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）是一种生物技术，重点是重新重新制定和优化交付的新方法 具有公认有效性的遗产药物可以满足特定服务不足和孤儿患者的未满足医疗需求 人群。 Advent正在开发其专有，优化水性维生素A的气溶胶配方 （Vita）棕榈酸盐，用于非侵入性（吸入）向早产儿的分娩以解决Vita缺乏症（VAD），并且 预防支气管肺发育不良（BPD），这是最严重，最昂贵的并发症。预防BPD是 此阶段IIB/SMA应用程序的重点和此FOA下的NHLBI主题，RFA-HL-23-008。 我们将建立I/II阶段SBIR奖的非常重要的数据，并以我们的创新性 继承的Vita公式：1）避免肌肉内（IM）注射和滥用的弊端 当前口头形式的局限性，克服常规NICU利用的重大障碍，2） 提高效率的目标靶器 - 器官 - 我们的体内数据显示出与IM给药相比的重要好处 缓解高氧性肺损伤（在我们的BPD动物模型中），同时提供足够的全身传递 如研究策略和我们最近的出版物中所讨论的那样（47）。 与Harbour-Ucla医疗中心的Virender Rehan博士合作，我们已经完成了所有第一阶段 具体目标并正在结束II期的目标，证明了遗传的Vita：1）刺激肺部成熟 （评估出现视黄醇受体，表面活性剂蛋白和磷脂上调的肺生物标志物 合成以及成熟的生物标志物，同时提高了与IM给药相似的血清Vita水平）； 2）（VS IM）急剧减少了高氧化肺组织损伤（评估肺组织组织形态和 减少肺部生物标志物）； 3）保留肺功能（初步的长期PFT数据）。 在IIB期，我们将进一步完善遗传的Vita剂量剂量策略来减轻高氧肺损伤（BPD 通过研究良好特征的过早羔羊BPD模型，以逐步的方法进行预防） 随着成熟的活动，可以准备开始对早产儿的首次临床研究 BPD的发展。 IIB期特异性的目的是：1：雾化Vita的剂量方案的优化 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）时间框架，以及在“成年”中长期（慢性阶段）的时间表，评估类似的生物标志物， 根据I/II期，形态学和PFT评估。目标2：进行药物制造开发 以及我们在严格的GLP和GMP控件下进行制定的规模。目标3：进行GLP毒理学 在小（大鼠）和大（狗）物种中的研究以支持临床准备。成功的措施将是 生成支持我们新型非侵入性治疗的进一步发展的数据，以防止BPD（和 处理VAD），包括满足足够CMC要求进入诊所的VITA公式， GLP毒理学的完成，显示出适当的安全性，用于在风险早产新生儿中的第一名研究。