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
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 2022
UL http://openres.ersjournals.com/content/early/2022/10/13/23120541.00433-2022.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 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.FootnotesThis manuscript has recently been accepted for publication in the ERJ Open Research. It is published here in its accepted form prior to copyediting and typesetting by our production team. After these production processes are complete and the authors have approved the resulting proofs, the article will move to the latest issue of the ERJOR online. Please open or download the PDF to view this article.Conflict of Interest: Hunter Gillies, Ralph Niven, and Benjamin Dake are employees of Aerovate Therapeutics, Inc.Conflict of Interest: Murali M. Chakinala received research grants/funding from Acceleron Pharma, Actelion, Eiger Biopharmaceuticals, Gossamer Bio, Medtronic, and United Therapeutics Corporation; served as a consultant for Actelion, Altavant Sciences, Inc., Express Scripts Holding Company, Liquidia Technologies, Inc., PhaseBio Pharmaceuticals, United Therapeutics Corporation, and WebMD LLC (Medscape).Conflict of Interest: Jeremy P. Feldman received honoraria from Acceleron Pharma, Altavant Sciences, Bayer, Gilead Sciences, and United Therapeutics Corporation.Conflict of Interest: Marc Humbert received research grants/funding from Acceleron Pharma, Aerovate Therapeutics, Altavant Sciences, Inc., Bayer, Janssen Pharmaceuticals, Merck, Morphogen-IX Limited, and United Therapeutics Corporation; and received honoraria from Acceleron Pharma, Actelion, Bayer, GlaxoSmithKline, Merck, and United Therapeutics Corporation.Conflict of Interest: Martin Kankam is an employee of Altasciences Kansas, Inc.; and received research grants/funding from Actelion, Acurx, Biogen, BioXcel, DynPort Vaccine Company, Grifols, Jazz Pharmaceuticals, Novo Nordisk, Novus, Pfizer, Urovant Sciences, ViroDefense, and the US Food and Drug Administration/National Institutes of Health.Conflict of Interest: Nicholas S. Hill, Marius M. Hoeper, and Vallerie V. McLaughlin have no disclosures to declare.