PARmedics

Pharmacokinetic and Efficacy Studies of the Aerosolized PAR2 Antagonist, C781, for the Treatment of Asthma

 

Industry: Medical

Country: USA

Website: https://www.parmedics.com/

Current treatments for asthma primarily focus on reducing exacerbations using inhaled medications that inhibit general inflammation, such as corticosteroids. Although these treatments are effective for some patients, asthma exacerbations continue to cause significant morbidity and mortality in those with more severe disease, leading to airway injury, lung function decline, and death. Exacerbations in severe asthmatics are particularly concerning due to their high health care costs and lost productivity, amounting to $21 billion annually in the US. Therefore, there is a critical need for new therapies for asthma treatment.

 

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 by allergens or endogenous agonists triggers complex cellular signaling (β-arrestin and Gq/Ca2+) that contributes to the physiological response. Research using genetically modified animals has shown that PAR2/β-arrestin signaling can lead to harmful 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).

 

In this SBIR Phase II project, PARMedics will optimize the production and aerosolized formulation of C781. We will conduct pivotal IND-enabling preclinical studies to evaluate its in vitro toxicology, pharmacokinetics, and dose-range establishment using two preclinical animal models (Sprague-Dawley rats and Beagle dogs). The efficacy of inhaled C781 will also be assessed in two preclinical models (humanized PAR2 mice and dogs). Completion of this project will support a Phase IIb application to complete inhalation IND-enabling toxicity studies, paving the way for an investigational new drug (IND) filing and future clinical trials.