First-in-human intrapulmonary intratarget microdosing of a novel dual inflammasome inhibitor of NLRP 1/ NLRP 3 in ex vivo human lungs and patients with interstitial lung disease

The development of lung-directed therapeutics is limited by poor translational fidelity between preclinical models and early-phase clinical trials. We report a first-in-human Phase 0 intratarget microdosing study demonstrating the feasibility of intrapulmonary delivery and pharmacological interrogation of a novel inflammasome inhibitor. A 100 g microdose of ADS032, a dual NLRP1/NLRP3 inhibitor, was administered to distal airways via bronchoscopy in patients with interstitial lung disease, informed by optimisation in ex vivo human lung perfusion and ventilation systems. Clinical-grade manufacture, formulation, stability, and toxicology enabled intrapulmonary administration. Using liquid chrom