Advent Therapeutics Inc. (Advent) is a biotech company focusing on the development, reformulation and optimized delivery of legacy drugs to address serious unmet medical needs in the underserved neonatal and pediatric 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 associated serious complications such as bronchopulmonary dysplasia (BPD, the focus of our Phase I SBIR and this Phase II application), retinopathy of prematurity (ROP), and neonatal sepsis ? all costly complications with significant morbidity/mortality. Our innovative inhaled (non-invasively dosed) vitA formulation 1) avoids the drawbacks of invasive intramuscular (IM) injections and absorption limitations of current oral forms, overcoming significant hurdles to more frequent NICU utilization, and 2) provides direct-to-target-organ delivery for increased efficacy, with our Phase I in vivo data showing significant benefit over IM dosing in mitigating hyperoxic lung damage (our BPD animal model), while providing adequate systemic delivery to also treat VAD. In collaboration with Dr. Virender Rehan at Harbor-UCLA Medical Center, we have accomplished our Phase I Specific Aims, demonstrating that: 1) inhaled vitA stimulates lung maturation as demonstrated via assay of lung biomarkers showing upregulation of retinol receptors, surfactant protein and phospholipid synthesis, and maturation biomarkers while simultaneously raising serum vitA levels similar to IM dosing; and 2) inhaled vitA dramatically (vs IM) reduces hyperoxic lung tissue damage via examination of lung tissue histomorphometry and reduction of lung-injury biomarkers. In Phase II, we will further refine the inhaled vitA dosing strategy for mitigating hyperoxic lung damage in a step-wise approach by studying the well characterized pre-weaned rat model as in Phase I and then expanding our studies to a pre-term rabbit model, with lung maturation status more closely mimicking human preterm infant lung to allow for translation of our findings into the clinical. Phase II Specific Aims are: 1: Optimize the dosing regimen of aerosolized vitA for mitigating hyperoxic lung damage in our rat model for the ?neonatal? timeframe (acute phase) and long term sequalae into adulthood (chronic phase) using similar biomarkers and morphologic evaluation as per Phase I.
Aim 2 : Extend acute and chronic phase benefits of inhaled vitA to the premature rabbit model.
Aim 1 & 2 measures of success will be demonstration of improved lung maturation and mitigation of lung injury vs IM-dosed controls, with an ideal outcome of showing lung status similar to healthy normal controls.
Aim 3 : Optimize aerosol characterization/delivery (initial in vitro experiments done concurrent with Aim 1), and subsequently conduct in vivo IND-enabling toxicology/PK studies.
Aim 3 measures of success will be generation of data supporting further development of a potentially superior, non-invasive therapy for preventing BPD (and treating VAD), which will have significant clinical, financial, and societal implications.
The consequences of inadequately treated vitamin A deficiency (VAD) in premature neonates including increased risk for bronchopulmonary dysplasia (BPD), retinopathy of prematurity (ROP) and sepsis, are associated with poor clinical outcomes in these fragile patients and require costly long-term treatment. Advent Therapeutics is developing an aerosol formulation of its proprietary optimized, water miscible vitamin A palmitate (vitA) for non-invasive delivery of the drug to preterm infants, enabling dosing by inhalation and thus obviating the need for intramuscular (IM) injection, and allowing potential increased effectiveness by delivery directly to the lung (a direct-to-target-organ treatment for BPD), while simultaneously providing systemic vitamin A availability important for treating VAD and the other related complications. Dosing vitA by inhalation should overcome current hurdles limiting vitamin A supplementation use in the NICU, enabling much higher vitamin A utilization, thereby reducing risk and cost of BPD in preterm infants.