ALLSCHWIL, Switzerland, Dec. 19, 2007 (PRIME NEWSWIRE) -- Actelion Ltd. (SWX:ATLG) announced today the initiation of the phase III study SERAPHIN (Study with an Endothelin Receptor Antagonist in Pulmonary arterial Hypertension to Improve cliNical outcome) for its highly potent, tissue-targeting endothelin receptor antagonist (ERA) Actelion-1 (ACT-064992). The study is designed to evaluate the safety and efficacy of Actelion-1 in delaying disease progression and mortality in patients with pulmonary arterial hypertension (PAH).
Dr. Lewis Rubin, advisor to the SERAPHIN steering committee, commented: "There has been tremendous progress in the field of pulmonary hypertension over the past ten years. It is exciting to evaluate the potential of a tissue-targeting ERA to further change the course of this devastating disease."
Isaac Kobrin, MD, Head of Clinical Development, added: "I believe that with Actelion-1, our highly experienced discovery team has used its twenty years of experience in the field of endothelin science to take ERA therapy to the next level. We appreciate the dedication of the Steering Committee in designing the largest-ever study in PAH with a clearly defined morbidity/mortality endpoint."
Jean-Paul Clozel, MD, Chief Executive Officer of Actelion, commented: "Actelion and Tracleer have revolutionized PAH therapy. A large number of supportive studies in many PAH sub-populations, together with a first-in-class educational marketing approach, have made Tracleer the cornerstone of therapy in PAH. With Actelion-1, we are renewing our commitment to the PAH community and our dedication to true innovation with the potential to once more transform medicine."
About SERAPHIN
The SERAPHIN study is a global study and will enroll more than 500 patients from at least 180 centers, randomized 1:1:1 to receive two different doses of Actelion-1 (3 mg and 10 mg once daily) or placebo. The centers represent over 40 countries in North and South America, Europe, Asia Pacific and Africa.
The SERAPHIN study will evaluate the clinical benefit of Actelion-1 through the primary endpoint of morbidity and all-cause mortality in patients with symptomatic PAH.
Dr. Gerald Simonneau, advisor to the SERAPHIN steering committee, commented: "We raise the bar again with SERAPHIN by embarking on a morbidity-mortality trial from the beginning in order to demonstrate the potential of Actelion-1."
Full evaluation of benefit and risks
In a phase II study in 379 hypertensive patients, ACT-064992 was significantly better than placebo and better than enalapril 24 hrs. after drug intake in reducing blood pressure. In this patient population, ACT-064992 was generally well tolerated. The overall frequency of adverse events was similar to those observed in the placebo group. Similar to other endothelin receptor antagonists, ACT-064992 may potentially exhibit known class effects such as a propensity for elevated liver enzymes, which will be monitored in the SERAPHIN study. Additional interaction studies concluded prior to the start of the SERAPHIN study have shown no clinically relevant interaction with warfarin, sildenafil, or ketoconazole.
About Pulmonary Arterial Hypertension (PAH)
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 function of the heart and lungs is severely compromised, manifested by a limited exercise capacity, and, ultimately, a reduced life expectancy. Approximately 100,000 people in Europe and the United States are afflicted with either primary or secondary forms of the disease related to conditions or tissue disorders that affect the lungs, such as scleroderma, lupus, HIV/AIDS or congenital heart disease.
PAH is associated with structural changes in both the pulmonary vasculature and the right ventricle. Recent advances (1) in the understanding of the pathogenic factors leading to the pulmonary vascular disease have led to the development of new therapies targeting specific pathways (the prostacyclin pathway, the endothelin pathway, and the nitric oxide pathway) (2). The available therapies have positive effects in PAH, but they do not provide a cure, and in many patients the disease will progress. PAH remains a serious life-threatening condition (2,3). Early recognition and an understanding of the selection and timing of therapeutic options remain critical elements in the optimal management of patients with this disorder.
About endothelin and PAH
Endothelin-1 (ET-1), a 21 amino acid-peptide, is one of the most potent vasoconstrictors and mitogens for smooth muscle, and contributes to increased vascular tone and proliferation in pulmonary vasculopathy. There are two distinct receptors for ET-1, endothelin receptor A (ETA) and endothelin receptor B (ETB). The two receptors have unique binding locations and affinities for the endothelin peptide. The ETA receptors are expressed on pulmonary vascular smooth muscle cells, whereas ETB receptors are present both on pulmonary vascular cells and on smooth muscle cells. When activated, the ETA receptor located in pulmonary vascular smooth muscle cells mediates a potent vasoconstrictive response and ETB receptors on endothelial cells mediate vasodilatation via increased production of nitric oxide and prostacyclin. ET-1 is also known to be a potent mitogen, with the ability to induce cell proliferation in vascular smooth muscle cells. It has been shown that both the ETA and ETB mediate the mitogenic action of ET-1. Laboratory and clinical investigations have clearly shown that ET-1 is over-expressed in several forms of pulmonary vascular disease. ET-1 is likely a major player in the vasodilator and vasoconstrictor imbalance, as well as in the abnormal pulmonary vascular remodeling present in the development and progression of PAH.
About Actelion-1
Actelion-1 (ACT-064992) is a tissue-targeting Endothelin Receptor Antagonist that has been discovered in an in-house research program. Through complete blockade of tissular endothelin, Actelion-1 is expected to protect tissue from the damaging effect of elevated endothelin, specifically in the cardiovascular system. In pre-clinical studies, Actelion-1 also exhibited effects suggesting that it maintains the integrity of the vascular wall and improves long-term outcome. Accordingly, Actelion-1 may provide therapeutic benefit in a wide range of cardiovascular indications.
About Tracleer(r) in Pulmonary Arterial Hypertension (PAH)
Tracleer(r) (bosentan), the first oral dual endothelin receptor antagonist, is approved for the treatment of pulmonary arterial hypertension (PAH) and made available by Actelion subsidiaries in the United States, the European Union, Japan, Australia, Canada, Switzerland and other markets worldwide.
Tracleer requires attention to two significant safety concerns: Potential for serious liver injury (including rare cases of liver failure and unexplained hepatic cirrhosis in a setting of close monitoring) -- Liver monitoring of all patients is essential prior to initiation of treatment and monthly thereafter. Tracleer treatment must not be initiated in women of childbearing potential unless they practice reliable contraception and participate in monthly pregnancy testing. Due to these risks, Tracleer is only supplied through a controlled distribution.
References
1. Farber HW; Loscalzo J. Mechanisms of disease: pulmonary arterial
hypertension. N. Eng. J. Med. 2004; 351: 1655-65.
2. Humbert M; Sitbon O; Simonneau G. Treatment of pulmonary arterial
hypertension. N. Eng. J. Med. 2004; 351: 1425-36.
3. Humbert M; Morrell NW; Archer SL; et al. Cellular and molecular
pathobiology of pulmonary arterial hypertension. J. Am. Coll.
Cardiol. 2004; 43: Suppl. 12: 13S-24S.
4. Tracleer(r) SPC.
Actelion Ltd.
Actelion Ltd. is a biopharmaceutical company with its corporate headquarters in Allschwil/Basel, Switzerland. Actelion's first drug Tracleer(r), an orally available dual endothelin receptor antagonist, has been approved as a therapy for pulmonary arterial hypertension. Actelion markets Tracleer(r) 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. At the end of September 2006, Tracleer(r) was commercially available in 35 countries worldwide. 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 1,500 employees focus on the discovery, development and marketing of innovative drugs for significant unmet medical needs. Actelion shares are traded on the SWX Swiss Exchange (ticker symbol: ATLN).