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

Advent Therapeutics（Advent）是一家专注于重新配制和优化递送的新方法的生物技术公司 已证明有效的传统药物，以解决特定服务不足和孤儿患者未满足的医疗需求 人口数量。Advent正在开发其专有的、优化的水溶性维生素A气雾剂配方 （vitA）棕榈酸酯，用于向早产儿非侵入性（吸入）递送，以解决vitA缺乏症（VAD），和 预防支气管肺发育不良（BPD），其最严重和昂贵的并发症。预防BPD是 IIB/SMA阶段申请的重点和本FOA中特别关注的NHLBI主题，RFA-HL-23-008。 我们将建立在非常重要的数据支持我们的第一/第二阶段SBIR奖与我们的创新 吸入的维生素A制剂：1）避免了侵入性肌内（IM）注射和吸收的缺点 目前口服形式的局限性，克服常规NICU使用的重大障碍，和2）提供直接- 靶器官给药以提高疗效-我们的体内数据显示， 减轻高氧肺损伤（在我们的BPD动物模型中），同时提供足够的全身递送， 按照研究策略和我们最近的出版物（47）中的讨论来治疗VAD。 在海港-加州大学洛杉矶分校医学中心的Virender Rehan博士的合作下，我们已经完成了第一阶段的所有工作， 具体目标和正在结束第二阶段的目标，证明吸入维生素A：1）刺激肺成熟 （显示视黄醇受体、表面活性剂蛋白和磷脂的上调的肺生物标志物的测定 合成，以及成熟生物标志物，同时提高血清维生素A水平，类似于IM给药）; 2)显著（与IM相比）降低高氧肺组织损伤（肺组织组织形态计量学评估和 肺损伤生物标志物的减少）;和3）保留肺功能（初步的长期PFT数据）。 在IIB期，我们将进一步完善吸入维生素A的剂量策略，以减轻高氧肺损伤（BPD 预防），通过研究表征良好的早产羔羊BPD模型， 与IND使能活动准备好开始在有风险的早产儿中进行首次人体临床研究 BPD的发展。IIb期的具体目标是：1：优化雾化维生素A的给药方案 用于减轻早产羔羊BPD模型中的高氧肺损伤，重点是“新生儿”（急性 阶段）时间范围内，并且还在较长期（慢性期）进入“成年期”，评估类似的生物标志物， 根据I/II期进行形态学和PFT评价。目标2：进行药物生产开发 并在严格的GLP和GMP控制下扩大我们的配方。目标3：开展GLP毒理学 在小型（大鼠）和大型（犬）物种中进行研究，以支持临床准备。衡量成功的标准将是 生成数据，支持进一步开发我们用于预防BPD的新型非侵入性疗法（以及 治疗VAD），包括满足足够的CMC要求以进入临床的vitA制剂， 并完成GLP毒理学研究，显示在高危早产儿中进行的首次人体研究具有充分的安全性。

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.