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

描述（由申请人提供）：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及其并发症的治疗相关的费用每年超过24亿美元。目前，通过气管内插管（ETT）注入动物源性表面活性剂是治疗RDS的标准护理方法，并与机械通气（MV）相结合。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，无创呼吸机策略，如鼻持续气道正压通气（nCPAP）被越来越多地采用，但nCPAP的使用阻碍了早期表面活性剂替代治疗的使用和获益。目前可用的气溶胶产生装置在输送表面活性剂方面取得了有限的成功。为了克服有效雾化表面活性剂的关键障碍，Discovery实验室公司（Discovery Labs）正在开发一种雾化技术平台，该平台专门用于无创输送其专有的含有KL4肽的合成表面活性剂（lucinactant）。开发这种“一流的”药物装置联合治疗的目的是为了避免对有RDS风险的早产儿进行ETT插管输送表面活性剂的需要，其次，避免在这一脆弱人群中使用动物源性产品。原型和第一代气溶胶装置和输送系统已经开发出来，证明了输送雾化发光活性剂的技术可行性；在RDS的早产动物模型（羔羊）中也证明了其有效性。探索实验室目前正在开发第二代设备，计划用于临床。I期提案的目标是对该装置进行全面测试，并对雾化药物产品进行表征，以确保其对早产儿的输送进行优化。在I期完成后，Discovery实验室打算进入II期目标，在患有或有RDS风险的早产儿中进行一项2a期开放标签、多中心、剂量递增的试点试验。尽管超出了本提案的范围，但将进行一项扩大的2b期研究，随后将进行关键的3期研究，这将支持将药物-器械组合产品作为预防和治疗RDS的治疗策略提交NDA。

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.