Imatinib in Pulmonary Arterial Hypertension Patients with Inadequate Response to Established Therapy

Abstract

Rationale: Pulmonary arterial hypertension (PAH) is a progressive condition with a poor prognosis. Platelet-derived growth factor receptor (PDGFR) signaling plays an important role in its pathobiology. Objectives: To assess safety, tolerability, and efficacy of the PDGFR inhibitor imatinib in patients with PAH. Methods: Patients with PAH in functional classes II-IV were enrolled in a 24-week randomized, double-blind, placebo-controlled pilot study. Patients received imatinib (an inhibitor of PDGFR activity) 200 mg orally once daily (or placebo), which was increased to 400 mg if the initial dose was well tolerated. The primary endpoints were safety and change from baseline in the 6-minute-walk distance (6MWD). Secondary endpoints included hemodynamics and functional classification. Measurements and Main Results: Fifty-nine patients enrolled (imatinib [n 5 28]; placebo [n 5 31]); 42 completed the study. Dropouts were equally matched between the two groups. In the intention-to-treat (ITT) population there was no significant change in the 6MWD (mean 6 SD) in the imatinib versus placebo group (122 6 63 versus 21.0 6 53 m). There was a significant decrease in pulmonary vascular resistance (imatinib 2300 6 347 versus placebo -78 6 269 dynes Á s Á cm 25 , P , 0.01) and increase in cardiac output (imatinib 10.6 6 1.2 versus placebo 20.1 6 0.9 L/min, P 5 0.02). Serious adverse events occurred in 11 imatinib recipients (39%) and 7 placebo recipients (23%). Three deaths occurred in each group. Post hoc subgroup analyses suggest that patients with greater hemodynamic impairment may respond better than patients with less impairment. Conclusions: These data from a Phase II study are consistent with imatinib being well tolerated in patients with PAH, and provide proof of concept for further studies evaluating its safety, tolerability, and efficacy in PAH. Clinical trial registered with www.clinicaltrials.gov (NCT00477269).

Imatinib is Partially Effective for the Treatment of Pulmonary Capillary Hemangiomatosis

“…These results suggest that the administration of imatinib in addition to other therapies, such as endothelin receptor blockers and phosphodiesterase-5 inhibitors, has the potential to be effective for severe pulmonary artery hypertension. In the present case, the PVR before treatment with imatinib was 1,310 dynesec/cm 5 . Therefore, imatinib appeared to be effective for this patient.…”

“…Imatinib may be specifically effective for PCH due to the inhibitory effects of several tyrosine kinase activities (3)(4)(5). Moreover, imatinib exhibits antiproliferative and proapoptotic effects on smooth muscle cells stimulated with platelet-derived growth factor (PDGF) in subjects with idiopathic PAH (8).…”

“…Right heart catheterization demonstrated a pulmonary arterial pressure (PAP) of 64/22/35 mmHg (systolic/diastolic/mean) and a pulmonary capillary wedge pressure of 2 mmHg. The pulmonary vascular resistance (PVR) was 1,310 dynesec/cm 5 . Perfusion lung scintigraphy did not show any abnormal perfusion defects.…”

Nuclear IL-33 regulates soluble ST2 receptor and IL-6 expression in primary human arterial endothelial cells and is decreased in idiopathic pulmonary arterial hypertension

“…The behaviour of vascular cells in IPAH has been likened to mitogenic cells [36][37][38] and excessive expression or activity of growth factors including platelet-derived growth factor (PDGF), epidermal growth factor (EGF) and vascular endothelial growth factor (VEGF) contributes to pulmonary vascular remodelling. In keeping with these data, inhibition of EGF and PDGF receptors has beneficial effects on haemodynamic, remodelling, and survival in experimental PAH [39][40]. It is therefore possible that sST2 may also function as a co-factor to so far unrecognised growth factor receptors and, thereby, contribute to excessive pulmonary vascular and right ventricular remodelling associated with IPAH.…”

Pulmonary tumour thrombotic microangiopathy

“…Immunohistochemical studies support a basis for blockade of PDGF in PTTM [4,8,9]. PDGF signalling is also implicated in PAH [42], although clinical studies of imatinib in PAH have been complicated by adverse events including subdural haematomas in patients receiving anticoagulation [43]. 29].…”