Nebulized ALX1 as a Treatment for Difficult Non-tuberculous Mycobacterial Lung Infections

SUMMARY Non-tuberculosis mycobacteria (NTM) infections are currently treated with a multiple antibiotic regimen that often fails to result in sputum culture conversion. In fact, culture conversion rates remain less than 50% despite treatment periods over 12 months, highlighting the refractory nature of the disease. In individuals with compromised lung function (e.g., bronchiectasis), infection often leads to NTM pulmonary disease (NTM-PD) and severe lung function decline over time. Repeated use of unsuccessful antibiotic regimens engenders antimicrobial resistance (AMR), further reducing treatment options and impacting morbidity. New antimicrobial therapies to effectively treat NTM-PD without promoting AMR are greatly needed. Nitric oxide (NO) is an endogenous broad-spectrum antimicrobial agent produced by the immune system (i.e., macrophages and neutrophils) in response to pathogens. In certain diseases, the levels of naturally produced NO are often inadequate to elicit a successful response. The innovative delivery of water-soluble NO-releasing prodrugs via inhalation provides a means for delivering NO locally into the lungs in a controlled manner while limiting off-target effects. In published studies, we have demonstrated the in vitro and in vivo (preclinical) potential of our NO-releasing formulation to treat Mycobacterium abscessus. Our drug candidate, ALX1, is unique in that it enables nebulization of a low molecular weight NO prodrug that has potent broad-spectrum antibacterial activity with no documented resistance to date. The objective of this SBIR Phase II project is to evaluate the pharmacokinetics and optimize the dosing regimen of inhaled ALX1 needed to inform dose selection for a Phase 2 proof-of-concept clinical trial in NTM-diagnosed bronchiectasis patients. Specifically, we seek to: 1) determine the dose proportionality and relationship between local lung and systemic plasma concentrations of the NO-releasing prodrug following inhalation in rodents and, 2) demonstrate the optimum pharmacologic effect of ALX1 formulation to treat M. abscessus infections in rodents when delivered via inhalation, either once or twice daily. Upon completion of these objectives, we will be positioned with information to successfully translate efficacious ALX1 doses in animals to predicted effective doses in bronchiectasis patients.