Optimization of LGM2605 for use as a device in lung transplant

标题：《LGM2605在肺移植中的应用优化》 项目摘要/摘要 LignaMed，LLC正在开发一种新的小分子设备LGM2605，该设备将被使用和管理 通过FDA批准的体外肺灌流(EVLP)，改善体外供肺的肺功能参数 移植手术的进展。根据FDA的装置规定，LGM2605将从供体肺中完全清除 在移植之前。这项工作支持了NHLBI促进预防和治疗HLBI的努力 肺部疾病和增强个人的健康，以活得更长和更有成就感，还解决 NHLBI声明了扩大捐赠者肺池的目标。慢性肺部疾病影响着3500万美国人， 每年造成近40万人死亡。肺移植是治疗慢性阻塞性肺疾病患者的唯一救命方法 某些类型的终末期肺部疾病。然而，该程序的可用性有限，因为不是所有的捐赠者 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供体肺在移植前和 在保存过程中，由于产生了活性氧物种(ROS)和随后的氧化肺组织 损坏。这种损伤也与移植后最终的原发移植物功能障碍(PGD)有关。PGD 发生于与储存和移植操作相关的缺血/再灌注(I/R)损伤。同种异体移植物 与I/R产生的ROS和其他氧化剂结合在一起的质量会导致直接损害，从而降低 可移植的肺池。因此，阻断ROS是减少ROS损伤的关键一步。 LignaMed的新设备通过独特的三管齐下的行动模式来影响反应性ROS，通过a) 直接清除自由基，b)激活Nrf2/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内流减少ROS的产生(中性粒细胞/ 巨噬细胞)。LGM2605具有优异的类药物性能，包括理想的物理化学性质和 口服生物利用度。对小鼠和非人灵长类动物的PK/PD研究表明，口服、静脉注射和 皮下分布，而在EVLP模型中的研究表明，与肺组织的良好暴露 雾化药物。当给小鼠服用LGM2605时，可以预防辐射引起的肺部炎症和 纤维化和改善肺功能参数和动脉血氧分压。此外，当给药时 通过EVLP与宾夕法尼亚大学克里斯蒂博士的团队合作进行的试点研究， LGM2605显著改善/恢复了以前未能改善/恢复的供肺的肺功能参数 符合“移植可行”的验收标准。在此快速通道SBIR提案中，我们的第一阶段目标将侧重于 描述吸入LGM2605的动力学。在第二阶段，我们将验证影响的程度和 确定扩大患者群体的安全性。LignaMed已经提交了背景和会议 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)