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).

PROJECT NARRATIVE: The nation’s opioid epidemic has remained a public health emergency since 2017, marked by high rates of opioid use and abuse among adults and a correlated rising incidence of Neonatal Opioid Withdrawal Syndrome (NOWS) in infants exposed to opioids in utero. There are no FDA-approved pharmacotherapies for the treatment of NOWS to manage the distressing symptoms from the condition which results in reliance on off-label use of narcotic medications not formulated for use in neonates, containing ingredients which are not recommended in infants due to safety concerns and lacking well-studied dosing recommendations that adequately characterize the benefits and risks of treatment, particularly their effects on the developing brain. The proposed research program will complete manufacturing and clinical trial activities necessary to evaluate and support approval of a pediatric-appropriate formulation of lofexidine, a non-opioid medication approved for mitigation of opioid withdrawal symptoms in adults, as a first line-therapy in NOWS patients through 2 clinical trials to i) identify an optimal dosing regimen of lofexidine for treatment of NOWS and ii) evaluate the risks and benefits of its use in improving withdrawal symptoms, limiting infant exposure to other off-label narcotic medications and shortening the infant’s overall stay in the hospital.