Imatinib is a tyrosine kinase inhibitor that has been on the market for more than 20 years to treat a type of leukemia. It acts by turning off tyrosine kinases. You can think of tyrosine kinases as critical switches in cells that turn on and off critical pathways. Too much of an “on” signal leads to dysregulated cell proliferation and growth—such as seen in the pulmonary arteries of PAH patients or in the bone marrow of patients with leukemia. Imatinib revolutionized the treatment for chronic myelogenous leukemia.
A decade ago, we participated in a groundbreaking clinical trial investigating the role of Imatinib in the treatment of pulmonary arterial hypertension. This study included the sickest patients with more than a third of patients on three other PAH-specific medications. After 24 weeks, the active treatment group had a 32-meter improvement in six-minute walk distance and a 32% decrease in pulmonary vascular resistance. Side effects were common with many patients experiencing nausea and edema. Of note, there were more bleeding complications in the imatinib group, though all of these patients were also taking blood thinners. Unfortunately, Novartis chose not to pursue further development of oral imatinib large relating to loss of patent protection. Thus, for the past 9 years this potentially important therapy has languished on the shelf.
Fast forward nine years and we are rediscovering the importance of imatinib. Aerovate has just started a phase2/3 clinical trial using inhaled imatinib. This innovative clinical trial will test several doses of inhaled imatinib against placebo. The primary endpoints are pulmonary vascular resistance and six-minute walk distance. The concept of using imatinib by inhalation seeks to maximize the benefits of the medication in the lungs while minimizing the systemic side effects of the medication.
If inhaled imatinib can deliver the efficacy results seen with oral imatinib but reduce the side effects, this new medication may be a game-changer for patients with PAH.