- Macitentan (Opsumit®) significantly reduced risk of morbidity/mortality events
- Macitentan currently in world-wide regulatory review
ALLSCHWIL / BASEL, SWITZERLAND - 29 August 2013 - Actelion (SIX: ATLN) announced today that the New England Journal of Medicine (NEJM) has published the results of SERAPHIN, the pivotal study with macitentan (Opsumit®) in patients with pulmonary arterial hypertension (PAH).
Dr Tomás Pulido, MD, Professor of Medicine and Head of the Cardiopulmonary Department, Ignacio Chávez National Heart Institute, Mexico City, primary author of the NEJM paper, commented: "I am very proud to be part of this exceptional study. The results published today in the NEJM show valuable long-term morbidity/mortality data from SERAPHIN, the largest-ever trial in PAH. I expect this landmark study to set a new standard in how the evidence for PAH therapies is measured."
The NEJM paper reports the findings of the SERAPHIN study, a Phase III trial in which 742 patients received either macitentan or placebo. The risk of a morbidity/mortality event - primary endpoint of the study - was reduced by 45% (p<0.001) with macitentan 10mg compared to placebo.
Dr Pulido concluded: "The SERAPHIN study considered several indicators of PAH progression in a robustly defined endpoint and demonstrated that macitentan significantly reduced the risk of morbidity and mortality in both treatment-naïve patients and those on background therapy for PAH."
The effect of macitentan on the primary endpoint was observed irrespective of whether or not patients were already treated with other therapies for PAH. About two thirds of the patients were taking phosphodiesterase-5 inhibitors when they entered the study. Macitentan was well tolerated in the SERAPHIN study. Compared with placebo, a higher proportion of macitentan-treated patients had nasopharyngitis, headache, and anemia. One patient in each treatment group discontinued due to anemia.
Gérald Simonneau M.D., Professor of Pneumology and Head of the Department of Pneumology and Intensive Care Unit, Hôpital Kremlin Bicêtre, Paris-Sud University, France, advisor on SERAPHIN and a senior author of the paper, commented: "The data published today are very exciting. It is relevant for both patients and physicians treating PAH. It is the first time we have seen data on patients evaluated over such a long period of time with outcome as a primary focus. The results suggest that macitentan, upon approval, has the potential to offer a new treatment option for PAH physicians and our patients."
A significant treatment effect was also observed on the combined secondary outcome measure of the impact of macitentan on PAH-related hospitalization and death. The 10mg macitentan treatment group showed a reduction in risk of hospitalization and death of 50% p<0.001 compared to placebo.
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. In the last decade, major advances in treatment have led to improvements in some measures of patient outcomes. Despite these advances in PAH, survival rates are unacceptably low and PAH remains incurable.
Jean-Paul Clozel, M.D. and Chief Executive Officer of Actelion commented: "Today's publication in the New England Journal of Medicine illustrates what can be achieved by combining high quality drug discovery with comprehensive clinical development. Very importantly this publication was only made possible by the unwavering commitment of the PAH community. The data from this positive study with macitentan provide the basis for the ongoing worldwide regulatory filings and we will continue to work with the Health Authorities to help bring this potentially important treatment for PAH to patients as soon as possible."
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NOTES TO THE EDITOR
ABOUT THE STUDY DATA PUBLISHED IN THE NEJM
Patients were randomized to placebo (n=250), macitentan 3 mg (n=250), or macitentan 10 mg (n=242). The primary end point occurred in 46.4%, 38.0%, and 31.4% of the patients in these groups, respectively. The hazard ratio for macitentan 3 mg versus placebo was 0.70 (97.5% CI, 0.52 to 0.96; p=0.01) and the hazard ratio for macitentan 10 mg versus placebo was 0.55 (97.5% CI, 0.39 to 0.76; p<0.001). Worsening of pulmonary arterial hypertension was the most frequent primary end point event. The effect of macitentan on this end point was observed irrespective of background therapy for pulmonary arterial hypertension. 
ABOUT THE SAFETY AND TOLERABILITY PROFILE REPORTED IN NEJM
Macitentan was well tolerated in the SERAPHIN study. 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 compared to placebo, with 52% and 45% of patients in the macitentan 3 mg and 10 mg groups respectively, and 55% of patients in the placebo group experiencing serious adverse events.
Compared with placebo, a higher proportion of macitentan-treated patients had nasopharyngitis, headache, and anemia. One patient in each treatment group discontinued due to 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, 3.4 percent of patients on 10 mg of macitentan and in 3.6 percent of patients on 3 mg of macitentan. In addition, no difference in fluid retention (edema) was observed between macitentan and placebo). 
ABOUT MACITENTAN (OPSUMIT®)
Macitentan (Opsumit®) is a novel dual endothelin receptor antagonist (ERA) that resulted from a tailored drug discovery process with the target of developing an ERA optimized for efficacy and safety . Macitentan has a number of potentially key beneficial characteristics including increased in vivo preclinical efficacy versus existing ERAs resulting from sustained receptor binding  and physicochemical properties that allow enhanced tissue penetration . The clinical pharmacology program also indicated a low propensity of macitentan for drug-drug interactions [6,7,8] .
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 . 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 America, Latin America, Europe, Asia-Pacific and Africa and was completed in the first half of 2012, with 287 patients having an adjudicated event.
ABOUT MACITENTAN (OPSUMIT®) SUBMISSIONS TO HEALTHCARE AUTHORITIES
On 22nd October 2012 Actelion announced that it had submitted a new drug application to the US Food and Drug Administration (FDA) seeking approval for macitentan (Opsumit®) in patients with pulmonary arterial hypertension.
On 22nd November 2012 Actelion announced that it had successfully submitted the Market Authorization Application to the European Medicines Agency (EMA) and a validation letter had been received.
Regulatory review is also ongoing in Canada, Switzerland, Australia, Taiwan and Mexico.
ABOUT PULMONARY ARTERIAL HYPERTENSION [9, 10]
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 three 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.
|1.||Pulido T et al. Macitentan and Morbidity and Mortality in Pulmonary Arterial Hypertension. N Engl J Med 2013;369:809-18.|
|2.||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).|
|3.||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.|
|4.||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|
|5.||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.|
|6.||Sidharta PN et al. Macitentan: Entry-into-humans study with a new endothelin receptor antagonist. Eur J Clin Pharmacol. 2011;67(10):977-84|
|7.||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|
|8.||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.|
|9.||Galiè N, Hoeper MM, Humbert M, et al; ESC Committee for Practice Guidelines (CPG). Guidelines for the diagnosis and treatment of pulmonary hypertension: the Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS), endorsed by the International Society of Heart and Lung Transplantation (ISHLT). Eur Heart J 2009;30:2493-537|
|10.||Benza RL, Miller DP, Barst RJ, Badesch DB, Frost AE, McGoon MD. An evaluation of long-term survival from time of diagnosis in pulmonary arterial hypertension from REVEAL. Chest 2012;142:448-56.|
Actelion Ltd is a biopharmaceutical company with its corporate headquarters in Allschwil/Basel, Switzerland. Actelion's first drug Tracleer® (bosentan), 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 2,300 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®).
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