Phase 2b trial of inhaled imatinib for treatment of pulmonary arterial hypertension

INTRODUCTION/BACKGROUND: Oral imatinib, a tyrosine kinase inhibitor, demonstrated efficacy in pulmonary arterial hypertension (PAH) studies but was poorly tolerated. We report here the findings of a study using a dry powder inhaled version of imatinib (AV-101). AIMS AND OBJECTIVES: IMPAHCT (NCT05036135) was designed to assess the efficacy, safety, tolerability, and optimal dose of AV-101 as an add-on treatment for PAH, using a novel phase 2b/3 adaptive study design. Here we report the phase 2b results. METHODS: The phase 2b part assessed 3 doses of AV-101 (10 mg, 35 mg, and 70 mg), administered twice a day, vs placebo for 24 weeks as an add-on treatment in adults with PAH. Change in pulmonary vascular resistance (PVR) was the primary endpoint. Secondary endpoints included the change in other hemodynamic variables, 6-minute walk distance (6MWD), World Health Organization functional class, Registry to Evaluate Early and Long-Term PAH Disease Management Lite 2 risk score, clinical worsening, clinical improvement, N-terminal proB-type natriuretic peptide, quality of life, safety, and tolerability. RESULTS: In total, 202 patients were randomized. Baseline characteristics were broadly well balanced between groups. There were no significant improvements vs placebo in PVR (42.8 dyn·s·cm-5 in the AV-101 10-mg group, -5.5 dyn·s·cm-5 in the AV-101 35-mg group, -57.0 dyn·s·cm-5 in the AV-101 70-mg group, and 19.5 dyn·s·cm-5 in the placebo group), 6MWD, or other secondary endpoints at any dose. Pharmacokinetic measures supported delivery of drug to the lung and into the plasma. The incidence of cough increased with dose. No safety concerns were identified. CONCLUSIONS: Add-on dry powder inhaled imatinib (AV-101) was not effective in lowering PVR at any of the studied doses in patients with PAH. The phase 3 part of the IMPAHCT study was halted.