Positioning Imatinib for pulmonary arterial hypertension: a dose finding phase 2 study

RATIONALE: Imatinib 400mg daily reduces pulmonary vascular resistance and improves exercise capacity in patients with pulmonary arterial hypertension. Concerns about safety and tolerability limit its use.

OBJECTIVES: To identify a safe and tolerated dose of oral imatinib between 100mg and 400mg daily and evaluate its efficacy.

METHODS: Oral imatinib was added to the background therapy of 17 patients with pulmonary arterial hypertension, including 13 implanted with devices providing daily measurements of cardiopulmonary haemodynamics and physical activity. The first patient started on 100mg daily. The next 12 patients, recruited serially, started on 200mg, 300mg or 400mg daily, following a Continuous Reassessment Method sequence. An extension cohort (patients 14 to 17) received 100mg or 200mg daily.

MEASUREMENTS AND MAIN RESULTS: The Continuous Assessment Method recommended starting dose was 200mg daily. The most common side effect was nausea. Imatinib reduced mean pulmonary artery pressure (-6.5 mmHg, 95%CI -2.4 to -10.6, P<0.01) and total pulmonary resistance (-2.8 Wood Units, 95%CI -1.5 to -4.2, P<0.001) with no significant change in cardiac output. The reduction in total pulmonary resistance was dose and exposure-dependent; the reduction from baseline with imatinib 200mg daily was -20.3% (95%CI -14.3 to -26.3%). Total pulmonary resistance and night heart rate declined steadily over the first 28 days of treatment and remained below baseline up to 40 days following imatinib withdrawal.

CONCLUSIONS: Oral imatinib 200mg daily is well tolerated as an add-on treatment in pulmonary arterial hypertension. A delay in the return of cardiopulmonary haemodynamics to baseline was observed after stopping imatinib. Clinical trial registration available at www.

CLINICALTRIALS: gov, ID: NCT04416750 This article is open access and distributed under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/).