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
Quinn, T. M.; Li, F.; Wheeler, B.; Dickson, S.; Hamilton, K.; Fernando, A.; Lochenie, C.; Mair, J.; McNamara, S.; Linton, K.; Gaughan, E.; O'Connor, R.; Pellicoro, A.; Russell, K.; Bruce, A.; Denham, S.; Homer, N.; Mansell, A.; Shankar-Hari, M.; Rossi, A.; Akram, A.; Finlayson, K.; Hirani, N.; Dhaliwal, K.
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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 chromatography-mass spectrometry, ADS032 was detected in plasma, bronchoalveolar lavage fluid, distal airway micro-aspirates, and recovered cells, with spatially resolved sampling achieved without cross-contamination. Fluorescent labelling enabled direct visualisation of alveolar drug uptake ex vivo. These findings establish intrapulmonary intratarget microdosing as a human-relevant platform for early pharmacological evaluation of lung therapeutics prior to Phase 1 trials.
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