Vasospasm occurs 5-14 days following SAH and leads to strokes and neurological deficits that cause significant disability to patients and is a major cause of death. As many as 70% of people who have aneurysmal SAH may have arterial narrowing and even with the most advanced surgical and endovascular advances in securing the aneurysm, the outcomes remain poor with up to 30% developing neurological deficits or dying2.
This Phase IIa study with 34 patients demonstrated that patients given the i.v. endothelin receptor antagonist clazosentan continuously for up to 14 days suffered from significantly fewer and less severe cases of vasospasm compared to placebo. Only 40% of patients treated with clazosentan developed cerebral vasospasm, as diagnosed on angiography, compared to 88% of patients treated with placebo (p=0.008).1
Furthermore, there were fewer patients with new cerebral infarcts in the clazosentan group – 15% versus 44% in the placebo group. Overall the nature and severity of adverse events were comparable between the two treatment groups. Infusions of clazosentan were generally well tolerated, with no clinically relevant effects on blood pressure or other vital signs.1
Dr Peter Vajkoczy, Neurosurgeon at the Department of Neurosurgery, University Hospital, Mannheim, and the main author of the study comments: "While our understanding of cerebral vasospasm has continued to improve, a solution to this challenge is yet to be found. However, these results are certainly promising and it is important that these findings are assessed and confirmed in a larger population to identify how clazosentan may have an impact in clinical practice."
The July edition of JNS also carries an editorial focusing on the clazosentan study. Dr Neal Kassell, Professor and Co-chairman of the Department of Neurological Surgery at the University of Virginia comments: "It is encouraging to finally, after nearly one-half century of futile investigations, be able to introduce into clinical trials an agent that, based on experimental studies, has a real potential for preventing vasospasm and, based on preliminary clinical studies, appears to be without significant side effects (including hypotension), as well as exhibiting a suggestion of efficacy."
Following detailed discussions with regulatory authorities worldwide, the findings of this study have already led to the initiation of a comprehensive Phase IIb/III development programme for clazosentan. A multi-centre, international, double-blind, randomized, placebo-controlled, parallel group, dose-finding study CONSCIOUS-1 (Clazosentan to Overcome Neurological iSChemia and Infarct OccUrring after Subarachnoid hemorrhage) will analyse the efficacy of 3 dose levels of clazosentan in preventing the occurrence of cerebral vasospasm following SAH, assessed by angiography. As a secondary endpoint, the study will also assess the ability of clazosentan to reduce the occurrence of early morbidity/mortality as well as overall safety and tolerability of the drug.
CONSCIOUS-1 is expected to recruit 400 patients in approximately 70 centers in 13 countries worldwide. Study results are expected in the first half of 2006. These results will determine the need, size and duration of a Phase III study.
Two pre-clinical studies suggest impact of clazosentan on endothelin receptors A and B This study follows the publication in the June edition of the JNS of two pre-clinical studies which characterised the inhibitory effect of clazosentan on endothelin A (ETA) receptor mediated contraction and endothelin B (ETB) receptor mediated relaxation.3,4
Notes to editors:
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 haemorrhage (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 haemorrhage without treatment. Rebleeding occurs in 50% of the aneurysms within the first six months, and about half of patients die after a rebleed and a further 20% become disabled.5
Actelion Ltd
Actelion Ltd is a biopharmaceutical company with its corporate headquarter in Allschwil/Basel, Switzerland. Actelion's first drug, Tracleer®, 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 as well as 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).
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References:
1. 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.
2. Harrod, CG, Bendok BR, Batjer HH et al. Prediction of cerebral vasospasm in patients presenting with aneurysmal subarachnoid hemorrhage: a review. Neurosurgery. April 2005. 56, 633-652.
3. Vatter H, Zimmermann M, Tesanovic V et al. Cerebrovascular characterization of clazosentan, the first nonpeptide endothelin receptor antagonist clinically effective for the treatment of cerebral vasospasm. Part I: Inhibitory effect on endothelinA receptor–mediated contraction. Journal of Neurosurgery. June 2005. 102, 1101-1107.
4. Vatter H, Zimmermann M, Tesanovic V et al Cerebrovascular characterization of clazosentan, the first nonpeptide endothelin receptor antagonist shown to be clinically effective for the treatment of cerebral vasospasm. Part II: Effect on endothelinB receptor–mediated relaxation. Journal of Neurosurgery. June 2005. 102, 1108-1114.
5. Wolf PA. Epidemiology of intracerebral haemorrhage. In: Carlos SK, Louis RC, editors. Intracerebral haemorrhage. United States of America: Butterworth Heinemann, 1996: 23.
Journal
Journal of Neurosurgery