A Novel ENaC Blocker/Osmolyte Inhalation Solution for the Treatment of Muco-Obstructive Lung Diseases

ABSTRACT Muco-obstructive lung diseases, e.g., COPD, asthma, CF, and PCD, cause major health problems to many citizens of the US. Recent CT data have identified mucus plugging as a major contributor to the pathogenesis and mortality of muco-obstructive lung diseases, including COPD. Ironically in 2023, there are no therapeutic agents available dedicated to the clearance of mucus plugs from patients in need. CT data demonstrating that mucus plugs persist in COPD subjects for > 3 yrs suggest that current COPD therapeutics are not helpful in mucus clearance. A combination of in vitro biophysical studies and clinical research studies over the past decade have established that mucus plugging is a predictable consequence of the increased mucus concentration. Increased mucus concentration typically reflects defects in the epithelial ion/fluid transport pathways that control mucus hydration. A rational therapeutic strategy to clear mucus plugs from the lungs of patients in need is to rehydrate the accumulated, hyperconcentrated mucus. This application is designed to support the enabling studies of a novel mucus hydrator combination therapy, including a next-generation ENaC blocker (P-1155) formulated with an osmolyte, to IND status. The medicinal chemistry design of P-1155 builds off the success in the clinic of the P-1037/hypertonic saline (HS) combination for the chronic therapy of primary ciliary dyskinesia (PCD). The P-1037/HS experience strongly emphasizes the importance of both: 1) an osmolyte for effective clinical activity; and 2) high protein binding for a high degree of extra-renal excretion and, hence, safety. Based on the perceived need for a rapidly active muco-kinetic agent for the treatment of both stable and exacerbating COPD or asthmatic subjects, P-1155 has been modified to accelerate the kinetics of onset of action while preserving P-1037 safety attributes. Two specific aims encompass a two-phase development plan. Phase I will select the osmolyte for co-formulation with P-1155, the choices being NaGluconate vs HS/Sulfobutylether-β- Cyclodextrin (SBECD), based on: 1) P-1155 formulation/stability studies; and 2) efficacy studies in a muco- obstructive mouse model. Phase II will include IND-required aerosol formulation, ADME/PK studies, and a 28- day GLP rat inhalation toxicology study. Accordingly, the application proposes two Specific Aims: Specific Aim 1: Phase I studies designed to select a P-1155 formulation. SA1A: P-1155 formulation and stability studies. SA1B: 7/28d βENaC muco-obstructive mouse model efficacy studies. Specific Aim 2: Phase II studies designed to advance a P-1155 formulation to an IND. SA2A: Aerosol delivery formulation studies of P-1155/osmolyte solutions. SA2B: ADME/PK studies, including hepatic excretion, plasma protein binding, and P-1155 metabolism. SA2C: 28d rat GLP inhalation toxicology study of selected P-1155 formulation. The ultimate goal of the SBIR submission is to file an IND for P-1155 focused on subjects with COPD.