Aerosolized Vitamin A: Developing a Prevention for Hyperoxic Lung Injury and Bronchopulmonary Dysplasia, with Focus on Neonatal Lung Maturation

Advent Therapeutics (Advent) is a biotech focusing on novel approaches to reformulate and optimize delivery of legacy drugs with proven efficacy to address unmet medical needs of specific underserved and orphan patient populations. Advent is developing an aerosol formulation of its proprietary, optimized water miscible vitamin A (vitA) palmitate for non-invasive (inhaled) delivery to preterm infants to address vitA deficiency (VAD), and prevent bronchopulmonary dysplasia (BPD), its most serious and costly complication. Prevention of BPD is the focus of this Phase IIB/SMA application and a NHLBI topic of specific interest under this FOA, RFA-HL-23-008. We will be building on the very significant data supported by our Phase I/II SBIR award with our innovative inhaled vitA formulation that: 1) avoids the drawbacks of invasive intramuscular (IM) injections and absorption limitations of current oral forms, overcoming significant hurdles for routine NICU utilization, and 2) provides direct- to-target-organ delivery for increased efficacy- our in vivo data show significant benefit over IM dosing in mitigating hyperoxic lung damage (in our BPD animal model), while providing adequate systemic delivery to also treat VAD as discussed in the Research Strategy and in our recent publication (47). In collaboration with Dr. Virender Rehan at Harbor-UCLA Medical Center, we have completed all Phase I Specific Aims and are wrapping up Phase II Aims, demonstrating that inhaled vitA: 1) stimulates lung maturation (assay of lung biomarkers showing upregulation of retinol receptors, surfactant protein and phospholipid synthesis, as well as maturation biomarkers, while simultaneously raising serum vitA levels similar to IM dosing); 2) dramatically (vs IM) reduces hyperoxic lung tissue damage (assessment of lung tissue histomorphometry and reduction of lung-injury biomarkers); and 3) preserves pulmonary function (preliminary longer-term PFT data). In Phase IIB, we will further refine inhaled vitA dosing strategies for mitigating hyperoxic lung damage (BPD prevention) in a step-wise approach by studying the well characterized premature lamb BPD model and proceed with IND-enabling activities to be ready to begin first-in-man clinical studies in preterm infants at risk for development of BPD. Phase IIb Specific Aims are: 1: Optimization of the dosing regimen of aerosolized vitA for mitigating hyperoxic lung damage in a premature lamb BPD model, focusing on both the “neonatal” (acute phase) timeframe, and also over the longer term (chronic phase) into “adulthood”, assessing similar biomarkers, morphologic, and PFT evaluation as per Phase I/II. Aim 2: proceeding with drug manufacturing development and scale-up of our formulation under stringent GLP and GMP controls. Aim 3: conducting GLP toxicology studies in both small (rat) and large (dog) species to support clinic-readiness. Measures of success will be generation of data supporting further development of our novel non-invasive therapy for preventing BPD (and treating VAD), including a vitA formulation that meets adequate CMC requirements to proceed into the clinic, and completion of GLP toxicology showing adequate safety for first-in-man studies in at-risk preterm neonates.