We have identified a novel gene and protein and have developed a highly specific human monoclonal antibody that neutralizes and reduces acute and chronic lung inflammation.
ACUTE INFLAMMATORY LUNG INJURY AND VENTILATOR-INDUCED LUNG INJURY
Scientists at Aqualung Therapeutics (ALT) have championed the employment of approaches that interrogate the entire genome in order to identify novel candidate genes as potential therapeutic targets in inflammatory lung disorders. These efforts successfully identified the gene encoding nicotinamide phosphoribosyl-transferase (NAMPT) as a novel candidate gene and cytokine in preclinical models of ARDS and ventilator-induced lung injury or VILI. NAMPT is an inflammatory protein that is secreted into the bloodstream in response to exposure to mechanical ventilation and potently induces lung inflammation by binding to the Toll-like receptor 4 (TLR4), a major lung inflammation-producing receptor. Given this essential role in VILI, ALT has developed a human therapeutic monoclonal antibody (mAb), known as enamptcumab (ENA), to treat VILI. Delivered intravenously, ENA neutralizes circulating NAMPT, thus reducing the incidence of VILI and potentially improving survival in the critically ill and in patients undergoing complicated surgeries. ENA is an innovative mAb therapy, that is designed to prophylactically-administered at the time of patient intubation and placement on MV i.e. before VILI develops. This approach distinguishes ENA therapy from the many failed drugs that targeted a single cytokine (i.e. TNF-a, IL-1b, IL-6 etc.) and were delivered after the presence of established lung injury and inflammation. Because levels of multiple cytokines are already markedly elevated, a process known as “cytokine storm”, these single cytokine-directed therapies were ineffective in reducing inflammation. In the absence of a currently effective therapy to treat VILI, and with unacceptable ICU mortality rates, ENA mAb therapy will create a new market and is expected to improve outcomes, drive healthcare cost reductions, and provide cost savings to hospitals and insurers. These attributes will allow ENA to be established as the standard of care further driving additional market penetration. Given that mechanical Ventilation (MV) is routinely used in hospitals for both simple and highly complex surgeries (over 20M cases in US/year) and in the ICU (1.1M cases in US/year), ENA, will likely disrupt this untapped market and address an unmet medical need in the critically ill.
IDIOPATHIC PULMONARY FIBROSIS
As with therapeutic approaches to lung inflammation in acute lung injury and VILI, Aqualung Therapeutics, Corp. identified extracellular NAMPT as a novel druggable therapeutic target in IPF developing the intravenously-delivered human monoclonal antibody i.e. enamptcumab or ENA, to neutralize NAMPT, attenuate lung fibrosis progression, and reduce IPF morbidity and mortality. NAMPT is an inflammatory protein that is secreted into the bloodstream and potently induces lung inflammation by binding to the Toll-like receptor 4 (TLR4). Given that IPF is characterized by the lack of disease resolution, adverse side effects, and substantial financial burden of with use of currently approved therapies, there is a serious need for novel, highly efficacious therapies against IPF. ENA is an innovative therapy to reduce IPF mortality and reduce healthcare costs, addressing a serious unmet medical need. The feasibility and proof of concept of the Aqualung NAMPT neutralizing human antibody, ENA, is currently being evaluated as an ameliorating therapy in established preclinical IPF via effects on previously untargeted pathways.
Lung inflammation now recognized as a key contributor to the pulmonary vascular remodeling that is essential to the development of PAH and contributing directly to PAH’s unacceptably high mortality. ALT scientists, via genomic–intensive approaches, identified nicotinamide phosphoribosyltransferase (NAMPT) as a novel candidate gene and cytokine in PAH. PAH subjects exhibit increased blood NAMPT protein levels and NAMPT is robustly expressed in lung endothelial cells (EC) of remodeled vessels from PAH subjects. Aqualung Therapeutics will utilize the human monoclonal antibody, enamptcumab or ENA, to neutralize NAMPT in PAH, attenuate lung inflammation and vascular remodeling via reduced signaling through its receptor, Toll like receptor 4 (TLR4). NAMPT dysregulates processes implicated in pulmonary vascular remodeling such as resistance to apoptosis, cell proliferation, and smooth muscle cell survival.