Nebulized ALX1 as a treatment for Pseudomonas aeruginosa infections in bronchiectasis patients

SUMMARY Bronchiectasis is characterized by dysregulated inflammation that leads to enlarged airways (bronchi) that are less able to clear mucus secretions, increasing the levels of bacteria in the lungs and chronic inflammation. This vicious cycle leads to breakdown of the airways and permanent lung damage; recurring respiratory infections in bronchiectasis cause significant morbidity and mortality. Pseudomonas aeruginosa infections are particularly deleterious with a 30-50% 5-year mortality rate in these patients. In addition to the multi-drug resistance mechanisms in this pathogen, airway mucus and the biofilm matrix both frustrate the immune response and mitigate the effectiveness of antibiotics. Repeated, intermittent use of unsuccessful antibiotic regimens lead to antimicrobial resistance (AMR), further reducing treatment options. New antimicrobial therapies to effectively treat bacterial lung infections without promoting AMR are greatly needed. Nitric oxide (NO) is an endogenous broad-spectrum antibacterial agent produced by the immune system (e.g., macrophages and neutrophils) to battle pathogens. In certain diseases, the levels of naturally produced NO are often inadequate to successfully fight infections. The inhalation of NO-releasing prodrugs provides a means for delivering NO locally into the lungs (i.e., at site of infection) in a controlled manner. In preliminary studies, we have demonstrated the in vitro and in vivo (preclinical) potential of a novel NO- releasing formulation (ALX1) to eradicate Pseudomonas aeruginosa. ALX1 is unique in that it enables nebulization of a low molecular weight NO donor, MD3, that has potent broad-spectrum antibacterial activity. The objective of this SBIR Phase II project is to answer critical questions needed to initiate Phase II proof-of-concept clinical trials in diseased patients. Specifically, we seek to: 1) enhance product quality and establish long-term stability of the formulation (ALX1) required to carry out efficacy studies in humans; 2) identify optimal dosing paradigms (i.e., QD versus BID) for nebulization of ALX1 in an established rodent model of pulmonary lung infection; and, 3) synthesize radiolabeled MD3 and study the biological fate of the API when administered to the lungs. Upon completion of these grant objectives, along with execution of Phase I safety trials in parallel, we will be positioned to embark on dosing of bronchiectasis patients for first- in-human efficacy readouts.