- Approval granted by European Commission on 20 December 2013
- Opsumit approved as monotherapy or in combination with another PAH therapy for the long-term treatment of WHO Functional Class II to III PAH patients
- First EU launch planned in Germany in February 2014
ALLSCHWIL, SWITZERLAND - 20 December 2013 - Actelion Ltd (SIX: ATLN) today announced that Opsumit® (macitentan), a novel dual endothelin receptor antagonist (ERA), has been granted marketing authorisation for the long-term treatment of PAH in the EU by the European Commission. Opsumit, as monotherapy or in combination, is indicated for the longterm treatment of pulmonary arterial hypertension (PAH) in adult patients of WHO Functional Class (FC) II to III.
Efficacy has been shown in a PAH population including idiopathic and heritable PAH, PAH associated with connective tissue disorders, and PAH associated with corrected simple congenital heart disease.
Macitentan 10mg is also described as reducing the risk of PAH related death or hospitalization for PAH up to end of treatment (EOT) by 50% (HR 0.50; 97.5% CI: 0.34 to 0.75; logrank p < 0.0001). Macitentan 10mg improved quality of life assessed by the SF-36 questionnaire.
Dr Nazzareno Galiè from the Institute of Cardiology, University of Bologna, Bologna, Italy spoke of the impact of the availability of Opsumit, "We are all very pleased with the approval of Opsumit in Europe. For the first time we can offer patients a therapy that has demonstrated improvement in long term clinical outcome showing a significant effect in naive patients and patients who are already on a specific PAH treatment."
The EU label was based in part on data from the landmark Phase III SERAPHIN study which was published in the New England Journal of Medicine in August 2013, the SERAPHIN study demonstrated that treatment with macitentan 10 mg resulted in a 45% risk reduction (hazard ratio [HR] 0.55; 97.5% CI: 0.39 to 0.76; p < 0.0001) of the composite morbidity-mortality endpoint up to (EOT) when compared to placebo.
Jean-Paul Clozel, M.D. and Chief Executive Officer of Actelion commented: "We are delighted with today's announcement as we believe that Opsumit represents a major step forward for the management of PAH. Our company strategy of sustaining and growing our PAH franchise has yet again been bolstered by this approval. This achievement marks a significant moment for the PAH community in Europe as the first and only PAH treatment with proven long-term efficacy, from controlled clinical trials in PAH, and will now offer hope of a better future to those living with this disease. Actelion is now working to make this important medicine available to patients around European markets in the coming months."
The most commonly reported adverse drug reactions are nasopharyngitis (14.0%), headache (13.6%) and anaemia (13.2%). The majority of adverse reactions are mild to moderate in intensity.
Opsumit was approved by the FDA on 18 October 2013 and by Health Canada in November 2013. It is also undergoing regulatory assessment in other countries including Switzerland.
NOTES TO THE EDITOR
ABOUT OPSUMIT® (MACITENTAN)
Opsumit (macitentan) is a novel dual endothelin receptor antagonist (ERA) that resulted from a tailored drug discovery process with the target of developing an ERA to address efficacy and safety [2,3].
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 Opsumit (macitentan) - 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 enrolment 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 SERAPHIN STUDY DATA
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=0.0108) and the hazard ratio for macitentan 10 mg versus placebo was 0.55 (97.5% CI, 0.39 to 0.76; p<0.0001). 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
The most commonly reported adverse drug reactions with Opsumit are nasopharyngitis (14.0%), headache (13.6%) and anaemia (13.2%). The majority of adverse reactions are mild to moderate in intensity.
ABOUT OPSUMIT (MACITENTAN) SUBMISSIONS TO HEALTHCARE AUTHORITIES
Approval of the new drug application for Opsumit (macitentan) was issued by the US Food and Drug Administration (FDA) on 18 October 2013 for the treatment of pulmonary arterial hypertension (PAH, WHO Group I) to delay disease progression. Disease progression included: death, initiation of intravenous (IV) or subcutaneous prostanoids, or clinical worsening of PAH (decreased 6-minute walk distance, worsened PAH symptoms and need for additional PAH treatment). Opsumit also reduced hospitalization for PAH.
Health Canada approved Opsumit for the long-term treatment of pulmonary arterial hypertension (PAH, WHO Group l) to reduce morbidity in patients of WHO Functional Class II or III whose PAH is either idiopathic or heritable, or associated with connective tissue disease or congenital heart disease in November 2013.
Regulatory reviews are ongoing in Switzerland, Australia, Taiwan, Mexico, Korea and Israel.
ABOUT PULMONARY ARTERIAL HYPERTENSION [4, 5]
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.
In PAH, survival rates are unacceptably low and PAH remains incurable.
- Pulido T et al. Macitentan and Morbidity and Mortality in Pulmonary Arterial Hypertension. N Engl J Med 2013;369:809-18.
- 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.
- Iglarz M. et al. Pharmacology of macitentan, an orally active tissue targeting dual endothelin receptor antagonist. J Pharmacol Exp Ther. 2008;327(3):736-745.
- Proceedings of the 4th world symposium on pulmonary hypertension. J Am CollCardiol 2009;54(1 Suppl).
- 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.
- 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 leading biopharmaceutical company focused on the discovery, development and commercialization of innovative drugs for diseases with significant unmet medical needs.
Actelion is a leader in the field of pulmonary arterial hypertension (PAH). Our portfolio of PAH treatments covers the entire spectrum of care, from WHO Functional Class (FC) II through to FC IV, with oral, inhaled and intravenous medications. Actelion is also offering treatments for a number of specialist diseases including Type 1 Gaucher disease, Niemann-Pick type C disease, Digital Ulcers in patients suffering from systemic sclerosis, and mycosis fungoides in patients with cutaneous T-cell lymphoma.
Founded in late 1997, with now over 2,400 dedicated professionals covering all key markets around the world including the US, Japan, China, Russia and Mexico, Actelion has its corporate headquarters in Allschwil / Basel, Switzerland.
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