Actelion Pharmaceuticals Ltd / Phase III PAH outcome study with macitentan (Opsumit) presented at CHEST - Significant reduction in the risk of morbidity and mortality . Processed and transmitted by Thomson Reuters ONE. The issuer is solely responsible for the content of this announcement.
ALLSCHWIL/BASEL, SWITZERLAND - 23 October 2012 - Actelion (SIX: ATLN) announced that the results from the Phase III long-term outcome study with macitentan (Opsumit®) in patients with pulmonary arterial hypertension (PAH) were presented by Lewis J. Rubin, M.D. today at the 2012 annual CHEST meeting of the American College of Chest Physicians (ACCP) in Atlanta, USA. In the pivotal, long-term, event-driven SERAPHIN study, macitentan administered once daily provided a significant and clinically relevant reduction in the risk of morbidity and mortality.
SERAPHIN met its primary endpoint by demonstrating that macitentan 10 mg once daily reduced the risk of morbidity and mortality by 45 percent as compared to placebo (p<0.0001), providing a strong and sustained benefit to patients suffering from PAH. Macitentan 3 mg once daily reduced the risk of morbidity and mortality by 30 percent (p=0.0108).
In this Phase III double-blind, placebo-controlled trial, 742 patients suffering from PAH were randomized to placebo, macitentan 3 mg or macitentan 10 mg. Mean exposure to study treatment was 85.3 weeks for placebo patients (n=249), 99.5 weeks for patients on 3 mg (n=250) and 103.9 weeks for patients on 10 mg (n=242).
When entering the study, 64 percent of patients were already receiving therapy for PAH, almost exclusively in the form of phosphodiesterase-5 inhibitors. At baseline, 53 percent of patients were in WHO Functional Class I/II, 47 percent were in Functional Class III/IV.
Lewis J. Rubin, M.D., Emeritus Professor, University of California, San Diego and Senior Advisor on SERAPHIN, commented: "The SERAPHIN study clearly has shown that treatment with macitentan results in an improved outcome of patients with PAH and macitentan has the potential to change the course of the disease. The rigorous methodology and conduct of the SERAPHIN study as the first PAH outcome study also sets a new standard on how to evaluate emerging PAH therapies".
Consistent secondary endpoint findings
The study also demonstrated that macitentan reduces the risk of death due to PAH or hospitalization for PAH, one of the secondary endpoints of the study, by 33 percent (3 mg, p=0.0146) and 50 percent (10 mg, p<0.0001) as compared to placebo. In addition, the evaluation of survival, while not statistically significant, showed that macitentan 10 mg reduced the risk of all-cause mortality by 36 percent (p=0.2037).
Patients treated with macitentan 10 mg once a day also experienced a clinically relevant functional improvement, as shown by the baseline adjusted, placebo corrected mean increase in 6-minute walking distance measured at month 6 (secondary endpoint) by 23 meters (p=0.007) with a more pronounced treatment effect in patients in WHO Functional Class III/IV at baseline (+37 meters; p=0.009).
Safety and tolerability
Macitentan in this patient population was well tolerated. The overall incidence of adverse events reported and treatment discontinuations due to adverse events in patients was similar across all groups. The incidence of serious adverse events was lower in patients treated with macitentan as compared to placebo with 52 percent and 45 percent of patients in the macitentan 3 mg and 10 mg groups, respectively, who experienced serious adverse events, and 55 % of patients in the placebo group. The most frequent adverse events associated with the use of macitentan are nasopharyngitis, headache and anemia.
Elevations of liver alanine or aspartate aminotransferases greater than three times the upper limit of normal were observed in 4.5 percent of patients receiving placebo, in 3.6 percent of patients on 3 mg of macitentan and in 3.4 percent of patients on 10 mg of macitentan. In addition, no difference was observed between macitentan and placebo on fluid retention (edema).
A decrease in hemoglobin - reported as an adverse event - was observed more frequently on macitentan than placebo, with no difference in treatment discontinuation between groups.
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About macitentan (Opsumit®)
Macitentan (Opsumit®) is a novel dual endothelin receptor antagonist (ERA) that resulted from a tailored drug discovery process with the target to develop an ERA optimized for efficacy and safety [2]. Macitentan has a number of potentially key beneficial characteristics i.e., increased in vivo preclinical efficacy vs. existing ERAs resulting from sustained receptor binding [3] and physicochemical properties that allow an enhanced penetration into tissue [4]. A clinical pharmacology program indicated a low propensity of macitentan for drug-drug interactions [5,6,7]
About macitentan (Opsumit®) submissions to healthcare authorities
On 22nd October 2012 Actelion announced that it had submitted a new drug application to the Food and Drug Administration (FDA) seeking approval for macitentan (Opsumit®) in patients with pulmonary arterial hypertension.
About the SERAPHIN study
SERAPHIN (Study with an Endothelin Receptor Antagonist in Pulmonary arterial Hypertension to Improve cliNical outcome) was the largest and longest randomized, controlled study in PAH patients to include a clearly defined morbidity/mortality primary endpoint [1]. The pivotal Phase III study was designed to evaluate the efficacy and safety of macitentan (Opsumit®) - a novel dual endothelin receptor antagonist that resulted from a tailored drug discovery process - through the primary endpoint of time to first morbidity and all-cause mortality event in patients with symptomatic PAH.
Global enrollment was completed in December 2009 with a total of 742 patients. Patients were randomized 1:1:1 to receive two different doses of macitentan (3 mg and 10 mg once daily) or placebo. Patients were allowed to receive PAH background therapy throughout the study, either PDE-5 inhibitors or oral/inhaled prostanoids. This event-driven study was conducted in 151 centers from almost 40 countries in North and Latin America, Europe, Asia-Pacific and Africa and was completed in the first half of 2012, with 287 patients having an adjudicated event.
About Pulmonary Arterial Hypertension
Pulmonary arterial hypertension (PAH) is a chronic, life-threatening disorder characterized by abnormally high blood pressure in the arteries between the heart and lungs of an affected individual. The symptoms of PAH are non-specific and can range from mild breathlessness and fatigue during normal daily activity to symptoms of right heart failure and severe restrictions on exercise capacity and ultimately reduced life expectancy.
PAH is one group within the classification of pulmonary hypertension (PH). This group includes idiopathic PAH, heritable PAH and PAH caused by factors which include connective tissue disease, HIV infection and congenital heart disease.
The last decade has seen significant advances in the understanding of the pathophysiology of PAH, which has been paralleled with developments of treatment guidelines and new therapies. Drugs targeting the 3 pathways that have been established in the pathogenesis of PAH are endothelin receptor antagonists (ERAs), prostacyclins and phosphodiesterase-5 inhibitors. PAH treatments have transformed the prognosis for PAH patients from symptomatic improvements in exercise tolerance 10 years ago to delayed disease progression today. Improved disease awareness and evidence-based guidelines developed from randomized controlled clinical trial data have highlighted the need for early intervention, goal-oriented treatment and combination therapy.
Despite these advances in PAH, survival rates are unacceptably low and PAH remains incurable.
References
1. For a general discussion of a clinically meaningful outcome end-point, please see: Proceedings of the 4th world symposium on pulmonary hypertension. J Am Coll Cardiol 2009;54(1 Suppl).
2. Bolli MH et al. The Discovery of N-[5-(4-Bromophenyl)-6-[2-[(5-bromo-2-pyrimidinyl)oxy]ethoxy]-4-pyrimidinyl]-N'-propylsulfamide (Macitentan), an Orally Active, Potent Dual Endothelin Receptor Antagonist. J Med Chem. 2012; 55:7849-61.
3. Gatfield J, Mueller Grandjean C, Sasse T, Clozel M, Nayler O (2012). Slow Receptor Dissociation Kinetics Differentiate Macitentan from Other Endothelin Receptor Antagonists in Pulmonary Arterial Smooth Muscle Cells. PLOS ONE 7(10): e47662. doi:10.1371/journal.pone.0047662
4. Iglarz M et al. Pharmacology of macitentan, an orally active tissue-targeting dual endothelin receptor antagonist. J Pharmacol Exp Ther. 2008;327(3):736-45.
5. Sidharta PN et al. Macitentan: Entry-into-humans study with a new endothelin receptor antagonist. Eur J Clin Pharmacol. 2011;67(10):977-84
6. Bruderer S et al. Absorption, distribution, metabolism, and excretion of macitentan, a dual endothelin receptor antagonist, in humans. Xenobiotica. 2012 Sep;42(9):901-10
7. Bruderer S et al. Effect of cyclosporine A and rifampin on the pharmacokinetics of macitentan, a tissue-targeting dual endothelin receptor antagonist. AAPS J. 2012;14(1):68-78.
Actelion Ltd
Actelion Ltd is a biopharmaceutical company with its corporate headquarters in Allschwil/Basel, Switzerland. Actelion's first drug Tracleer®, an orally available dual endothelin receptor antagonist, has been approved as a therapy for pulmonary arterial hypertension. Actelion markets Tracleer through its own subsidiaries in key markets worldwide, including the United States (based in South San Francisco), the European Union, Japan, Canada, Australia and Switzerland. Actelion, founded in late 1997, is a leading player in innovative science related to the endothelium - the single layer of cells separating every blood vessel from the blood stream. Actelion's over 2,400 employees focus on the discovery, development and marketing of innovative drugs for significant unmet medical needs. Actelion shares are traded on the SIX Swiss Exchange (ticker symbol: ATLN) as part of the Swiss blue-chip index SMI (Swiss Market Index SMI®).
For further information please contact:
Roland Haefeli
Senior Vice President, Head of Investor Relations & Public Affairs
Actelion Pharmaceuticals Ltd, Gewerbestrasse 16, CH-4123 Allschwil
+41 61 565 62 62
+1 650 624 69 36
www.actelion.com (http://www.actelion.com/)
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