RT Journal Article SR Electronic T1 AV-101, a novel inhaled dry-powder formulation of imatinib, in healthy adult participants: a phase 1 single and multiple ascending dose study JF ERJ Open Research JO erjor FD European Respiratory Society SP 00433-2022 DO 10.1183/23120541.00433-2022 VO 9 IS 2 A1 Hunter Gillies A1 Ralph Niven A1 Benjamin T. Dake A1 Murali M. Chakinala A1 Jeremy P. Feldman A1 Nicholas S. Hill A1 Marius M. Hoeper A1 Marc Humbert A1 Vallerie V. McLaughlin A1 Martin Kankam YR 2023 UL http://openres.ersjournals.com/content/9/2/00433-2022.abstract AB Background Oral imatinib has been shown to be effective, but poorly tolerated, in patients with advanced pulmonary arterial hypertension (PAH). To maintain efficacy while improving tolerability, AV-101, a dry powder inhaled formulation of imatinib, was developed to deliver imatinib directly to the lungs.Methods This phase 1, placebo-controlled, randomised single ascending dose (SAD) and multiple ascending dose (MAD) study evaluated the safety/tolerability and pharmacokinetics of AV-101 in healthy adults. The SAD study included five AV-101 cohorts (1 mg, 3 mg, 10 mg, 30 mg, 90 mg) and placebo, and a single-dose oral imatinib 400-mg cohort. The MAD study included three AV-101 cohorts (10 mg, 30 mg, 90 mg) and placebo; dosing occurred twice daily for 7 days.Results 82 participants (SAD n=48, MAD n=34) were enrolled. For the SAD study, peak plasma concentrations of imatinib occurred within 3 h of dosing with lower systemic exposure compared to oral imatinib (p<0.001). For the MAD study, systemic exposure of imatinib was higher after multiple doses of AV-101 compared to a single dose, but steady-state plasma concentrations were lower for the highest AV-101 cohort (90 mg) compared to simulated steady-state oral imatinib at day 7 (p=0.0002). Across AV-101 MAD dose cohorts, the most common treatment-emergent adverse events were cough (n=7, 27%) and headache (n=4, 15%).Conclusions AV-101 was well tolerated in healthy adults, and targeted doses of AV-101 significantly reduced the systemic exposure of imatinib compared with oral imatinib. An ongoing phase 2b/phase 3 study (IMPAHCT; clinicaltrials.gov identifier NCT05036135) will evaluate the safety/tolerability and clinical benefit of AV-101 for PAH.AV-101, a dry-powder inhaled formulation of imatinib, reduces systemic exposure to imatinib versus oral imatinib and is well tolerated in healthy adults. An ongoing phase 2b/3 study will evaluate AV-101 in patients with pulmonary arterial hypertension. https://bit.ly/3Tlh6ru