Optimization of LGM2605 for use as a device in lung transplant

标题："LGM2605用作肺移植器械的优化" 项目总结/摘要 LignaMed，LLC正在开发一种新型小分子装置LGM2605， 通过FDA批准的离体肺灌注（EVLP），以改善离体供体肺的肺功能参数， 移植手术的进展。根据FDA器械法规，将从供体肺中完全清除LGM2605 移植前。这项工作支持了国家HLBI促进预防和治疗 肺疾病和增强个人的健康，活得更长，更充实的生活，还解决 NHLBI的目标是扩大供体肺库。慢性肺病影响着3500万美国人， 每年导致近40万人死亡。肺移植是唯一的挽救生命的治疗方法， 某些类型的终末期肺病。然而，该程序的可用性有限，因为并非所有供体 肺移植是安全的这种供体肺的短缺导致20%的肺死亡 等待移植的移植候选人这种短缺的部分原因是在移植前和移植后对供体肺的损伤。 在保存期间由于活性氧（ROS）的产生和随后的肺组织氧化 损害这种损伤也与移植后最终的原发性移植物功能障碍（PGD）有关。PGD 缺血/再灌注（I/R）损伤与储存和移植操作有关。移植 I/R产生的ROS和其他氧化剂导致直接损害， 一堆可移植的肺因此，阻断ROS是减少ROS诱导的损伤的关键步骤。 LignaMed的新设备通过独特的三管齐下的作用模式来影响活性ROS，通过： 直接清除自由基，B）激活Nrf 2/抗氧化反应元件（ARE）途径和c） 通过抑制炎性小体和炎性细胞流入（中性粒细胞/ 巨噬细胞）。LGM2605具有优异的药物样性质，包括所需的理化性质， 口服生物利用度在小鼠和非人灵长类动物中的PK/PD研究已经显示出良好的口服、静脉内和口服给药效果。 皮下分布，而EVLP模型中的研究显示了对肺组织的极好暴露， 雾化药物当给予小鼠时，LGM2605可预防辐射诱导的肺部炎症， 纤维化和改善的肺功能参数和动脉血氧合。此外，当管理 通过与宾夕法尼亚大学克里斯蒂博士的小组合作进行的试点研究， LGM2605显著改善/恢复了以前未能改善的供体肺的肺功能参数。 符合"移植存活"验收标准。在这个快速通道SBIR提案中，我们的第一阶段目标将集中于 表征吸入的LGM2605的动力学。在第二阶段，我们将验证效果的大小， 确定扩大患者人群的安全性。LignaMed提交了一份背景资料和会议记录， 向FDA申请包裹。 (30行）

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)