Pulmonary arterial hypertension (PAH) is a progressive condition with a poor prognosis. Platelet-derived growth factor receptor (PDGFR) signalling plays an important role in the pathobiology of this disease. We previously evaluated the use of imatinib, which inhibits PDGFR activity, in a phase II randomized clinical trial in PAH to evaluate safety, tolerability, and dosing. That phase II 24-week study suggested that imatinib is safe and well tolerated, and provided proof of concept for further studies evaluating its efficacy in PAH and suggested that patients on combination therapy with worse hemodynamics appeared to respond better than less impaired patients. This supports the use of agents targeting proliferative growth factor pathways in PAH. Particularly in the most severely affected but an additional study is needed to confirm these findings.
The proposed trial will include 200 patients (males and females ≥ 18 years of age with a diagnosis of severe PAH, defined as symptomatic patients on ≥ 2 PAH therapies and PVR > 1,000 dynes.sec.cm-5, are being enrolled in a phase III 24-week, multi-center, international, double-blind, placebo-controlled randomized clinical trial evaluating oral imatinib (400 mg qd) as add-on therapy for severe PAH. The primary endpoint is 6MWD; secondary endpoints include: Time to clinical worsening (TTCW) and hemodynamics. Exploratory endpoints include echocardiography to assess right ventricular performance as a measure of efficacy in PAH treatment. All patients will be on ≥ 2 PAH therapies ( ≥ 3 months); treatment for WHO Class IV subjects must include a prostacyclin analog.
The data on the most severe patients was retrospective and underpowered, but suggested a clinical benefit. The results of the proposed trial will confirm these findings.
The phase II data suggested that PAH patients with more severe disease may have the greatest benefit-risk ratio; a new phase III study is focusing on this group.
Use of imatinib is not recommended until definitive evidence of safety and efficacy has been demonstrated.
Robyn Barst, Employee Steven Pascoe and Deborah Quinn are employes of Novartis.The other authors of this abstract receive support as advisors to Novartis.; Other Imatinib is approved for other indications.; No Product/Research Disclosure Information