ABSTRACT Bronchopulmonary Dysplasia (BPD) is the most common chronic respiratory disease in infants and is a devastating condition that disrupts the developmental program of the lung secondary to preterm birth. Preterm neonates exposed to mechanical ventilation develop moderate to severe BPD that affects their survival (10% mortality) and respiratory function, and to date, there are no specific drugs available to prevent or treat this life- threatening condition. The pathologic hallmarks of BPD are hyperoxia-induced pulmonary inflammation, increased cell death, dysregulated angiogenic factors culminating in impaired alveolarization, dysregulated vascularization of the lung and pulmonary hypertension. AyuVis Research, Inc, is developing a novel class of low molecular weight natural oligosaccharide-derived small molecules and the lead compound AVR-48 which activate macrophage to an intermediary phenotype via TLR4/CD163 signaling in human blood and mouse spleen mononuclear cells. In both mouse and preterm lamb BPD models, the lead candidate AVR-48 block inflammatory mediators in lung and upregulation of endogenous vascularization pathways. The lead compound AVR-48 enhances production of certain host anti-inflammatory molecule such as IL-10 and growth factor VEGF with vascularization effects remaining local to lungs, improving lung vascularization/alveolization leading to improved lung function and survival. AVR-48 also prevents the development of BPD associated pulmonary hypertension. Importantly, we have assessed the Maximum Tolerated Dose and determined the NOAEL dose of AVR-48 in both juvenile and adult rats, in adult dogs and efficacy/safety doses in preterm lamb BPD model via IV dosing, which we will use to determine the dose ranges of our proposed clinical studies. We have demonstrated all these above-mentioned therapeutic effects in two BPD models: intraperitoneal injection of AVR-48 prevents hyperoxia- induced BPD in a neonatal mice pup model at 10mg/kg dose and intravenous injection in invasive mechanical ventilator induced BPD in pre-term lambs at 3.0 mg/kg dose. In order to advance the lead candidate AVR-48, AyuVis is submitting IND application to the FDA and preparing for Phase-1 and Phase-2a clinical trials. Here we propose two clinical trial: 1) Evaluate the Safety and PK parameters of AVR-48 in a Phase-I SAD and MAD clinical trial in healthy adult volunteers and 2) Evaluate the Safety, PK and efficacy of AVR-48 in an exploratory Phase-2a clinical trial in pre-term infants at risk of developing BPD. The completion of both clinical trials will provide the essential safety and pharmacokinetic data required to continue the product development of AVR-48. The data yielded through the completion of the aims of this project will lead the way to the development of future clinical project, including a Phase 2b/3 clinical trial aimed to assess the efficacy of AVR-48 in preterm infants at risk of developing BPD using larger sample size. Ultimately, our clinical pipeline will bring to market a prophylactic treatment for BPD, where there is a vastly unmet clinical need.

NARRATIVE Bronchopulmunary Dysplasia (BPD) is a disease of pre-term infants whose lungs are injured upon exposure to excess oxygen from ventilators, impairing effective gas exchange in the lungs and AyuVis Research is developing a novel class of immunomodulating small molecule derived from chitin that decrease inflammation, improve lung vascularization, decrease pulmonary hypertension and altogether prevent the depelopment of BPD in preclinical large animal model. Our objective in this proposed grant application is to assess the safety and pharmacokinetic profile of our lead compound in a Phase I SAD/MAD Clinical Trial in healty human volunteers, followed by an exploratory efficacy Phase-2a Trial in preterm infants at-risk of developing BPD. These proposed studies are key stages in the development of our much needed prophylactic treatment for BPD in infants and treatment for other life-threatening lung conditions.