An early proof-of-concept study presented shows promising results for imatinib mesylate in the treatment of pulmonary arterial hypertension (PAH), a severe, incurable blood vessel disorder.

Preliminary findings from a 59-patient, multi-center Phase II clinical trial suggest imatinib mesylate provides a treatment benefit, as demonstrated by a significant improvement in pulmonary vascular resistance and a numerical increase in cardiac output, key hemodynamic measures used to monitor the progression of the disease. Improvements in the six-minute walk test, the primary endpoint of the study, approached, but did not reach, statistical significance.

These initial data were presented today at the European Respiratory Society (ERS) congress in Berlin, Germany, and further details on the study are expected to be published later this year. Imatinib mesylate is available for oncology indications as Gleevec(R) in the US, Canada and Israel and as Glivec(R) (imatinib), in countries outside of the US, Canada and Israel.

"The outcomes of this trial are clinically important given the rapid progression of PAH and the poor prognosis for these patients," said Professor Ardeschir Ghofrani, MD, Head of Pulmonary Hypertension Division, University Hospital Giessen und Marburg, Germany. "Our observations suggest that imatinib mesylate holds promise in treating PAH."

PAH is a debilitating disease that is characterized by a marked and sustained elevation in pulmonary artery pressure(1). The disease is rapidly progressive and can result in heart failure and death(1). There is no known cure for PAH and the goal of current treatments is to control symptoms of the disease(2). The prognosis for many PAH patients is similar to that of some advanced cancers, and with current treatment options, the five-year survival rate is 50%(3).

Imatinib mesylate is an orally administered targeted therapy that has successfully treated many patients with certain rare cancers. It works by inhibiting the activity of several proteins called tyrosine kinases, such as Bcr-Abl, c-KIT and platelet-derived growth factor receptor (PDGFR), which is also thought to be involved in the progression of PAH(3). In patients with PAH, PDGFR may cause smooth muscle cells in the pulmonary arteries to multiply, resulting in the constriction of these arteries(4).

Plans for research to further explore the potential of imatinib mesylate in PAH are ongoing and will be announced at a later date.

The double blind, placebo-controlled trial presented at ERS enrolled 59 patients with PAH to evaluate the effectiveness and safety of imatinib mesylate 400 mg. The study participants had previously failed to improve after receiving standard therapy with prostanoids, endothelin antagonists or PDE-5 inhibitors.

"There is a high unmet need for new treatments that address the underlying mechanisms of PAH," said David Epstein, President and CEO of Novartis Oncology. "These early findings support exploring the potential of imatinib mesylate in PAH in a larger randomized clinical trial."

1. It is estimated that approximately 130,000 to 260,000 people worldwide have PAH(5). The mean age at diagnosis is 35 years, and most patients present with moderate-to-severe disease. PAH occurs most often in otherwise healthy people, and more often in women than in men(4).

The exact process by which PAH develops is not known. However, it appears to be associated with a variety of disease processes, including chronic thromboembolic disease (blood clots), connective tissue diseases, congenital heart disease and exposure to external factors including appetite suppressants or infectious diseases such as HIV(3).

1. Novartis has also conducted early stage research with imatinib mesylate in another non-oncology disease called idiopathic pulmonary fibrosis (IPF), a condition in which the lungs become scarred over time, making it more and more difficult to breathe(6). Early clinical trial results in IPF did not show a significant treatment benefit over placebo, and clinical trials have therefore been halted.

About Gleevec

Gleevec(R) (imatinib mesylate) tablets are indicated for the treatment of newly diagnosed adult patients with Philadelphia chromosome-positive chronic myeloid leukemia (Ph+ CML) in the chronic phase. Follow-up is limited to 5 years. Gleevec is also indicated for the treatment of patients with Ph+ CML in blast crisis (BC), accelerated phase (AP), or in chronic phase (CP) after failure of interferon-alpha (IFN-alpha) therapy; adult patients with relapsed or refractory Ph+ acute lymphoblastic leukemia (Ph+ ALL); adult patients with myelodysplastic/myeloproliferative diseases (MDS/MPD) associated with PDGFR (platelet-derived growth factor receptor) gene rearrangements; adult patients with aggressive systemic mastocytosis (ASM) without the D816V c-KIT mutation or with c-KIT mutational status unknown; adult patients with hypereosinophilic syndrome (HES) and/or chronic eosinophilic leukemia (CEL) who have the FIP1L1-PDGFRα fusion kinase (mutational analysis or FISH demonstration of CHIC2 allele deletion) and for patients with HES and/or CEL who are FIP1L1-PDGFRα fusion kinase-negative or unknown; adult patients with unresectable, recurrent, and/or metastatic dermatofibrosarcoma protuberans (DFSP); patients with KIT (CD117)-positive unresectable and/or metastatic malignant gastrointestinal stromal tumors (GIST); pediatric patients with PH+ CML in the chronic phase who are newly diagnosed or whose disease has recurred after stem cell transplant or who are resistant to interferon-therapy. There are no controlled trials in pediatric patients demonstrating a clinical benefit, such as improvement in disease-related symptoms or increased survival.

Important safety information(7)

Fetal harm can occur when Gleevec is administered to a pregnant woman; therefore, women of childbearing potential should be advised to not become pregnant while taking Gleevec tablets and to avoid breast-feeding while taking Gleevec tablets because of the potential for serious adverse reactions in nursing infants. Sexually active female patients taking Gleevec should use adequate contraception. If the patient does become pregnant while taking Gleevec, the patient should be advised of the potential hazard to the fetus.

In adult Ph+ CML patients, severe (NCI Grades 3/4) lab abnormalities--including neutropenia (3.6%-48%), anemia (1%-42%), thrombocytopenia (