B29-25 Inhaled ALX1 Safety, Tolerability, and Dose Dependent Pharmacokinetics in Phase 1 Study: A Novel Approach for Targeted Delivery of Nitric Oxide to the Lungs

Introduction

Inhaled ALX1 solution is an aqueous formulation containing a Nitric Oxide (NO) releasing pro-drug dissolved in a phosphate buffer. Upon nebulization, the aerosolized droplets containing the diazeniumdiolate prodrug cover the bronchial mucosa and hydrolyze at physiological pH to release free NO into the airway surface liquid/mucus layer over time. This approach is in contrast to cumbersome, high dose inhaled NO gas which does not efficiently diffuse into the liquid airway layer and is instead transported rapidly via the alveoli into the systemic circulation, creating dose limiting toxicities including methemoglobinemia. Inhaled ALX1 is being developed for the management of patients with muco-obstructive chronic lung diseases (e.g. Bronchiectasis and COPD) as the sustained local release of NO has demonstrated dual mechanism anti-inflammatory and anti-microbial effects in nonclinical studies.

Methods

Safety and tolerability were assessed in a vehicle-controlled Phase 1 study in the U.S. (San Antonio, TX). A total of 48 healthy volunteers were dosed with inhaled ALX1 using a Pari Nebulizer in 4 Single Ascending Cohorts (doses 11, 43, 86, and 172 mg) and 2 Multiple Ascending Cohorts (doses 86 and 172 mg for 7 days). Pharmacokinetic parameters were calculated based on serial plasma samples quantified via LCMS for drug substance and analyzed via Phoenix WinNonlin™.

Results

No bronchodilators were given before dosing and zero subjects experienced bronchospasm. No dose limiting toxicities were observed with successful escalation above the calculated human effective dose. Transient decreases in blood pressure, an expected extension of NO pharmacological effect on vascular tone, were observed for most subjects above the 11 mg dose. Changes in Mean Arterial Pressure (MAP) were not dose dependent nor correlated with systemic bioavailability, with the greatest change of -12 mmHg at 2 hours for the 86 mg dose group; the levels returned to baseline by 24 hours post dose (all dose groups). There was no wheezing, no meaningful reductions in lung function (FEV1), no clinically significant lab abnormalities, nor emergence of methemoglobinemia at any dose level. Four subjects had a total of 5 treatment related AEs with 3 ALX1 subjects experiencing 4 mild-to-moderate AEs (headache, drowsiness). Pharmacokinetic analyses resulted in systemic exposure (mean Cmax and mean AUClast) increases in a dose proportional manner over the full dose range with a half-life (t½) of around 2 hours.

Conclusion

Inhaled ALX1 at doses up to 172 mg, were safe and well tolerated without development of bronchospasm, reduction in lung function, or systemic methemoglobinemia

This abstract is funded by: Vast Therapeutics