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

描述(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，是早产儿发病率和死亡率的主要原因。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，通过气管导管(ETT)经气管内注入动物来源的表面活性物质是治疗RDS的标准护理，同时结合机械通气(MV)。ETT插管和MV常常与医源性并发症有关，并可能导致这些婴儿的支气管肺发育不良(BPD)/慢性肺部疾病(CLD)。因此，无创呼吸机策略，如鼻腔持续正压(NCPAP)正被越来越多地使用，但nCPAP的使用排除了早期表面活性物质替代治疗的使用和益处。在用现有的气溶胶产生装置提供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，该平台专为非侵入性地输送其专有的含KL4肽的合成表面活性剂(Lucinactive)而设计。开发这一“一流”药物-设备组合疗法的目的是：第一，避免ETT插管向患有RDS或有RDS风险的早产儿输送表面活性物质；第二，避免在这一脆弱的人群中使用动物衍生产品。已经开发出原型和第一代气雾剂装置和输送系统，证明了输送雾化荧光素的技术可行性；在RDS的早产动物模型(LAMB)中也证明了有效性。探索实验室目前正在开发第二代设备，计划将其带入临床。第一阶段提案的目标是全面测试这一设备，并对雾化药物产品进行表征，以确保其最适合用于早产儿。在第一阶段完成后，Discovery Labs打算转向第二阶段目标，即在有RDS风险或有RDS风险的早产儿中进行试点阶段2a、开放标签、多中心、剂量递增试验。虽然超出了本提案的范围，但将进行一项扩大的2b阶段研究，随后将进行一项关键的第三阶段研究，该阶段应支持提交挖掘设备组合产品的NDA，作为预防和治疗RDS的治疗策略。

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.