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
Tom Quinn, Feng Li, Becky Wheeler, Stuart Dickson, Katie Hamilton, Anuruddika Fernando, Charles Lochenie, Joanne Mair, Sarah Mcnamara, Karen Linton, Erin Gaughan, Richard O’connor, Antonella Pellicoro, Kay Russell, Annya Bruce, Scott Denham, Natalie Homer, Ashley Mansell, Manu Shankar-Hari, Adriano Rossi, Ahsan Akram, Keith Finlayson, Nik Hirani, Kevin Dhaliwal
medRxiv Preprint Server May 5, 2026 preprint DOI: 10.64898/2026.05.05.26352329 via medRxiv
Summary
AI-generated from the abstractA first-in-human Phase 0 intratarget microdosing study shows that delivering a tiny dose of a new inflammasome inhibitor directly into the lungs of patients with interstitial lung disease is feasible. A 100 microgram microdose of ADS032, a dual NLRP1/NLRP3 inhibitor, was administered to distal airways via bronchoscopy. The drug was detected in plasma, bronchoalveolar lavage fluid, distal airway micro-aspirates, and recovered cells without cross-contamination. Fluorescent labeling allowed direct visualization of alveolar drug uptake in ex vivo human lung tissue. This intrapulmonary microdosing approach offers a human-relevant platform for early pharmacological evaluation of lung therapeutics before Phase 1 trials.
Study at a glance
| Characteristics | First-in-human Phase 0 intratarget microdosing study |
|---|---|
| Population | Patients with interstitial lung disease |
| Dose | 100 μg |
| Key finding | Intrapulmonary intratarget microdosing of a novel inflammasome inhibitor is feasible for early pharmacological evaluation in humans. |
Abstract
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 μg 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.