I-Corps Project plan for:STTR Phase I Development of therapeutics to treat fentanyl overdose using a validated animal model

项目摘要 根据疾病控制中心(CDC)的数据，合成阿片类药物目前是 在美国，过量死亡的常见原因，而海洛因和处方阿片类药物死亡 自2017年以来大幅下降。尽管纳洛酮的使用范围很广，但死于 芬太尼和芬太尼类似物(F/FA)继续上升，同时有越来越多的报道 F/FA对纳洛酮的抗性。大剂量快速注射F/FA可引起以下方面的呼吸道阻塞 声带关闭(VCC)和严重胸壁僵硬(CWR)在2分钟内，影响 持续10分钟，似乎对纳洛酮有抵抗力。相比之下，吗啡- 衍生鸦片类药物(如海洛因)会导致呼吸抑制和轻微的肌肉僵硬，即 对纳洛酮有反应，但尚不知道会在人类中引起VCC。这暗示着截然不同 F/FA诱导VCC与吗啡诱导VCC的药理学机制比较 Mu阿片受体介导的呼吸抑制。为了支持这一假设， 我们公布的药理数据显示F/FA，但不是吗啡或 纳洛酮对F/FA的脑脂浓度模型有亲和力。此外，我们还有 在我们的动物模型中显示，这可能调节这些F/FA诱导的效应。入内 体外数据包括可能与人体生理相关的F/FA浓度，基于 在现有条件下，芬太尼诱导的这些效应对大剂量纳洛酮具有抵抗力，可能涉及 这些非现场受体靶标。这一初步数据表明，有效的 过量用药的治疗需要一种重新概念化根本原因的生物模型 除呼吸抑制外，F/FA还包括VCC。目前没有联邦政府 药品监督管理局开发了一种新的治疗方法，专门针对F/FA过量。 在i-Corp项目下，该团队将寻求验证或修改其关于 市场、目标客户和关键市场需求。

Project Summary According to the Centers for Disease Control (CDC), synthetic opioids are currently the most common cause of overdose death in the U.S, while heroin and prescription opioid deaths have decreased significantly since 2017. Despite the widespread availability of naloxone, deaths from fentanyl and fentanyl analogues (F/FA) continue to rise in parallel with increasing reports of F/FA resistance to naloxone. High doses of rapidly injected F/FA cause airway obstruction from vocal cord closure (VCC) and severe chest wall rigidity (CWR) within 2 minutes, effects that persist for up to 10 minutes and appear to be resistant to naloxone. In contrast, morphine- derived opiates (e.g. heroin) cause respiratory depression and mild muscle rigidity that is responsive to naloxone but are not known to cause VCC in humans. This suggests distinct pharmacological mechanisms underlying F/FA-induced VCC, compared to morphine-induced respiratory depression mediated by mu opioid receptors. In support of this hypothesis, off-site targets our published pharmacological data demonstrate F/FA, but not morphine or naloxone, have affinity for models of brain lipid concentrations for F/FA. Additionally, we have demonstrated in our animal model that that may regulate these F/FA-induced effects. The in vitro data include F/FA concentrations that may be physiologically relevant to humans, based on available these fentanyl-induced effects are resistant to high dose naloxone and may involve these off-site receptor targets. This preliminary data suggests the development of effective therapies for overdose require a biological model that re-conceptualizes the underlying causes of F/FA to include VCC, in addition to respiratory depression. There is currently no Federal Drug Administration development of a new class of therapeutics, specific to F/FA overdose. Under the I-Corp project, the team will seek to validate or modify its hypotheses regarding the market, target customers, and critical market need.