343 - Developing Novel Drug Candidates In An Ovine Model Of Neonatal Hypoxic-Ischemic Encephalopathy - An Overview Of Neurobehavioral Outcomes

Poster Number: 343
Publication Number: 343.2923

Background: Perinatal asphyxia resulting in neonatal hypoxic-ischemic encephalopathy (HIE) is the leading cause of neonatal morbidity and mortality worldwide, accounting for ~1 million deaths. While therapeutic hypothermia is the standard of care in high-income countries, it’s efficacy is less notable in low and middle-income countries. This study summarizes the neurobehavioral outcomes of a novel drug development pipeline investigating multiple therapeutic agents in an ovine model of neonatal HIE.

Objective: This study summarizes the neurobehavioral outcomes of a novel drug development pipeline investigating multiple therapeutic agents in an ovine model of neonatal HIE.

Design/Methods: Asphyxia was induced in near term lambs (141-143 days gestation) via umbilical cord occlusion. Lambs were randomly assigned to receive the study drug or placebo perinatally. They were then assessed over a 6-day period to determine neurodevelopmental outcomes including motor function, activity at rest, and ability to feed. The severity of impairment was classified based on a composite score
from motor function, feeding and activity into normal, mild, moderate and severe group. The researchers performing all experiments, including injury model, providing post-injury care, and assessing neurobehavioral outcomes were blinded to group assignment until all measurements have been collected. Mixed-effects analysis was done for multiple comparisons to pooled placebo lambs. Differences were considered significant at p  < 0.05.

Results: We studied lambs that were treated with azithromycin, low- and high-dose caffeine, THDG3, clemastine and combined azithromycin and caffeine. Overall, perinatal caffeine administration demonstrated greatest benefit: ability to feed on Day 2 (p=0.0256) and increased activity on Day 1 (p=0.0034) and 2 (p=0.0391). A higher dose, as well as combined postnatal caffeine and azithromycin administration, along with THDG3, demonstrated significant toxicity and were discontinued early.

Conclusion(s): Perinatal caffeine administration provides significant improvement in neurodevelopmental outcomes in an ovine model of neonatal HIE. Our drug development platform enables development of therapeutic agents particularly targeting the low- and middle-income setting where therapeutic hypothermia is not the standard of care and earlier treatment approaches targeting the fetus in utero may be necessary to improve outcomes.