656 - Exploring Citrate-Functionalized Manganese Oxide Nanoparticles as a Supportive Therapy in Term Neonates at Risk of ABE: A Compassionate Use Trial

Publication Number: 1633.656

Asim K. mallick, NRS Medical College and Hospital, Kolkata, West Bengal, India; Aniruddha Adhikari, University of California, Los Angeles, Mobile, CA, United States; Vinod K.. Bhutani, Stanford University School of Medicine, Stanford, CA, United States

Background: Severe neonatal hyperbilirubinemia (SHB) remains a critical ethical and clinical challenge, particularly in marginalized communities with limited access to phototherapy and exchange transfusion (ExTx). Our previous preclinical rodent studies demonstrated the safety and efficacy of a single dose of citrate-functionalized tri-manganese tetrahydrate (C-Mn3O4) nanoparticles to reverse SHB.

Objective: Our compassionate prescription of this experimental agent resulted in an unplanned comparative dataset even though its use was not yet approved for clinical testing.

Design/Methods: Parents of full-term newborns hospitalized for SHB, who were receiving phototherapy in accordance with AAP guidelines and considered at risk for acute bilirubin encephalopathy, were invited to participate in a compassionate use protocol involving an experimental drug. A retrospective cohort of 207 neonates was divided into two arms: (i) experimental agent plus phototherapy, and (ii) phototherapy alone. Primary outcomes included neonatal mortality, phototherapy duration, and need for exchange transfusion (ExTx). Secondary outcomes assessed adverse events and post-discharge status.

Results: In 207/216 eligible neonates, 170 received C-Mn3O4 (Phase I) and 37 did not (Phase II). Mortality rates were markedly lower in Phase I compared to Phase II (1.2% vs. 16.2%), reflecting a 94% reduction in risk with Odds Ratio = 0.06 (95% CI:0.01-0.26) [Figure 1a]. The Relative Risk (RR) was 0.07 (95% CI:0.02-0.31), Absolute Risk Reduction (ARR) 15.0% (95% CI:2.1%-28.0%) and a Number Needed to Treat (NNT) of 7 (95% CI:3-20). The need for ExTx was significantly reduced, 17.1% of Phase I neonates versus 81.1% in Phase II (p < 0.0001, 2 (1) =24.8) [Figure 1b]. Duration of phototherapy was substantially shorter among treated infants (18.0 ± 9.8 h versus 57.4 ± 20.7 h with mean difference of -39.4 h (95% CI: -45.2 to -33.6), p< 0.0001), who were 13 times more likely to discontinue therapy (Hazards Ratio = 12.9; 95% CI: 6.8-24.4; p < 0.0001). In the absence of treatment, total serum bilirubin (TSB) levels rebounded following ExTx (p < 0.05). No significant adverse events were observed.

Conclusion(s): Our ethically constrained observations revealed that the compassionate-use of adjunctive C-Mn3O4 significantly enhanced the effectiveness of phototherapy, leading to marked reductions in neonatal mortality, phototherapy duration, and the need for ExTx among infants with SHB. These benefits were particularly pronounced in neonates with glucose-6-phosphate dehydrogenase (G6PD) deficiency.

Effects of the nanodrug on neonatal mortality and exchange transfusion (ExTx) frequency.
a) Neonatal mortality. The nanodrug treated cohort comprises infants from Phase IA (n = 124) and Phase IB (n = 46). Both the deaths in Phase IA were attributable to congenital cardiac anomalies and unrelated to bilirubin toxicity, and no deaths occurred in Phase IB. In the phototherapy-only cohort (phase III, n = 37), six deaths occurred, all secondary to bilirubin encephalopathy. b) ExTx frequency. Statistical comparison was restricted to Phase IB and Phase II cohorts with identical inclusion criteria and the AAP 2022 treatment guidelines. In the no nanodrug group (Phase II), four out of five infants died before ExTx could be performed. Of the 33 remaining infants, one required a second ExTx. For our calculations, each infant was counted only once.