Hunter Gillies, Ralph Niven, Benjamin T. Dake, Murali M. Chakinala, Jeremy P. Feldman, Nicholas S. Hill, Marius M. Hoeper, Marc Humbert, Vallerie V. McLaughlin, Martin Kankam
ERJ Open Research 2022; DOI: 10.1183/23120541.00433-2022

Abstract

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 5 AV-101 cohorts (1, 3, 10, 30, 90 mg) and placebo, and a single-dose oral imatinib 400-mg cohort. The MAD study included 3 AV-101 cohorts (10, 30, 90 mg) and placebo; dosing occurred twice daily for 7 days.

Results Eighty-two 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; NCT05036135) will evaluate the safety/tolerability and clinical benefit of AV-101 for PAH.