Imatinib is a small molecule inhibitor of BCR-ABL tyrosine kinase inhibitor that also inhibits platelet derived growth factor (PDGF) receptor and c-Kit tyrosine kinases. Imatinib activity interrupts cellular processes involved in cancer, cellular proliferation and other events. For AP04, our main interest involves inhibition of PDGF-mediated smooth muscle cell proliferation in patients with pulmonary arterial hypertension (PAH). PAH is a disease of the pulmonary vasculature involving smooth muscle cell proliferation and, together with other factors, formation of plexiform lesions blocking blood flow. Such blockage feeds increased pressures to the heart ultimately causing right heart failure. Approved therapies for PAH focus on vascular dilation and symptomatic mechanisms. Treatment with imatinib may mechanistically affect the pathophysiology of the disease itself, positioning imatinib as a potential PAH disease modifying agent.
A previous PAH study with oral imatinib met clinical endpoints in six minute walk distance, pulmonary vascular resistance and cardiac output. However, oral imatinib failed time to clinical worsening, in large part due to high oral dose-related severe adverse events. To address this issue and enable treatment, our nonclinical data suggests that small inhaled imatinib doses delivered directly to the lung result in oral-superior lung levels. Because these doses are small, resulting blood levels are well-below those following oral delivery, holding promise to substantially reduce oral-observed side effects while maintaining imatinib’s potential to positively impact disease in the lung.