since 2016. While the mu opioid receptor (MOR) antagonist naloxone has proven invaluable as an opioid overdose antidote, naloxone suffers from a very short duration of action (half- life ~1 hour) and is less effective against newer, longer-acting opioids, including fentanyl (half-life ~7-10 hours). This leads to a highly lethal and increasingly prevalent phenomenon known as “renarcotization,” whereby an overdose patient revived with naloxone re-enters an overdose state from residual fentanyl in the body. To counter renarcotization, naloxone must be given repeatedly and at significantly higher doses. While usually achievable in a hospital, renarcotization is often not recognized or monitored for outside of a medical setting and may lead to unexpected death. A critical, unmet need exists to develop a long-acting MOR antagonist formulation that prevents renarcotization by providing 12-24 hours of protection to allow opioid levels to drop below dangerous levels. The objective of this project is to advance development of CP216, a novel, long-acting naloxone formulation that utilizes an innovative design to address both primary and secondary overdose through a combination of free form naloxone for immediate effect and microencapsulated naloxone for sustained protection. This new formulation will be especially useful in rural areas, where access to emergency medical services is often delayed, or for Warfighters poisoned by weaponized opioids that need sustained protection while transported to definitive medical care. Other attempts to address renarcotization using high or frequent doses of naloxone or nalmefene have limited protection for high-potency opioids and can induce precipitated opioid withdrawal (POW) in those with opioid dependence. POW is a severe and potentially life-threatening condition and for this reason causes some overdose victims to refuse continued naloxone treatment after rescue. Still other efforts to chemically modify naloxone are subject to significant regulatory and technical risk. Consegna’s drug (CP216) is approvable through the accelerated 505(b)(2) regulatory pathway and is, according to recent studies, unlikely to induce POW and would therefore gain more acceptance among overdose patients. Consegna believes this project will have a positive impact on public health by leading to the first safe and effective product to completely address renarcotization.

项目摘要/摘要 2021年，超过8万名美国人死于芬太尼和其他高效阿片类药物。的出现 非法的、强效的合成阿片类药物，如芬太尼，是最近阿片类药物激增的一个关键因素， 相关死亡率自2016年以来增加了10倍。而μ阿片受体（莫尔）拮抗剂纳洛酮具有 作为阿片类药物过量解毒剂，纳洛酮被证明是非常宝贵的，其作用持续时间非常短（半小时）， 寿命约1小时），对更新，长效阿片类药物，包括芬太尼（半衰期约7-10小时）有效性较低。 这导致了一种被称为“重新毒品化”的高度致命和日益普遍的现象， 用纳洛酮复苏的过量患者由于体内残留的芬太尼而重新进入过量状态。 为了对抗再动脉化，必须反复给予纳洛酮并以显著更高的剂量给药。虽然通常 在医院中可以实现，但在医疗环境之外， 可能导致意外死亡存在开发长效莫尔拮抗剂的关键的未满足的需求 通过提供12-24小时的保护以使阿片样物质水平下降来防止再麻醉的制剂 低于危险水平。 该项目的目的是推进CP 216的开发，CP 216是一种新型长效纳洛酮制剂， 采用创新设计，通过结合免费的 形成纳洛酮的即时效应和微囊化纳洛酮的持续保护。这个新 配方在农村地区特别有用，因为农村地区获得紧急医疗服务的机会往往受到延误， 或被武器化阿片类药物中毒的战士，在运送到 明确的医疗护理。 使用高剂量或频繁剂量的纳洛酮或纳美芬来解决再动脉化的其他尝试有限 保护高效阿片类药物，并可诱导阿片类药物戒断（POW） 依赖战俘是一种严重的和潜在的威胁生命的条件，并因此导致一些 过量的受害者拒绝继续纳洛酮治疗后抢救。还有其他化学修饰的努力 纳洛酮存在重大监管和技术风险。Consegna的药物（CP 216）通过 加速505（B）（2）调节途径，根据最近的研究，不太可能诱导POW， 因此会在过量用药的患者中获得更多的接受。 Consegna认为，该项目将对公共卫生产生积极影响， 有效的产品，以完全解决再麻醉。