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