Development of medication for the treatment of respiratory depression due to opioid (prescribed or illicit) overdose/multidrug (polysubstance) overdose in a hospital or community setting.

开发用于治疗医院或社区环境中阿片类药物（处方或非法）过量/多种药物（多物质）过量导致的呼吸抑制的药物。

• 批准号: 10545511
• 负责人: Joseph V Pergolizzi
• 金额: $ 31.97万
• 依托单位: ENALARE THERAPEUTICS INC.
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10545511
• 关键词: Alcohols; Alfentanil; Analgesics; Animal Testing; Appearance; Behavior; Biological Availability; Blood; Bolus Infusion; Breathing; Carotid Body; Central Nervous System Depressants; Cessation of life; Chemicals; Clinic; Clinical; Clinical Research; Communities; Consumption; Continuous Infusion; Data; Development; Dose; Double-Blind Method; Drug Exposure; Drug Kinetics; Enrollment; Fentanyl; Formulation; Future; Half-Life; Hospitals; Human; Hypoxia; Injections; Intramuscular; Intravenous; Intravenous Bolus; Intravenous infusion procedures; Life; Medicine; Mental Depression; Modeling; Molecular; Naloxone; Narcotics; Neuraxis; Normal Range; Opioid; Overdose; Oxygen; Patients; Pharmaceutical Preparations; Pharmacodynamics; Phase; Placebo Control; Placebos; Plasma; Population; Process; Program Development; Protocols documentation; Randomized; Research; Respiration; Route; Running; Safety; Site; Stimulant; Therapeutic Agents; Therapeutic Effect; Therapeutic Equivalency; Toxic effect; Ventilatory Depression; Withdrawal; cohort; community setting; drug development; efficacy study; efficacy testing; healthy volunteer; human data; improved; large-conductance calcium-activated potassium channels; medical countermeasure; mimetics; mortality; novel; opioid overdose; opioid use; opioid user; pharmacokinetics and pharmacodynamics; phase 2 designs; polysubstance abuse; pre-clinical; preservation; real world application; respiratory; safety study; screening panel; sedative; simulation; stability testing; ventilation; Alcohols; Alfentanil; Analgesics; Animal Testing; Appearance; Behavior; Biological Availability; Blood; Bolus Infusion; Breathing; Carotid Body; Central Nervous System Depressants; Cessation of life; Chemicals; Clinic; Clinical; Clinical Research; Communities; Consumption; Continuous Infusion; Data; Development; Dose; Double-Blind Method; Drug Exposure; Drug Kinetics; Enrollment; Fentanyl; Formulation; Future; Half-Life; Hospitals; Human; Hypoxia; Injections; Intramuscular; Intravenous; Intravenous Bolus; Intravenous infusion procedures; Life; Medicine; Mental Depression; Modeling; Molecular; Naloxone; Narcotics; Neuraxis; Normal Range; Opioid; Overdose; Oxygen; Patients; Pharmaceutical Preparations; Pharmacodynamics; Phase; Placebo Control; Placebos; Plasma; Population; Process; Program Development; Protocols documentation; Randomized; Research; Respiration; Route; Running; Safety; Site; Stimulant; Therapeutic Agents; Therapeutic Effect; Therapeutic Equivalency; Toxic effect; Ventilatory Depression; Withdrawal; cohort; community setting; drug development; efficacy study; efficacy testing; healthy volunteer; human data; improved; large-conductance calcium-activated potassium channels; medical countermeasure; mimetics; mortality; novel; opioid overdose; opioid use; opioid user; pharmacokinetics and pharmacodynamics; phase 2 designs; polysubstance abuse; pre-clinical; preservation; real world application; respiratory; safety study; screening panel; sedative; simulation; stability testing; ventilation

ABSTRACT Respiratory depression from drug overdose, if untreated, can cause serious life-threatening complications, including respiratory arrest and death. Substance-induced respiratory depression from overdose of opioids, other central nervous system depressants such as sedatives and alcohol, and increasingly polysubstance abuse is a leading cause of mortality and has risen in parallel with the marked increase in narcotics consumption. ENA-001 is a therapeutic agent which stimulates ventilation – without reversing analgesic effects, or precipitating withdrawal – for treatment of patients with respiratory and central nervous system (CNS) depression due to opioid or polysubstance overdose in a hospital or community setting. It is a novel compound that is expected to be classified as a New Chemical Entity. The primary molecular mechanism underlying the ventilatory stimulant effects of ENA-001 appears to be functional inhibition of BK channels of the carotid bodies, thereby acting as a hypoxia-mimetic. ENA-001 has been administered to humans during four clinical studies, with a fifth underway. Following two ascending dose studies to establish a dosing range for IV infusion, a continuous infusion of ENA- 001 was shown to stimulate respiration in the presence of a strong opioid (alfentanil) while preserving the analgesic effects of alfentanil. ENA-001 maintained oxygen saturation and ETCO2 within normal range (P < 0.05, P < 0.01, respectively vs placebo) with greater MV than placebo (p < 0.01). The next stage in development is to characterize the efficacy of intramuscular (IM) and intravenous (IV) bolus injections (rapid dosing) as suitable routes of administration for suspected overdose in the clinic or community setting. In this proposal, Enalare will study the PK/PD and efficacy of IV bolus and IM ENA-001 in a population of healthy volunteers. Phase 1 is PK/PD studies using Model Informed Drug Development (MIDD) to identify initial IM and IV bolus dosing for Aim 2. The MIDD process will use existing PK and PD data from the multiple IV continuous infusion studies in humans, along with data from preclinical IM and IV bolus delivery models such as the recently completed IM bioavailability study and ongoing IM bioequivalence study, to determine dosing targets to achieve rapid attainment of effective plasma drug exposure, thus optimal therapeutic effects (efficacy), from bolus dosing. Phase 2 will be a Single Ascending Dose Study of the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of ENA-001 administered as IM and IV bolus injections. The study protocol is an 8-period ascending, repeated, single dose, safety and tolerability study comparing the effects of ENA-001 with placebo in 2 panels of screened healthy volunteers. Study periods will be conducted for IM (4-periods) and IV (4-periods) bolus injections, and will be randomized, double-blinded, and placebo-controlled. The information gained from this proposal will be used to define subsequent studies of efficacy in simulations of opioid-induced respiratory depression and will give ample information on the efficacy of IM and IV ENA-001 bolus injections on ventilation and mimics, as much as possible, real-life (i.e., street) conditions.

抽象的 药物过量的呼吸道抑郁症，如果未经治疗，可能会导致严重威胁生命的并发症， 包括呼吸逮捕和死亡。药物过量的药物诱导的呼吸抑制，阿片类药物， 其他中枢神经系统抑制剂，例如镇静剂和酒精，以及越来越多的多物质滥用 是死亡率的主要原因，并且与麻醉品消费量显着增加并行。 ENA-001是一种刺激通风的治疗剂 - 不反转镇痛作用或沉淀 提取 - 用于治疗呼吸道和中枢神经系统（CNS）抑郁症患者 在医院或社区环境中，Oopioid或多核酸固定会过量。这是一种新颖的化合物 被归类为新的化学实体。通气刺激剂的基础分子机制 ENA-001的影响似乎是对颈动脉体BK通道的功能抑制，从而充当 低氧模拟。在四项临床研究中，ENA-001已向人类施用，其中五分之一正在进行中。 经过两项升剂剂量研究以建立静脉输注的剂量范围，连续输注ENA- 001显示在存在强的阿片类药物（Alfentanil）的情况下刺激呼吸 阿芬太尼的镇痛作用。 ENA-001将氧饱和度和ETCO2保持在正常范围内（P < 0.05，p <0.01，分别与安慰剂大于安慰剂（p <0.01）。下一阶段发展 是将肌内（IM）和静脉内（IV）注射（快速给药）的效率表征为合适的 可疑在诊所或社区环境中涉嫌过量的行政途径。在此提案中，Enalare将 研究健康志愿者人群中IV大量和IM ENA-001的PK/PD和效率。第1阶段是 PK/PD研究使用模型知情药物开发（MIDD）来识别初始IM和IV剂量的剂量 2。MIDD过程将使用来自多个IV连续输注研究的现有PK和PD数据 人类，以及来自临床前IM和IV推注的数据，例如最近完成的IM 生物利用度研究和正在进行的IM生物等效性研究，以确定剂量目标以实现快速 从推注剂量中获得有效的血浆药物暴露，从而获得最佳的治疗作用（有效）。 第2阶段将是对安全性，耐受性，药代动力学和 ENA-001的药效学为IM和IV注射。研究方案是一个8周期 上升，重复，单剂量，安全性和耐受性研究，将ENA-001与安慰剂进行比较 在2个筛选的健康志愿者中。将针对IM（4周期）和IV（4个周期）进行研究期 注射剂，并将被随机，双盲和安慰剂对照。从中获得的信息 该建议将用于定义随后的阿片类药物诱导呼吸道模拟效率的研究 抑郁症并将提供有关IM和IV ENA-001注射效率的充分信息 和模仿现实生活（即街道）条件。