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

Coment Treateutics(Advent)是一种生物技术，专注于重新配制和优化给药的新方法 已证实有效的传统药物，以满足特定服务不足和孤儿患者未得到满足的医疗需求 人口。Coment正在开发一种气雾剂配方，该配方是其专有的、优化的水可混溶维生素A (维生素A)棕榈酸酯用于早产儿非侵入性(吸入)分娩，以解决维生素A缺乏症(VAD)，以及 预防其最严重和最昂贵的并发症--支气管肺发育不良(BPD)。预防BPD是 这一阶段IIB/SMA应用的重点和本FOA项下特别感兴趣的NHLBI主题，RFA-HL-23-008。 我们将以我们的第一阶段/第二阶段SBIR奖支持的非常重要的数据为基础，通过我们的创新 吸入型维生素A配方：1)避免了侵入性肌肉注射和吸收的缺点 当前口头形式的局限性，克服了常规NICU使用的重大障碍，以及2)提供了直接- 靶向器官递送以提高疗效--我们的体内数据显示，与肌注剂量相比， 减轻高氧性肺损伤(在我们的BPD动物模型中)，同时提供足够的全身给药 如《研究战略》和我们最近的出版物(47)中所讨论的那样对待VAD。 在与港湾-加州大学洛杉矶分校医疗中心的Virender Rehan博士的合作下，我们已经完成了所有阶段 特定的目标和正在结束的第二阶段目标，表明吸入维生素A：1)刺激肺成熟 (检测显示视黄醇受体、表面活性蛋白和磷脂上调的肺生物标志物 合成，以及成熟生物标志物，同时提高血清维生素A水平，类似于肌注剂量)； 2)显著(Vs IM)减少高氧性肺组织损伤(肺组织形态计量学评估和 减少肺损伤生物标志物)；以及3)保护肺功能(初步的较长期PFT数据)。 在IIB阶段，我们将进一步完善吸入维生素A的剂量策略，以减轻高氧性肺损伤(BPD 预防)，通过研究具有良好特征的早产儿bpd模型并继续进行 随着支持IND的活动准备好开始对有风险的早产儿进行首例人临床研究 BPD的发展。第二阶段的具体目标是：1：优化雾化维生素A的给药方案 用于减轻早产羔羊BPD模型中的高氧性肺损伤，重点是“新生儿”(急性 阶段)时间框架，以及进入“成年期”的较长期(慢性阶段)，评估类似的生物标记物， 根据阶段I/II进行形态和PFT评估。目标2：继续进行药物制造开发 并在严格的GLP和GMP控制下扩大我们的配方。目标3：进行GLP毒理学研究 对小型(老鼠)和大型(狗)物种的研究，以支持临床准备。衡量成功的标准将是 数据的生成支持我们预防BPD的新型非侵入性疗法的进一步开发(和 治疗VAD)，包括符合进入临床的足够CMC要求的VITA配方， 完成GLP毒理学研究，表明对高危早产儿进行首例人体研究是足够安全的。

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.