eNAMPTOR™ IN ACUTE AND CHRONIC INFLAMMATORY 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 phosphoribosyltransferase (NAMPT) as a novel candidate gene and therapeutic target in preclinical models of ARDS, ventilator-induced lung injury or VILI, pulmonary hypertension and pulmonary fibrosis. NAMPT is an intracellular enzyme that under conditions of cellular stress, is secreted into the bloodstream to act as a highly proinflammatory cytokine. In the circulation, Nampt potently induces lung inflammation by binding to the Toll-like receptor 4 (TLR4), a major lung inflammation-producing receptor via the activation of the NFkB inflammatory pathway and resulting in an explosion of cytokines released into the lung to produce marked lung inflammation and the untoward effects on lung homeostasis.
Utilizing a phage display library approach to identify affinity neutralizing anti-Nampt human monoclonal antibodies, ALT in partnership with Gennova BioPharmaceuticals Inc. has identified eNamptor™ as a novel therapy for acute and chronic inflammatory lung diseases.
eNAMPTOR™ IN ACUTE VENTILATOR-INDUCED LUNG INJURY:
Insights into the devastating pathobiology of acute respiratory distress syndrome (ARDS) and ventilator-induced lung injury (VILI) have been incremental and viable therapies have not yet been realized. We previously utilized genomic–intensive approaches to identify NAMPT, encoding nicotinamide phosphoribosyltransferase (NAMPT, as a novel VILI/ARDS gene target. Excessive mechanical stress elaborated by exposure of inflamed lungs to mechanical ventilation is a potent stimulus for Nampt expression in the lung and secretion into the bloodstream to induce lung inflammation by binding to the Toll-like receptor 4 (TLR4), a major lung inflammation-producing receptor. We demonstrated that excessive mechanical stress induces spatially-localized NAMPT expression with robust expression and secretion by lung endothelial cells (ECs) into the circulation with extracellular NAMPT (eNAMPT) a novel biomarker in ARDS. Blood eNAMPT levels as well as NAMPT promoter polymorphisms (SNPs) are associated with ARDS severity (increased ventilator days, ARDS mortality). Also, eNAMPT is essential to VILI development as reductions in eNAMPT availability (neutralizing antibodies, siRNAs, NAMPT+/- mice) dramatically attenuates the severity of lung injury in preclinical ARDS/VILI models.
Given this essential role in VILI, ALT has developed a human therapeutic monoclonal antibody (mAb), known as eNamptor™ to treat VILI. Delivered intravenously, eNamptor™ neutralizes circulating NAMPT, thus reducing the incidence of VILI and potentially improving survival in the critically ill and in patients undergoing complicated surgeries. eNamptor™ 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 eNamptor™ 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 eNamptor™ 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 eNamptor™ 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 20 million cases in US/year) and in the ICU (1.1 million cases in US/year), eNamptor™, will likely disrupt this untapped market and address an unmet medical need in the critically ill.
eNAMPTOR™ IN 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 eNamptor™, 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. eNamptor™ 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, eNamptor™ is currently being evaluated as an ameliorating therapy in established preclinical IPF via effects on previously untargeted pathways.
eNAMPTOR™ IN PULMONARY HYPERTENSION:
Pulmonary arterial hypertension (PAH) is a fatal disease without effective curative therapies. 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. Parallel genomic studies in PAH and IPF subjects revealed NAMPT as a top upregulated gene in peripheral blood mononuclear cell (PBMC) expression microarrays concomitant with increased blood NAMPT protein levels. IN PAH, we demonstrated that NAMPT is robustly expressed by lung endothelial cells (EC) in remodeled vessels from PAH subjects and in EC isolated from several preclinical PAH models. Based on dramatic attenuation of PAH severity (reduced inflammation, EC and SMC proliferation, resistance to apoptosis) by neutralizing or inhibiting extracellular NAMPT (eNAMPT) (Abs, Nampt+/- mice), Nampt is an excellent therapeutic target in pulmonary hypertension.
Aqualung Therapeutics will utilize the human monoclonal antibody, enamptcumab or eNamptor™, as a targeted therapy that focuses on inflammatory pulmonary vascular remodeling, a key feature of the PAH pathobiology. Neutralizing NAMPT in PAH will 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.