Basel, July 9, 2010 – The proof of concept study to assess the safety, tolerability and efficacy of QTI571 (imatinib) in patients with pulmonary arterial hypertension (PAH) is published today in the American Journal of Respiratory and Critical Care Medicine (Am J Respir Crit Care Med, also known as The Blue Journal)1. QTI571, a tyrosine kinase inhibitor, was studied in patients with PAH not adequately controlled with currently licensed medications1. QTI571 significantly improved exercise capacity and pulmonary haemodynamics compared with placebo in patients with severe PAH1.
The 24-week proof of concept study, which involved 59 patients in the intention to treat (ITT) population, showed a significant decrease in pulmonary vascular resistance (PVR) (p=0.0004)1 and a significant increase in cardiac output (p=0.02)1 when compared with placebo, but the primary endpoint, mean 6-minute walking distance (6MWD), did not change significantly (p=0.21)1. However, a post-hoc subgroup analysis of the same data among severe patients demonstrated a significant increase in 6MWD1. This difference suggests that more severe PAH patients may respond better to QTI571. QTI571 was generally well-tolerated in PAH patients1. While nausea and headache were more common with QTI571 than with placebo, the majority of adverse events in both groups was deemed to be mild or moderate in intensity1.
An open-label extension study in 16 patients who had been treated with QTI571 for two to three years, looking at long-term safety and tolerability, was presented in May at the American Thoracic Society 2010 International Conference in New Orleans, USA. The initial improvement in exercise capacity (6MWD) was maintained in these patients over this period2.
As a result of the proof of concept findings, a Phase III trial (IMPRES: Imatinib in Pulmonary arterial hypertension, a Randomized Efficacy Study) continues to recruit 200 patients in 14 countries to further investigate the efficacy and safety of QTI571 in severe PAH2.
“These published results are encouraging, although we need to await the results of the ongoing Phase III trial to provide definitive evidence of safety and efficacy,’’ said Professor Ardeschir Ghofrani, MD, Giessen, Germany. “For patients with a poor prognosis and few remaining treatment options, clinicians need new approaches to treat this rapidly progressive disease.”
Current treatment options for PAH focus on vasodilation, whereas QTI571 primarily targets the underlying cause of the disease by counteracting uncontrolled growth of arterial smooth muscle cells. QTI571 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 thought to be involved in the progression of PAH. In patients with PAH, PDGFR may cause smooth muscle cells in the pulmonary arteries to multiply, resulting in the constriction of these arteries5.
“New treatment options for PAH need to go beyond treating symptoms and look at the underlying cause of the disease,” said Trevor Mundel, MD, Global Head of Development at Novartis Pharma AG. “These latest data reinforce the Novartis commitment to improving patients’ respiratory health, especially for patients with serious diseases such as PAH.”
PAH is a debilitating disease characterized by a marked and sustained elevation in pulmonary artery pressure6. PAH affects approximately 130,000 to 260,000 people worldwide5 and is progressive, leading to heart failure and death6. Apart from transplantation, there is no known cure for PAH and the goal of current treatments is to control symptoms of the disease7. The prognosis for many PAH patients is similar to that of some advanced cancers8. QTI571 is in the early stages of investigation as a potential therapy for PAH and is not approved in any market for treatment of PAH. Imatinib is approved under the trade names Gleevec®/Glivec® for the treatment of certain cancers.
*In this study severe PAH was defined as patients with a pulmonary vascular resistance (PVR) of = 1,000.
Disclaimer The foregoing release contains forward-looking statements that can be identified by terminology such as “potential,” “to further investigate,” “suggest,” “may,” “encouraging,” “commitment,” or similar expressions, or by express or implied discussions regarding potential new indications or labeling for QTI571 or regarding potential future revenues from QTI571. You should not place undue reliance on these statements. Such forward-looking statements reflect the current views of management regarding future events, and involve known and unknown risks, uncertainties and other factors that may cause actual results with QTI571 to be materially different from any future results, performance or achievements expressed or implied by such statements. There can be no guarantee that QTI571 will be approved for any additional indications or labeling in any market. Nor can there be any guarantee that QTI571 will achieve any particular levels of revenue in the future. In particular, management’s expectations regarding QTI571 could be affected by, among other things, unexpected clinical trial results, including unexpected new clinical data and unexpected additional analysis of existing clinical data; the company’s ability to obtain or maintain patent or other proprietary intellectual property protection; unexpected regulatory actions or delays or government regulation generally; competition in general; government, industry and general public pricing pressures; the impact that the foregoing factors could have on the values attributed to the Novartis Group’s assets and liabilities as recorded in the Group’s consolidated balance sheet, and other risks and factors referred to in Novartis AG’s current Form 20-F on file with the US Securities and Exchange Commission. Should one or more of these risks or uncertainties materialize, or should underlying assumptions prove incorrect, actual results may vary materially from those anticipated, believed, estimated or expected. Novartis is providing the information in this press release as of this date and does not undertake any obligation to update any forward-looking statements contained in this press release as a result of new information, future events or otherwise.
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References 1. Ghofrani HA, Morrell NW, Hoeper MM, Olschewski H et al., Imatinib in Pulmonary Arterial Hypertension Patients with Inadequate Response to Established Therapy. AJRCC 2010. ePub ahead of publication: http://ajrccm.atsjournals.org/cgi/content/abstract/201001-0123OCv1 2. Barst RJ, Ghofrani HA, Morrell NW, Hoeper MM et al., Imatinib Mesylate Treatment for Severe Pulmonary Arterial Hypertension: A Proposed Phase III 24-Week Double-Blind Placebo-Controlled Randomized Clinical Trial. Abstract presented at ATS 2010 International Conference, New Orleans, USA, 17 May 2010 3. Ghofrani HA, Morrell NW, Hoeper MM Olschewski H et al., Long Term Use of Imatinib in Patients With Severe Pulmonary Arterial Hypertension, Abstract presented at ATS 2010 International Conference, New Orleans, USA, 18 May 2010 4. Kawut SM, Horn EM, Berekashvili KK, et al., New predictors of outcome in idiopathic pulmonary arterial hypertension. Am J Cardiol. 2005 15;95(2):199-203 5. Novartis data on file 6. Schermuly RT et al., Reversal of experimental pulmonary hypertension by PDGF inhibition. J Clin Invest. 2005 Oct;115(10):2811-21 7. National Library of Medicine Medical Encyclopedia. Pulmonary hypertension. http://www.nlm.nih.gov/medlineplus/ency/article/000112.htm (accessed May 2010) 8. Barst RJ, PDGF signaling in pulmonary arterial hypertension. J Clin Invest. 2005;15(10):2691-2694
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