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

雾化维生素 A：开发高氧性肺损伤和支气管肺发育不良的预防方法，重点关注新生儿肺成熟

• 批准号: 10581259
• 负责人: Craig Gelfand
• 金额: $ 99.51万
• 依托单位: ADVENT THERAPEUTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-01 至 2026-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10581259
• 关键词: Acute; Address; Adult; Aerosols; Age; All-Trans-Retinol; Animal Model; Animals; Authorization documentation; Award; Biological Assay; Biological Markers; Biotechnology; Bronchopulmonary Dysplasia; Canis familiaris; Chronic Phase; Clinic; Clinical; Clinical Research; Collaborations; Complication; Confidential Information; Data; Data Set; Development; Dose; Drug Delivery Systems; Effectiveness; Engineering; Enteral; FDA approved; Formulation; Funding; Gene Expression Regulation; Gene Proteins; Generations; Goals; Guidelines; Human; Hyperoxia; Inhalation; Injections; Intramuscular; Intramuscular Injections; Life; Long-Term Care; Lung; Measures; Medical; Medical center; Medicine; Modeling; Morphology; National Heart, Lung, and Blood Institute; Nebulizer; Neonatal; Newborn Infant; Oral; Organ; Orphan; Oryctolagus cuniculus; Outcome; Pathway interactions; Patients; Pharmaceutical Economics; Pharmaceutical Preparations; Phase; Phospholipids; Population; Premature Infant; Prevention; Process; Production; Productivity; Program Development; Proteins; Publications; Publishing; Pulmonary Inflammation; Pulmonary function tests; Rattus; Regimen; Research; Retinopathy of Prematurity; Risk; Rodent; Safety; Science; Secure; Sepsis; Serum; Severities; Small Business Innovation Research Grant; Structure of parenchyma of lung; Supplementation; Testing; Therapeutic; Toxic effect; Toxicology; Up-Regulation; Validation; Vitamin A; Vitamin A Deficiency; Water; Work; absorption; aerosolized; animal data; authority; chemical stability; clinic ready; commercialization; cost; drug development; drug efficacy; drug testing; evaluation/testing; first-in-human; in vivo; innovation; interest; lamb model; liver injury; long-term sequelae; lung development; lung injury; lung maturation; manufacture; meetings; neonatal sepsis; neonate; novel; novel strategies; oxidative damage; patient population; postnatal; pre-clinical; premature; preservation; preterm newborn; prevent; product development; protein expression; pulmonary function; receptor; reconstitution; research clinical testing; retinyl palmitate; scale up; side effect; success; surfactant

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.

Advent Therapeutics (Advent) 是一家生物技术公司，专注于重新配制和优化给药的新方法 经证实有效的传统药物可满足特定服务不足和孤儿患者未满足的医疗需求 人口。 Advent 正在开发一种其专有的、优化的水溶性维生素 A 的气雾剂配方 (vitA) 棕榈酸酯，用于无创（吸入）早产儿分娩，以解决维生素 A 缺乏症 (VAD)，以及 预防支气管肺发育不良（BPD），这是其最严重和最昂贵的并发症。 BPD 的预防是 该 IIB/SMA 期申请的重点以及本 FOA RFA-HL-23-008 下特别感兴趣的 NHLBI 主题。 我们将利用我们的创新技术，以 I/II 期 SBIR 奖项支持的非常重要的数据为基础 吸入式 vitA 配方：1) 避免了侵入性肌内 (IM) 注射和吸收的缺点 当前口服形式的局限性，克服了常规 NICU 使用的重大障碍，以及 2) 提供了直接 向靶器官递送以提高疗效——我们的体内数据显示，在以下方面比肌注给药具有显着优势 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输送 按照研究策略和我们最近的出版物 (47) 中的讨论对待 VAD。 我们与 Harbour-UCLA 医疗中心的 Virender Rehan 博士合作，完成了所有第一阶段 具体目标正在结束第二阶段目标，证明吸入 vitA：1) 刺激肺部成熟 （肺生物标志物检测显示视黄醇受体、表面活性蛋白和磷脂上调 合成以及成熟生物标志物，同时提高血清 vitA 水平，类似于肌注给药）； 2) 显着（与 IM 相比）减少高氧肺组织损伤（肺组织组织形态计量学评估和 减少肺损伤生物标志物）； 3) 保留肺功能（初步长期 PFT 数据）。 在 IIB 阶段，我们将进一步完善吸入 vitA 剂量策略，以减轻高氧肺损伤（BPD 通过研究特征良好的早产羔羊 BPD 模型，以逐步的方法进行预防）并继续 开展 IND 支持活动，准备开始针对有风险的早产儿的首次人体临床研究 BPD的发展。 IIb 期具体目标是： 1：优化雾化 vitA 的给药方案 用于减轻早产羔羊 BPD 模型中的高氧肺损伤，重点关注“新生儿”（急性 阶段）时间范围，以及从较长时期（慢性阶段）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 评估。目标2：继续药品生产开发 并在严格的 GLP 和 GMP 控制下扩大我们的配方。目标 3：进行 GLP 毒理学研究 对小型（大鼠）和大型（狗）物种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），包括满足进入临床所需的足够 CMC 要求的 vitA 配方， GLP 毒理学的完成表明对高危早产新生儿进行首次人体研究具有足够的安全性。