Development of Lofexidine as a First-line Non-Opioid Pharmacologic Treatment for Neonatal Opioid Withdrawal Syndrome

项目总结： 阿片类药物在普通人群中的滥用速度惊人地增加，导致了公众健康 自2017年以来一直处于紧急状态。阿片类药物使用障碍的显著上升广泛影响了美国人，包括 导致新生儿阿片类药物戒断或新生儿阿片类药物依赖的婴儿增加的孕妇 戒断综合症(NOWS)。NOWS疫情导致医疗费用大幅增加， 由于住院时间和所需护理水平的增加，给医疗保健系统带来了负担。2016年，一个 正常婴儿出生后平均3天的住院护理费用为15,000美元，而出生时患有NOWS的婴儿 平均16.4天的住院护理费用为70,000美元。目前，还没有FDA批准的药物 可用于治疗NOWS。目前的药物治疗方法依赖于阿片类药物的非标签使用 和其他特工。阿片类药物治疗导致NOWS婴儿持续住院时间延长 由于呼吸抑制的风险，安全观察的监测是必要的。 通过与NIDA的成功合作，USWM开发了用于缓解阿片戒断的洛非西定 成人的症状。美国食品和药物管理局(FDA)批准洛非西定片(LUCEMYRA®)用于 这一迹象出现在2018年5月。由于洛非西定预期可用于治疗阿片类药物戒断 在儿童方面，USWM已经启动了一项开发计划，评估洛非西定用于新生儿患者。首字母 开始洛非西定治疗NOWS的临床试验的要求已经与FDA达成一致，包括 非临床安全性研究，儿科专用制剂的开发，以及对 儿科制剂在健康成人体内的药代动力学(PK)。通过与NIDA的战略联盟， USWM已经完成或即将完成在NOWS启动临床测试的所有先决条件 预计将开始为当前的申请提供资金。USWM现在提议延长共同开发 计划通过调查洛非西定在NOWS中的安全性和有效性。 该项目的目标是开发洛非西定作为治疗NOWS的一线药物。使用 特征明确、安全有效的新生儿非阿片类药物配方有望减少 需要阿片类药物和/或减少阿片类药物剂量/疗程的患者，允许在较短的医院内进行更安全的治疗 留下来。拟议研究的范围包括化学、制造和控制(CMC)活动和 支持儿科制剂注册所需的临床开发计划，以缓解 NOWS患者的戒断症状。该方案的主要里程碑包括：i)技术转让 和支持晚期临床试验材料(CTM)生产的制造活动(UG3目标1)，ii)第一 NOWS中的新生儿PK和剂量-反应研究支持剂量选择和关键研究设计决策 (UG3 AIMS 2和3)，III)制造第三阶段CTM并完成CMC注册包(UH3 AIM 1)，以及iv)一项关键研究，以确定用于NOWS的洛非西定的安全性和有效性(UH3目标2和3)。

PROJECT SUMMARY: An alarming increase in the rate of opioid abuse among the general population has resulted in a public health emergency since 2017. The striking rise in opioid use disorder has affected Americans broadly, including pregnant women with a resulting increase in infants born suffering from opioid withdrawal or Neonatal Opioid Withdrawal Syndrome (NOWS). The NOWS epidemic has led to significant increases in healthcare costs and burden on the healthcare system due to increased length of hospital stay and level of required care. In 2016, a normal infant averaged 3 days of hospital care post-birth costing $15,000, whereas an infant born with NOWS averaged 16.4 days of inpatient care costing $70,000. Currently, there are no FDA-approved medications available for treatment of NOWS. Current approaches to pharmacotherapy rely on the off-label use of opioids and other agents. Opioid therapy contributes to the extended hospitalization of NOWS infants as continuous monitoring for safety observations is necessary due to the risk of respiratory depression. Through a successful collaboration with NIDA, USWM developed lofexidine for the mitigation of opioid withdrawal symptoms in adults. The Food and Drug Administration (FDA) approved lofexidine tablets (LUCEMYRA®) for this indication in May 2018. Due to the anticipated utility of lofexidine for the treatment of opioid withdrawal in children, USWM has initiated a development program evaluating lofexidine for neonate patient use. Initial requirements to begin clinical trials of lofexidine for NOWS have been agreed upon with the FDA and include nonclinical safety studies, development of a pediatric-specific formulation, and an evaluation of the pharmacokinetics (PK) of the pediatric formulation in healthy adults. Through a strategic alliance with NIDA, USWM has completed or is on track to complete all prerequisites to initiate clinical testing in NOWS prior to the anticipated start of funding for the current application. USWM now proposes to extend the co-development program through investigation of the safety and efficacy of the new pediatric formulation of lofexidine in NOWS. The goal of this project is to develop lofexidine as a first-line medication for the treatment of NOWS. Use of a well-characterized, safe and effective neonatal formulation of a non-opioid therapy is expected to result in fewer patients requiring opioids and/or reduce opioid dose/duration, permitting safer treatment with shorter hospital stays. The scope of the proposed research includes chemistry, manufacturing and control (CMC) activities and the clinical development program required to support registration of the pediatric formulation for mitigation of withdrawal symptoms in patients with NOWS. Key milestones of the program include: i) a technology transfer and manufacturing activities to support late phase clinical trial material (CTM) production (UG3 Aim 1), ii) a first- in-neonate PK and dose-response study in NOWS to support dose selection and pivotal study design decisions (UG3 Aims 2 & 3), iii) manufacture of Phase 3 CTM and completion of the CMC registration package (UH3 Aim 1), and iv) a pivotal study to establish safety and efficacy of lofexidine for use in NOWS (UH3 Aims 2 & 3).