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

发展

• 批准号: 8058373
• 负责人: Robert Segal
• 金额: $ 58.18万
• 依托单位: DISCOVERY LABORATORIES, INC.
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-01-01 至 2013-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8058373
• 关键词: Acute; Aerosols; Animal Model; Animals; Applications Grants; Blood capillaries; Breathing; Bronchopulmonary Dysplasia; Chemical Surfactants; Chemicals; Chronic lung disease; Clinic; Clinical Research; Combined Modality Therapy; Complication; Development; Devices; Dose; Drug Impurity; Engineering; Ensure; Evaluation; Generations; Grant; Healthcare; Infant; Intratracheal Intubation; Intubation; Investigational Drugs; Laboratories; Lead; Lung; Lung diseases; Maximum Tolerated Dose; Mechanical ventilation; Morbidity - disease rate; Particle Size; Patients; Peptides; Performance; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Population; Premature Infant; Prevention; Prevention strategy; Randomized; Replacement Therapy; Risk; Safety; Small Business Innovation Research Grant; System; Target Populations; Technology; Testing; Therapeutic; Time; Tube; United States Food and Drug Administration; Ventilator; aerosolized; arm; capillary; cost; design; drug testing; endotracheal; meetings; mortality; nCPAP Ventilation; neonate; novel; open label; phase 3 study; prototype; respiratory distress syndrome; standard of care; success; surfactant

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.

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，每年与 RDS 及其并发症的治疗相关的费用超过 24 亿美元。目前，通过气管导管 (ETT) 气管内滴注动物源性表面活性剂是与机械通气 (MV) 结合治疗 RDS 的标准治疗方法。 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出现支气管肺发育不良 (BPD)/慢性肺病 (CLD)。因此，越来越多地采用鼻持续气道正压通气 (nCPAP) 等无创呼吸机策略，但 nCPAP 的使用妨碍了早期表面活性剂替代疗法的使用和益处。 利用目前可用的气溶胶发生装置输送表面活性剂方面取得的成功有限。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无创地输送其专有的含 KL4 肽的合成表面活性剂（lucinactant）。开发这种“一流”药物器械联合疗法的目的是消除对患有 RDS 或有 RDS 风险的早产儿使用 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。原型和第一代气雾剂装置和输送系统已经开发出来，证明了输送雾化发光剂的技术可行性；在 RDS 的早产动物模型（羔羊）中也证实了其功效。 Discovery Labs 目前正在开发第二代设备，计划将其投入临床。第一阶段提案的目标是全面测试该设备并对雾化药物产品进行表征，以确保其针对早产儿分娩进行优化。在第一阶段完成后，Discovery Labs 打算转向第二阶段的目标，即在患有 RDS 或有 RDS 风险的早产儿中进行 2a 期试点、开放标签、多中心、剂量递增试验。尽管超出了本提案的范围，但仍将进行一项扩大的 2b 期研究，随后进行关键的 3 期研究，该研究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。 公共健康相关性：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，是一个重大的医疗保健问题，每年造成的损失超过 24 亿美元。 RDS 目前采用动物源性表面活性剂进行治疗，只能通过婴儿气道的侵入性气管插管和机械通气进行给药，这两种方法都有风险。 Discovery Laboratories Inc.正在开发一种“一流”的药物装置组合疗法，利用新型气雾剂技术无创地输送合成表面活性剂，从而无需插管即可向患有 RDS 的早产儿输送表面活性剂，同时避免在这一脆弱人群中使用动物源性产品。