An Inhaled Microbiome-Targeted Biotherapeutic for Treatment of COPD

PROJECT SUMMARY - ResBiotic Inc. is developing its lead drug product, RB1000, a spray-dried powder com- prised of an inhaled biotherapeutic API for treatment of neutrophilic inflammation and disease progression in COPD patients. COPD is a chronic degenerative disease that is the fourth leading cause of death in the U.S., where it predominantly results from tobacco smoke exposure. Acute exacerbations are a sudden worsening of symptoms that can occur frequently, ≥ 2 per year in severe cases, and can result in reduced lung function, reduced health status, and increased risk for mortality. Treatment approaches including short- and long-acting bronchodilators, corticosteroids, phosphodiesterase inhibitors, cytokine blockers, and respiratory stimulants have been used but with limited clinical efficacy. Inhaled corticosteroids are used specifically to treat inflamma- tion but have potential for serious side effects, e.g., severe pneumonia and death. Combination therapies have demonstrated modest reductions in exacerbation frequency, but there is still significant room for improvement, as these therapeutics do not halt disease progression and often can have serious side effects. Recent research has demonstrated a strong association between neutrophilic inflammation that results from dysbiosis, i.e., an altered microbiome, of the lung in COPD. ResBiotic has demonstrated that heightened levels of proteobacteria can increase expression of matrix metalloproteinase 9 (MMP-9) and neutrophil elastase (NE), which are associ- ated with neutrophilic inflammation and can cause extracellular matrix degradation and airway remodeling. Res- Biotic has demonstrated in vitro and in vivo that anti-inflammatory Lactobacillus strains can reduce inflammation resulting from dysbiosis, including the expression of MMP-9 and NE, which may enable highly effective biother- apeutic drugs for COPD. Commercialization of a Lactobacillus-based biotherapeutic drug would provide an al- ternative anti-inflammatory approach with a different mechanism of action than currently available therapeutics. The goal of this proposal will be to develop a biotherapeutic drug that includes non-living components of a Lac- tobacillus bacterial extract that are responsible for the therapeutic response. Phase I will include screening dif- ferent cellular components at various dosages to identify several candidates that reduce MMP-9 expression in primary human bronchial epithelial cells taken from COPD patients. Phase II will include the development of a dry powder formulation of optimal candidates and safety and efficacy testing in preclinical mouse models of COPD. The deliverable for Phase II will be a lead candidate that has demonstrated efficacy in reduction of neutrophilic inflammation and improvements in lung function that is ready to advance to IND-enabling large mammal studies. Successful commercialization of the inhaled drug product RB1000 is expected to provide an alternative or complementary treatment modality to the standard of care to address neutrophilic inflammation resulting from dysbiosis in COPD, which is expected to reduce COPD exacerbations, potentially reduce disease progression, and improve patient quality of life.