Healthcare Industry News: TRACLEER
News Release - October 9, 2006
Actelion Ltd: Detailed Analysis of CONSCIOUS-1 Presented at CNSSignificant reduction of cerebral vasospasm in patients with aneurysmal subarachnoid hemorrhage
Post-hoc blinded central assessment shows dose-dependent trend towards improved morbidity/mortality
Discussions with regulatory authorities on appropriate pivotal trial design forthcoming
CHICAGO and ALLSCHWIL, Switzerland, Oct. 9, 2006 (Healthcare Sales & Marketing Network) -- Actelion Ltd (Other OTC:ALIOF.PK ) (Swiss:ATLN.SW ) announced today that the detailed analysis of the dose-finding study CONSCIOUS-1 (Clazosentan to Overcome Neurological iSChemia and Infarct OccUrring after Subarachnoid hemorrhage) has been presented at the Congress of Neurological Surgeons (CNS) in Chicago by R. Loch Macdonald, MD, PhD, Professor of Surgery and Radiation & Cellular Oncology at University of Chicago Hospitals. Dr. Macdonald is a member of the study steering committee.
The primary goal of CONSCIOUS-1 was to establish the potential of clazosentan to prevent cerebral vasospasm as a result of aneurysmal subarachnoid hemorrhage (aSAH) and to determine appropriate dosing. In addition to documenting the safety profile, the study was also designed to better understand the relationship between preventing cerebral vasospasm and morbidity/mortality, so as to provide the necessary information for the appropriate design and sample size determination of a pivotal morbidity/mortality study.
Study findings in detail
All three doses of i.v. clazosentan tested (1mg/h, 5mg/h and 15mg/h) reached statistical significance versus placebo for the primary endpoint: the reduction in the occurrence of moderate or severe cerebral vasospasm, as measured by digital subtraction angiography (DSA) at day 9 (plus/minus 2 days) post-aneurysm rupture. As per protocol, DSA analysis was based on central blinded and adjudicated assessment.
The effect was dose-related and most significantly seen with the dose of 15 mg/hour, a relative risk reduction compared to placebo of 65 percent (p less than 0.0001). Effects were also statistically significant for the 5mg dose (p=0.0003) and the 1mg dose (p=0.0027).
Detailed post-hoc analysis focusing especially on central blinded and adjudicated assessment of CT images was used to evaluate the key secondary composite endpoint: occurrence of morbidity/mortality (death, new cerebral infarcts, delayed ischemic neurological deficit DIND, rescue therapy) up to week 6. Clazosentan showed a trend in favor of reducing morbidity/mortality related to vasospasm. The trend was more pronounced on 5mg/h (relative risk reduction of 28 percent, p=ns) and 15mg/h (relative risk reduction of 26 percent; p=ns) and mainly the result of substantial reductions in new cerebral infarcts and DIND.
In this study, clazosentan showed -- as observed previously with other endothelin receptor antagonists -- a higher incidence versus placebo of adverse events such as fluid retention, also evidenced by excess cases of pulmonary complications, and hypotension, especially when used concomitantly with nimodipine.
Actelion to approach regulatory authorities for Phase III design
Dr. Macdonald commented: ``Initially, the preliminary analysis based on local blinded assessment of the key morbidity/mortality endpoint did not yield any trend information. In the meantime, we have learned that this apparent disconnect was the result of highly variable assessment criteria used in the image analysis by the 52 centers worldwide.''
Dr. Macdonald concluded: ``Blinded centralized reading and using consistent assessment guidelines, in contrast, showed that there is indeed a relationship between preventing cerebral vasospasm and reduction in morbidity/mortality in this patient population at high risk of life-long disability. With these results, therefore, further clinical evaluation is warranted to fully characterize the clinical benefit of clazosentan in aSAH.''
Dr. Isaac Kobrin, MD and Head of Clinical Development, commented: ``Detailed analysis of CONSCIOUS-1 has provided us with all the necessary information on methodology, dosing, safety and the relationship between vasospasm prevention and clinical benefit so as to appropriately design and power a pivotal clazosentan study in aSAH. We will now approach regulatory authorities to discuss the matter with the intention to agree on an appropriate trial design for a Phase III study.''
NOTES TO THE EDITOR:
CONSCIOUS-1 (Clazosentan to Overcome Neurological iSChemia and Infarct OccUrring after Subarachnoid hemorrhage) was a multi-centre, international, double-blind, randomized, placebo-controlled, parallel group, dose-finding study to evaluate the efficacy of 3 dose levels of clazosentan (15, 5 and 1mg/hour) in preventing the occurrence of cerebral vasospasm following SAH who underwent either clipping or coiling to stop the initial aneurysmal bleed, assessed by angiography. As a secondary endpoint, the study also evaluated the ability of clazosentan to reduce the occurrence of early morbidity/mortality as well as overall safety and tolerability of the drug.
CONSCIOUS-1 recruited 413 patients in 52 centers in 11 countries worldwide and was initiated after promising pre-clinical and clinical data that was published in the Journal of Neurosurgery in July 2005 (See note).
About cerebral vasospasm following SAH
Intravascular coiling or surgical clipping is usually required to secure the aneurysm so as to stop the bleeding and prevent further episodes. The vasospasm following SAH occurs when the acute rupture of an aneurysm of the cerebral vessels releases blood into the subarachnoid space of the brain. This blood progressively breaks down in the brain acutely up-regulating the release of endothelin in the subarachnoid space.
Endothelin, a known mediator of vasospasm in the cerebral vasculature, provides a rationale for the use of clazosentan, an intravenous endothelin receptor antagonist, for the prevention of vasospasm.
About aneurysmal SAH
A cerebral aneurysm refers to a blood vessel within the brain that weakens over time and undergoes widening. This usually occurs at the junctions of the large arteries at the base of the brain. As the blood vessel weakens, it begins to bulge out like a balloon. The larger the balloon becomes, the greater the risk it may burst, resulting in hemorrhage (bleeding) into the subarachnoid space (membranous space surrounding the brain) and the ensuing spasm (uncontrollable tightening) of the brain blood vessels, leading to oxygen shortage in the brain cells.
Over a quarter of people (27%) die within the first week following an aneurysmal subarachnoid hemorrhage without treatment. Rebleeding occurs in 50% of the aneurysms within the first six months, and about half of the patients die after a rebleed and a further 20% become disabled.
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. 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 focuses 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).
Note: Vajkoczy P, Meyer B, Weidauer S et al. Clazosentan (AXV-034343), a selective endothelin A receptor antagonist, in the prevention of cerebral vasospasm following severe aneurysmal subarachnoid hemorrhage: a randomized, double-blind, placebo-controlled, multicenter, Phase IIa study. Journal of Neurosurgery July 2005. 103, 9-17.
For further information please contact:
Actelion Ltd, Gewerbestrasse 16, CH-4123 Allschwil
Dr. R. Loch Macdonald, a member of the study steering committee, has agreed to share his detailed analysis of the dose-finding study CONSCIOUS-1, at an Actelion-hosted webcast/conference call. The investor conference call/webcast including discussion/Q&A will be on Monday, 9 October 2006, at 18.00 CEST / 11.00 a.m. CDT (Chicago) / 12.00 p.m. EDT / 17.00 BST.
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