Parmedics, Inc

Pharmacokinetic and Efficacy Studies of the Aerosolized PAR2 Antagonist, C781, for the Treatment of Asthma - Project Summary Current Treatments for Asthma Are Largely Aimed at Reducing the Incidence of Exacerbations With Inhaled Drugs That Inhibit General Inflammation, E.g., Corticosteroids. While Successful in a Subset of Patients, Asthma Exacerbations Remain a Significant Cause of Morbidity and Mortality in Those With More Severe Disease and Can Result in Airway Injury, Lung Function Decline and Death. Exacerbations in More Severe Asthmatics Are of Particular Concern, as Health Care Costs and Lost Productivity Account for $21 Billion/year in Us Annual Health Care Expenditures. Thus, There Is a Critical Need to Develop New Therapies to Be Used in the Treatment of Asthma. Protease-activated RECEPTOR-2 (PAR2) Is a G-protein-coupled Receptor Activated by Serine Proteases Released From Asthma-inducing Allergens (e.g., German Cockroach, Dust Mites and the Fungus Alternaria Alternata), as Well as by Mast Cell Tryptase, Human Airway Trypsin, Membrane Bound TMPRSS2 and Neutrophil Elastase. Activation of PAR2 via Allergens or Endogenous Agonists Results in Complex Cellular Signaling (β-arrestin and GQ/CA2+) That Contribute to the Physiological Response. Using Genetically Modified Animals, We Have Shown That PAR2/Β-ARRESTIN Signaling Can Lead to Detrimental Outcomes (e.g., Cytokine Production, Eosinophil/neutrophil Infiltration, Epithelial Hyperplasia, Mucus Secretion and Airway Hyperresponsiveness) While PAR2/GQ-CA2+ Pathways Can Be Beneficial (e.g., Broncho-relaxation). Our Decade-long Ligand-identification Program Has Resulted in Some of the Most Potent and Selective PAR2 Agonists and Antagonists, Including a Full PAR2 Antagonist (C391), and a Β-arrestin/elastase Selective Antagonist (C781) That Is a Promising Candidate for Targeting Only the Detrimental Effects of PAR2 in the Airway. Parmedics Has Completed an STTR Phase I That Has Proven the Feasibility of C781 as an Asthma Protectant. C781 Blocks PAR2 Activation Both in Vitro and in Vivo by Trypsin and Elastase, and Specifically Blocks Β-arrestin- 2 Recruitment and ERK1/2 Activation, With No Effect on Calcium Mobilization. C781 Represents the First Β- ARRESTIN/ERK1/2-BIASED PAR2 Antagonist and Reduces TH1 and TH2 Inflammatory Responses as Well as Multiple Measures of Airway Hyperresponsiveness (ahr). We Propose That C781 May Be Effective for Combating Acute Allergen-induced Asthma Exacerbations, as Well Reducing Pathology in Those With Moderate to Severe Disease and, by Reducing the Cytokine Production and Cellular Infiltration Associated With Chronic Disease. in This Sbir Phase Ii Project, Parmedics Will Optimize the Production and Aerosolized Formulation of C781. C781 Will Be Used to Perform Pivotal Ind-enabling Pre-clinical Studies to Evaluate Its in Vitro Toxicology, Pharmacokinetics and Dose-range Establishment Using Two Preclinical Animal Models (sprague-dawley Rats and Beagle Dogs). Efficacy of Inhaled C781 Will Also Be Assessed in Two Preclinical Models (humanized PAR2 Mice and Dogs). the Completion of This Project Will Support a Phase Iib Application Complete Inhalation Ind-enabling Toxicity Studies. This Will Allow the Filling of an Investigational New Drug Filling (IND) Enabling Future Clinical Trials.