Optimization of LGM2605 for use as a device in lung transplant

优化 LGM2605 作为肺移植设备的用途

• 批准号: 9558047
• 负责人: Jason D Christie
• 金额: $ 29.97万
• 依托单位: LIGNAMED, LLC
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-01 至 2020-02-09
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9558047
• 关键词: Acute; Address; Affect; Allografting; American; Antioxidants; Bioavailable; Biological Markers; Blood; Cells; Cessation of life; Chronic; Chronic lung disease; Collaborations; Data; Development; Devices; Effectiveness; Ensure; Exposure to; FDA approved; Free Radical Scavenging; Functional disorder; Funding; Gene Activation; Generations; Genetic Transcription; Goals; Grant; Health; Health Care Costs; Incidence; Individual; Inflammasome; Inflammation; Inflammatory; Inhalation; Intercept; Intravenous; Ischemia; Kinetics; Lead; Life; Link; Lung; Lung Inflammation; Lung Transplantation; Lung diseases; Medical Device; Modeling; Mus; National Heart, Lung, and Blood Institute; Operative Surgical Procedures; Oral; Oxidants; Oxidative Stress; Pathway interactions; Patients; Pennsylvania; Perfusion; Pharmaceutical Preparations; Phase; Physiological; Pilot Projects; Positioning Attribute; Prevention; Procedures; Production; Property; Pulmonary Fibrosis; Quality of life; Radiation; Reactive Oxygen Species; Regulation; Reperfusion Injury; Reperfusion Therapy; Research; Resources; Respiratory physiology; Response Elements; Running; Safety; Savings; Small Business Innovation Research Grant; Structure of parenchyma of lung; Testing; Tissues; Toxic effect; Transplant Recipients; Transplantation; United States National Institutes of Health; Universities; Work; aerosolized; base; clinically significant; cost outcomes; first-in-human; improved; improved outcome; macrophage; meetings; neutrophil; nonhuman primate; novel; patient population; preclinical efficacy; preclinical study; preservation; prevent; small molecule; subcutaneous; trial design

TITLE: “Optimization of LGM2605 for use as a device in lung transplant” Project Summary/Abstract LignaMed, LLC is developing a novel small molecule device, LGM2605, that will be utilized and administered via FDA approved ex vivo lung perfusion (EVLP), to improve lung function parameters of ex vivo donor lungs in advance of transplant surgery. Per FDA device regulations LGM2605 will be fully cleared from the donor lung prior to transplant. This work supports the efforts of the NHLBI to promote the prevention and treatment of lung diseases and enhance the health of individuals to live longer and more fulfilling lives, and also addresses an NHLBI stated goal of expanding the donor lung pool. Chronic lung diseases affect 35 million Americans and result in almost 400,000 deaths annually. Lung transplantation is the only life-saving therapy for patients with certain types of end-stage lung disease. However, the procedure has limited availability because not all donor lungs are safe for transplantation. This shortage of donor lungs results in the death of 20 percent of lung transplant candidates awaiting transplant. This shortage arises in part from damage to donor lungs prior to and during preservation due to generation of reactive oxygen species (ROS) and subsequent oxidative lung tissue damage. This damage is also linked to eventual primary graft dysfunction (PGD) after transplantation. PGD arises from ischemia/reperfusion (I/R) Injury associated with storage and transplant maneuvers. Allograft quality combined with ROS and other oxidants produced with I/R lead to direct damage that decreases the pool of transplantable lungs. Thus, blocking ROS is a critical step in reducing ROS-induced damage. LignaMed's novel device works through a unique three-prong mode of action to impact reactive ROS via a) direct free radical scavenging, b) activation of the Nrf2/antioxidant response element (ARE) pathway and c) decrease of ROS production via inhibition of inflammasome and inflammatory cell influx (neutrophils / macrophages) . LGM2605 has excellent drug-like properties including desirable physiochemical properties and oral bioavailable. PK/PD studies in mouse and non-human primates have shown good oral, intravenous and subcutaneous distribution while studies in the EVLP model show excellent exposure to lung tissue with aerosolized drug. When administered to mice, LGM2605 prevented radiation-induced lung inflammation and fibrosis and improved lung function parameters and arterial blood oxygenation. Moreover when administered via EVLP in pilot studies run in collaboration with Dr. Christie's group at the University of Pennsylvania, LGM2605 significantly improved/rehabilitated lung function parameters in donor lungs that previously failed to meet “transplant viable” acceptance criteria. In this Fast-track SBIR proposal, our Phase I aims will focus to characterize the kinetics of inhaled LGM2605. In Phase II we will validate the magnitude of the effect and determine safety in an expanded patient population. LignaMed has submitted a background and meeting request package to FDA. (30 lines)

标题：“在肺移植中用作设备的LGM2605优化” 项目摘要/摘要 Lignamed，LLC正在开发一种新型的小分子设备LGM2605，该设备将被利用和给药 通过FDA批准的离体肺灌注（EVLP），以改善体内供体肺的肺功能参数 移植手术的前进。根据FDA设备法规LGM2605将从供体肺中完全清除 移植之前。这项工作支持NHLBI促进预防和治疗的努力 肺部疾病并改善个人的健康，使生活更长，更充实的生活，也可以解决 NHLBI提出了扩大供体肺池的目标。慢性肺部疾病影响3500万美国人， 每年导致近40万人死亡。肺移植是唯一针对患者 某些类型的末期肺病。但是，该过程的可用性有限，因为并非所有捐助者 肺是安全的移植。供体肺部短缺导致肺的死亡20％ 等待移植的移植候选人。这种短缺部分是由于对供体肺的损害和 在生成活性氧（ROS）和随后的氧化肺组织的保存过程中 损害。该损伤还与移植后最终的原发性移植功能障碍（PGD）有关。 PGD 由缺血/再灌注（I/R）损伤引起，与存储和移植动作有关。同种异体移植 质量与I/R一起产生的ROS和其他氧化剂会导致直接损害，从而减少 可移植肺部的池。那是阻止ROS是减少ROS诱导损伤的关键步骤。 Lignamed的新型设备通过独特的三键作用方式来通过A影响反应性ROS） 直接自由基清除，b）NRF2/抗氧化剂响应元件的激活（AS）途径和C） 通过抑制炎性体和炎症细胞影响（中性粒细胞 / 巨噬细胞）。 LGM2605具有出色的类药物特性，包括理想的理化特性和 口服生物利用。小鼠和非人类素数中的PK/PD研究表现出良好的口服，静脉注射和 在EVLP模型的研究时，皮下分布显示出极好的暴露于肺组织 雾化药物。当对小鼠施用时，LGM2605防止了辐射诱导的肺注射和 纤维化和改善的肺功能参数和动脉血液氧合。此外，管理时 通过EVLP与宾夕法尼亚大学克里斯蒂（Christie）的小组合作进行试点研究， LGM2605显着改善/修复的肺功能参数 满足“移植可行”的接受标准。在这个快速的SBIR提案中，我们的I阶段目标将集中于 表征继承的LGM2605的动力学。在第二阶段，我们将验证效应的幅度和 确定扩大患者人群的安全性。 Lignamed提交了背景和会议 向FDA请求包。 （30行）