Citrate-functionalized manganese oxide nanoparticles in neonates ≥35 weeks gestation at risk of acute bilirubin encephalopathy: a phase 1 observational trial.

BACKGROUND

Our previous preclinical rodent studies demonstrated the safety and efficacy of citrate-functionalized tri-manganese tetroxide (C-Mn3O4) nanoparticles to reverse severe neonatal hyperbilirubinemia (SHB).

AIM: Primary objective was to evaluate whether a single oral dose of the nanodrug could reduce neonatal mortality due to SHB and secondarily reduce the need for exchange transfusion (ExTx).

METHODS

The nanodrug was administered to neonates (gestational age ≥35 weeks) admitted for SHB undergoing phototherapy (per AAP-guidelines) and deemed risk for ABE following parental consent. Clinical outcomes, including neonatal mortality, ExTx use and phototherapy duration were compared to a cohort managed after the experimental drug's use was paused.

RESULTS

In 207/216 eligible neonates, 170 received nanodrug (Phase I) and 37 did not (Phase II). Mortality was 1.2% vs. 16.2%, respectively; 94% reduction (OR = 0.06). ExTx was needed in 17.1% vs. 81.1% (p < 0.0001). Phototherapy duration was shorter: mean = 18.0 ± 9.8 h vs 57.4 ± 20.7 h; difference -39.4 h (95% CI: -45.2 to -33.6; HR = 12.9; p < 0.0001), with treated neonates 13-fold more likely to discontinue therapy at any given point-of-time. No significant clinical adverse events were reported.

CONCLUSIONS AND RELEVANCE: Pilot observations suggest prescriptive adjunctive-use of C-Mn3O4 NPs reduced neonatal mortality, decreased ExTx need among neonates with SHB and augmented phototherapy efficacy by shortening its duration.

IMPACT: Citrate-functionalized manganese oxide nanoparticles augments phototherapy by reducing frequency of neonatal mortality, exchange transfusions, and phototherapy duration in SHB neonates at-risk for acute bilirubin encephalopathy. This experimental chemical agent is the only drug since tin-mesoporphyrin to demonstrate clinical efficacy to reverse hyperbilirubinemia in human neonates. Successful implementation of this agent, when proven through randomized controlled trials, could alleviate current treatment gaps for SHB in resource-constrained communities.