Phase 1 Safety, Pharmacokinetic study followed by Phase 2a Proof-of-Concept study of AVR-48, a small molecule macrophage modulator to prevent bronchopulmonary dysplasia in neonates

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.