Optimization of LGM2605 for use as a device in lung transplant

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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.