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.
Footnotes
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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.
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- Received August 26, 2022.
- Accepted October 16, 2022.
- Copyright ©The authors 2022
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