Over the past decade, rates of opioid use among the general population has continued to rise in the United States. This astounding increase in opioid use has resulted in the government declaring a public health emergency in 2017. Compounding the problem, a concurrent rise in opioid use among pregnant females has resulted in a massive increase in infants born suffering from opioid withdrawal, termed 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. A normal infant averages 2.1 days of hospital care post-birth costing $3,500, whereas an infant born with NOWS averages 16.9 days of inpatient care costing $66,700. Currently, there are no FDA-approved medications available for treatment of NOWS. US WorldMeds (USWM) has developed lofexidine in collaboration with NIDA for the treatment of opioid withdrawal in adults, and anticipates possible Food and Drug Administration (FDA) approval for this use in May 2018. USWM now proposes to extend this successful co-development program through investigation of the safety and efficacy of lofexidine in NOWS. This application proposes a strategic alliance between USWM and the National Institute on Drug Abuse (NIDA) to complete development and registration prerequisites prior to initiation of clinical assessment of lofexidine in the neonatal patient population. The FDA has requested that USWM develop and establish safety information on lofexidine for neonate patient use. Initial requirements for registration of lofexidine for pediatric use are clearly defined and agreed upon with the FDA and include a total of five nonclinical studies in animals, seven clinical studies, and commitment to developing a pediatric specific formulation. The overall goal of this project is to develop a strategic alliance with NIDA and leverage this partnership to accelerate the development of the pediatric lofexidine program, with specific emphasis on the activities relevant for NOWS development. The research strategy in this proposal specifically targets the FDA requested development of lofexidine for NOWS treatment and will be supported by: 1) the development, scale up, and clinical trial material production of a neonatal-appropriate lofexidine formulation (Specific Aims 1 and 5), 2) completion of pivotal nonclinical studies to establish safety margins in nonclinical juvenile rodent models considered appropriate to assess safety related to early brain development and general toxicity (Specific Aims 2, 3, and 4), and 3) completion of a comparative bioavailability study with adult and pediatric formulations in normal healthy adult volunteers (Specific Aim 6).

Public Health Relevance

The nation?s opioid epidemic was declared a public health emergency in 2017 and is 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 pharmacologic interventions for the treatment of NOWS, resulting in medical reliance on off-label use of medications such as opioids and benzodiazepines to manage distressing symptoms in withdrawing infants; but these medications are not formulated for pediatric use and therefore are administered with ingredients not recommended for neonates which are associated safety concerns and have not been well studied to characterize benefits and dosing for this use. USWM intends to investigate lofexidine, a non-opioid medication, which has initially developed for opioid withdrawal in adults, as a potential first line-therapy in NOWS patients that could limit administration of current off label treatments: the initial development steps include formulation of a pediatric-appropriate dosage form, completion of nonclinical studies to inform safety, and an initial clinical study in adults to compare blood levels between the pediatric and adult formulations.

National Institute of Health (NIH)
National Institute on Drug Abuse (NIDA)
Research Project (R01)
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Special Emphasis Panel (ZDA1)
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Kline, Richard
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US Worldmeds, LLC
United States
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