Development & Utilization of a Novel Aerosol-Generating Technology to Deliver Luc

描述（由申请方提供）：呼吸窘迫综合征（RDS）是一种急性、严重的肺部疾病，是早产儿发病和死亡的主要原因。这是一个主要的医疗保健问题-在美国，与RDS及其并发症治疗相关的费用每年超过24亿美元。目前，通过气管内导管（ETT）气管内滴注动物源性表面活性剂是治疗RDS的标准治疗方法，与机械通气（MV）联合使用。ETT插管和MV通常与医源性并发症相关，并可能导致这些婴儿的支气管肺发育不良（BPD）/慢性肺病（CLD）。因此，非侵入性呼吸机策略，如鼻持续气道正压通气（nCPAP）正在越来越多地采用，但使用nCPAP排除了使用和早期表面活性剂替代治疗的好处。 在用当前可用的气溶胶生成装置递送表面活性剂方面已取得有限的成功。为了克服有效雾化表面活性剂的关键障碍，Discovery Laboratories Inc.（Discovery Labs）正在开发一种雾化技术平台，该平台专门设计用于非侵入性地递送其专有的含KL 4肽的合成表面活性剂（lucinactant）。开发这种"一流"药物-器械联合治疗的目的是为了消除ETT插管向患有RDS或有RDS风险的早产儿输送表面活性剂的需求，其次，避免在这一脆弱人群中使用动物源性产品。已经开发了原型和第一代气雾剂装置和递送系统，证明了递送气雾化Lucinactant的技术可行性;还在RDS的早产动物模型（羔羊）中证明了疗效。探索实验室目前正在开发第二代设备，计划将其用于临床。I期提案的目的是全面测试该器械并对雾化制剂进行表征，以确保其优化用于早产儿给药。在I期完成后，Discovery Labs计划进入II期，在患有RDS或有RDS风险的早产儿中进行一项2a期、开放标签、多中心、剂量递增的试验。尽管超出了本提案的范围，但将进行一项扩展的2b期研究，随后进行一项关键的3期研究，该研究应支持提交作为预防和治疗RDS的治疗策略的药物-器械组合产品的NDA。 公共卫生相关性：呼吸窘迫综合征（RDS）是一种严重的肺部疾病，是早产儿最常见的并发症，是一个重要的卫生保健问题，每年花费超过24亿美元。RDS目前使用动物源性表面活性剂治疗，只能通过婴儿气道的侵入性气管内插管和机械通气给药，这两种方法都有风险。探索实验室公司正在开发一种"一流的"药物-器械联合治疗，使用新型气雾剂技术无创地输送其合成表面活性剂，从而消除了插管向RDS早产儿输送表面活性剂的需要，同时避免在这一脆弱人群中使用动物源性产品。

DESCRIPTION (provided by applicant): Respiratory distress syndrome (RDS) is an acute, severe pulmonary disorder that is the leading cause of morbidity and mortality in preterm infants. It is a major healthcare concern - costs associated with treatment of RDS and its complications exceed $2.4 billion annually in the US. Currently, animal-derived surfactants instilled intratracheally via an endotracheal tube (ETT) are standard of care for treating RDS, in conjunction with mechanical ventilation (MV). ETT intubation and MV are often associated with iatrogenic complications and may lead to bronchopulmonary dysplasia (BPD)/ chronic lung disease (CLD) in these infants. Thus, non-invasive ventilator strategies such as nasal continuous positive airway pressure (nCPAP) are being increasingly employed, but use of nCPAP precludes the use and benefits of early surfactant replacement therapy. Limited success has been achieved in delivering surfactants with currently available aerosol-generating devices. To overcome the critical barrier of effectively aerosolizing surfactant, Discovery Laboratories Inc. (Discovery Labs) is developing an aerosolization technology platform that is specifically designed to noninvasively deliver its proprietary KL4 peptide-containing synthetic surfactant (lucinactant). The objective of developing this "first-in-class" drug-device combination therapy is to obviate the need for ETT intubation to deliver surfactants to preterm infants with or at risk for RDS, and second, avoid the use of animal- derived products in this fragile population. Prototype and first generation aerosol devices and delivery systems have been developed, demonstrating technical feasibility of delivering aerosolized lucinactant; efficacy has also been demonstrated in a preterm animal model (lamb) of RDS. Discovery Labs is currently developing a second generation device, which it plans to take into the clinic. The objective of the Phase I proposal is to fully test this device and conduct characterization of the aerosolized drug product to ensure that it is optimized for delivery to preterm infants. Following completion of Phase I, Discovery Labs intends moving to the Phase II objective of conducting a pilot phase 2a, open-label, multicenter, dose escalation trial in preterm infants with or at risk for RDS. Although beyond the scope of this proposal, an expanded phase 2b study will be conducted, to be followed by a pivotal, Phase 3, which should support submission of an NDA for the dug-device combination product as a therapeutic strategy for prevention and treatment of RDS. PUBLIC HEALTH RELEVANCE: Respiratory distress syndrome (RDS), a severe lung disorder that is the most commonly seen complication in infants born prematurely is a significant health-care concern, costing in excess of $2.4 billion annually. RDS is currently treated with animal-derived surfactants that can only be administered via invasive endotracheal intubation of the infant airway, and mechanical ventilation, both of which have risks. Discovery Laboratories Inc. is developing a "first-in-class" drug-device combination therapy using a novel aerosol technology to noninvasively deliver its synthetic surfactant, and hence obviate the need for intubation to deliver surfactants to preterm infants with RDS, and at the same time, avoid the use of animal-derived products in this fragile population.