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Main Category: Hypertension
Also Included In: Clinical Trials / Drug Trials;Â Â Cardiovascular / Cardiology
Article Date: 02 May 2012 - 5:00 PDT
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The initial analysis of Actelion's macitentan, a novel dual endothelin receptor antagonist that resulted from a tailored drug discovery process, has met its primary endpoint in a pivotal, long term, event-driven SERAPHIN Phase III trial. SERAPHIN (Study with an Endothelin Receptor Antagonist in Pulmonary arterial Hypertension to Improve cliNical outcome) was the largest randomized, controlled study in pulmonary arterial hypertension patients with a long-term treatment, designed to evaluate the efficacy and safety of macitentan, which includes a clearly defined morbidity/mortality primary end-point.
Macitentan potentially has several characteristics of major benefits, including increased in vivo preclinical efficacy, as compared with existing ERAs, which resulted from sustained receptor binding and tissue penetration properties, whilst a clinical pharmacology program demonstrated that macitentan has a low propensity for drug-to-drug interactions.
The study involved 742 patients with pulmonary arterial hypertension (PAH) in 151 centers in almost 40 countries within North and Latin America, Europe, Asia-Pacific and Africa, who were randomized 1:1:1 to either receive two different doses of macitentan (3 mg and 10 mg once daily) or placebo for a duration of up to three and a half years.
Global enrollment was completed in 2009 with the study being completed in the first half of 2012. Patients were allowed to receive PAH background therapy throughout the study, which consisted of either PDE-5 inhibitors or oral/inhaled prostanoids. The average study period for the 249 patients in the placebo group was 85.3 weeks, and 99.5 weeks for 250 patients in the 3mg macitentan group and 103.9 weeks for 242 patients in the 10 mg macitentan group. 287 patients had an adjudicated event during the study period.
The results showed that over the study period macitentan 3mg reduced the risk of a morbidity/mortality event by 30% (p=0.0108), whilst the 10mg dose reduced the risk by 45% (p
4.5% of patients in the placebo group experienced elevations of liver alanine or aspartate aminotransferases greater than three times the upper limit of normal compared with 3.6% of patients in the 3 mg macitentan group and 3.4% in the 10 mg macitentan group. There was no difference between macitentan and placebo on fluid retention (edema). Even though lower hemoglobin levels were more frequently observed as an adverse event in the macitentan group than the placebo group, there was no difference in treatment discontinuation between groups. Jean-Paul Clozel, M.D. and Chief Executive Officer of Actelion declared:
"I am extremely pleased with the outstanding SERAPHIN results. We are committed to working with the Health Authorities to bring this potentially important advancement in PAH to patients as soon as possible. Submission of the registration dossier to Health Authorities worldwide is expected by the fourth quarter of 2012."
Lewis J. Rubin, M.D., Emeritus Professor, University of California, San Diego and Senior Advisor on SERAPHIN added:
"With this well-designed PAH study, Actelion pursued an ambitious goal to focus on outcome benefits as the primary endpoint. The impressive results of this landmark study are setting a new standard in how to conduct studies in this devastating disease."
Senior Advisor on the SERAPHIN study, Gerald Simonneau M.D., Professor of Pneumology and Head of the Department of Pulmonary Disease and Intensive Care Unit at the Hospital Antoine Beclere-Clamart in France said:
"As a physician with more than 30 years experience in the fight against this terrible disease, I am very excited by the outcome of this study. These results represent an important milestone in the history of clinical trials in PAH and show that macitentan has the potential to offer a new treatment paradigm for these patients."
Secondary efficacy endpoints, including change from baseline to month 6 in six-minute walk-distance, change from baseline to month 6 in WHO functional class and time - over the whole treatment period - to either death due to PAH or hospitalization due to PAH, also showed a dose-dependent effect (p
Guy Braunstein, M.D. and Head of Global Clinical Development commented:
"Our thanks go to the investigators and their staff in almost 40 countries, who participated in this compelling study. I truly believe that these results with macitentan will translate into clinical benefits for patients suffering from PAH. The Company will now rapidly analyze this largest ever clinical study in PAH in full detail, in view of regulatory filings later this year."
A pivotal Phase III program to evaluate macitentan started in December 2011 in patients with ischemic digital ulcers that are linked to systemic sclerosis, and after excellent preclinical results, researchers also started a Phase I/Ib open-label study with macitentan in patients with recurring glioblastoma.
Full data from this study will be presented at upcoming congresses and through publications.
Written By Petra Rattue
Copyright: Medical News Today
Not to be reproduced without permission of Medical News Today
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