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Press Release

The New England Journal of Medicine Publishes Macitentan Morbidity and Mortality Study in Pulmonary Arterial Hypertension

Canada NewsWire

  • Macitentan significantly reduced risk of morbidity/mortality events
  • Macitentan currently in world-wide regulatory review

LAVAL, QC, Aug. 29, 2013 /CNW/ - Actelion Pharmaceuticals Canada Inc. announced today that the New England Journal of Medicine (NEJM) has published the results of SERAPHIN (Study with Endothelin Receptor Antagonist in Pulmonary Arterial Hypertension to Improve Clinical Outcome), the pivotal study with macitentan in patients with pulmonary arterial hypertension (PAH).

Dr. Sanjay Mehta, MD, FRCPC, FCCP, professor of medicine at the University of Western Ontario and director of the Southwest Ontario Pulmonary Hypertension Clinic at the London Health Sciences Center in London, Ontario, and an author of the NEJM paper, commented:  "The SERAPHIN study focused on several important indicators of PAH progression and demonstrated that macitentan significantly reduced the risk of morbidity and mortality in both treatment-naive patients and patients already on background therapy for PAH."

The NEJM paper reports the findings of this Phase III trial - the largest and longest of its kind - in which 742 patients received either macitentan or placebo. The risk of a morbidity/mortality event - the primary endpoint of the study - was reduced by 45 per cent (p<0. 001) with macitentan 10 mg compared to placebo.

"The data published today are exciting and relevant for both patients and physicians treating PAH," said Dr. Mehta who also chairs the Medical Advisory Committee of the Pulmonary Hypertension Association of Canada. "The results suggest that macitentan may set a new standard of care since this is the first time we have seen data on PAH patients evaluated in a long-term study with clinical outcome as a primary focus."

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 10 mg macitentan treatment group showed a reduction in risk of hospitalization and death due to PAH of 50 per cent (p<0. 001) compared to placebo.

The effect of macitentan on the morbidity and mortality 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 (sildenafil or tadalafil) when they entered the study.

"I am honoured to be part of this important study. The results show valuable long-term morbidity/mortality data and I expect this landmark study to set a new standard in how the evidence for PAH therapies is measured," added Dr. Mehta.

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.

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.

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 per cent, 38.0 per cent, and 31.4 per cent of the patients in these groups, respectively. The hazard ratio for macitentan 3 mg versus placebo was 0.70 (97.5 per cent CI, 0.52 to 0.96; P=0.01) and the hazard ratio for macitentan 10 mg versus placebo was 0.55 (97.5 per cent CI, 0.39 to 0.76; P<0.001). Worsening of PAH was the most frequent primary endpoint event. The effect of macitentan on this endpoint was observed irrespective of background therapy for PAH. [1]

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 per cent and 45 per cent of patients in the macitentan 3 mg and 10 mg groups respectively, and 55 per cent 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 per cent of patients receiving placebo, 3.6 per cent of patients on 3 mg of macitentan and in 3.4 per cent of patients on 10 mg of macitentan. In addition, no difference in fluid retention (edema) was observed between macitentan and placebo. [1]

ABOUT MACITENTAN

Macitentan 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 [3]. Macitentan has a number of potentially key beneficial characteristics including increased in vivo preclinical efficacy versus existing ERAs resulting from sustained receptor binding [4] and physicochemical properties that allow enhanced tissue penetration [5]. The clinical pharmacology program also indicated a low propensity of macitentan for drug-drug interactions [6,7,8] .

ABOUT THE SERAPHIN STUDY

SERAPHIN was the largest and longest randomized, placebo-controlled study in PAH patients and the first to include a clearly defined, clinically-important morbidity/mortality primary endpoint [2]. The pivotal Phase III study was designed to evaluate the efficacy and safety of macitentan - a novel dual ERA that resulted from a tailored drug discovery process - through the primary endpoint of time to first morbidity or 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 centres 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 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 by development 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.

ACTELION LTD

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®).

References

  1. Pulido T, Adzerikho I, Channick RN, Delcroix M, Galiè N, Ghofrani H-A, et al. Macitentan and Morbidity and Mortality in Pulmonary Arterial Hypertension. N Engl J Med. 2013;369(9):809-818.
  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.

The above information contains certain "forward-looking statements", relating to the company's business, which can be identified by the use of forward-looking terminology such as "estimates",  "believes", "expects", "may", "are expected to", "will", "will continue", "should", "would be", "seeks",  "pending" or "anticipates" or similar expressions, or by discussions of strategy, plans or intentions.  Such statements include descriptions of the company's investment and research and development programs and anticipated expenditures in connection therewith, descriptions of new products expected to be introduced by the company and anticipated customer demand for such products and products in the company's existing portfolio. Such statements reflect the current views of the company with respect to future events and are subject to certain risks, uncertainties and assumptions. Many factors could cause the actual results, performance or achievements of the company to be materially different from any future results, performances or achievements that may be expressed or implied by such forward-looking statements. Should one or more of these risks or uncertainties materialize, or should underlying assumptions prove incorrect, actual results may vary materially from those described herein as anticipated, believed, estimated or expected.


SOURCE: Actelion

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