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Imatinib Mesylate Treatment for Severe Pulmonary Arterial Hypertension: A Proposed Phase III 24–Week Double-Blind Placebo-Controlled Randomized Trial

Robyn Barst

Hossein-Ardeschir Ghofrani

Nicholas Morrell

Marius Hoeper

Horst Olschewski

Andrew Peacock

Shelley Shapiro

S. Pascoe

D. A. Quinn


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Conference: 2010 International PHA Conference and Scientific Sessions

Release Date: 06.24.2010

Presentation Type: Abstracts

Barst RJ1, Ghofrani HA2, Morrell NW3, Hoeper MM4, Olschewski H5, Peacock AJ6, Shapiro S7, Pascoe S8, Quinn DA9.
1. Professor Emerita, Columbia University, New York, NY, USA
2. University Hospital Giessen and Marburg GmbH, Giessen, Germany
3. Addenbrookes and Papworth Hospitals, Cambridge, UK
4. Medizinische Hochschule, Hannover, Germany
5. Medical University Graz Auenbruggerplatz, Graz, Austria
6. Golden Jubilee National Hospital, Glasgow, UK
7. West Los Angeles Veterans Administration Healthcare Center, Los Angeles, CA, USA
8. Novartis Pharma AG, Basel, Switzerland
9. Novartis Pharmaceuticals, Cambridge, MA, USA

BACKGROUND: Pulmonary arterial hypertension (PAH) is a progressive condition with a poor prognosis. Platelet-derived growth factor receptor (PDGFR) signaling 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.

METHODS: 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, are being enrolled in a Phase III 24-week, multi-center, international, double-blind, placebo-controlled randomized clinical trial evaluating oral imatinib (400 mg q.d.) 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.

RESULTS: 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.

CONCLUSIONS: 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 in PAH is not recommended until definitive evidence of safety and efficacy has been demonstrated.