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

项目摘要/摘要 2021年，超过8万美国人死于芬太尼和其他高效阿片类药物。新技术的出现 芬太尼等非法、高效的合成阿片类药物是导致最近阿片类药物激增的关键因素。 相关死亡率，自2016年以来增加了十倍。而MU阿片受体(MOR)拮抗剂纳洛酮 作为一种阿片类过量解毒剂，纳洛酮被证明是无价的，作用时间非常短(一半) 寿命约1小时)，对较新的长效阿片类药物，包括芬太尼(半衰期约7-10小时)效果较差。 这导致了一种高度致命且日益普遍的现象，称为“重新矿化”，即 用纳洛酮苏醒的过量患者从体内残留的芬太尼重新进入过量状态。 为了对抗再矿化，必须反复给予纳洛酮，而且剂量要大得多。虽然通常 可在医院内实现的再区域化，在医疗环境之外通常不被识别或监控 并可能导致意外死亡。开发一种长效MOR拮抗剂是一种关键的、尚未得到满足的需求 通过提供12-24小时的保护以允许阿片类药物水平下降来防止再电离化的配方 低于危险水平。 该项目目标是推进CP216的开发，这是一种新型的长效纳洛酮制剂， 利用创新的设计，通过组合免费的 形成纳洛酮即刻生效，微囊化纳洛酮持续保护。这是一项新的 这一提法在农村地区将特别有用，因为那里获得紧急医疗服务的机会经常被推迟， 或被武器化阿片类药物毒死的战士，在运送到 绝对的医疗护理。 使用大剂量或频繁剂量的纳洛酮或纳美芬来解决再矿化的其他尝试有限 对高效力阿片类药物的保护，并可诱导阿片类药物沉淀性戒断(POW) 依赖。战俘是一种严重的、可能危及生命的疾病，因此导致一些 服药过量患者拒绝继续纳洛酮治疗后抢救。还有其他一些化学修饰的努力 纳洛酮面临重大的监管和技术风险。Consegna的药物(CP216)可通过 加速的505(B)(2)调控通路，根据最近的研究，不太可能诱发POW和 因此会在服药过量患者中获得更多的接受。 Consegna相信，这个项目将对公共卫生产生积极影响，导致第一个安全和 有效的产品，可完全解决重碳化问题。

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.