Healthcare Industry News: TRACLEER
News Release - November 12, 2007
Actelion: Pivlaz (Clazosentan) Phase III Study Initiated to Demonstrate Prevention of Vasospasm-Related Morbidity and All-Cause Mortality After Aneurysmal Subarachnoid HemorrhageALLSCHWIL, Switzerland, Nov. 12, 2007 (Healthcare Sales & Marketing Network) -- Actelion Ltd (Swiss:ATLN.SW ) announced today the initiation of the phase III program, CONSCIOUS-2, for the endothelin receptor antagonist Pivlaz(r) (Clazosentan). The study is designed to evaluate the safety and efficacy of Pivlaz(r) in reducing vasospasm-related morbidity and all-cause mortality following aneurysmal subarachnoid hemorrhage (aSAH). In earlier studies, the use of Pivlaz(r) was associated with up to 65 percent reduction in vasospasm, a contraction of blood vessels in the brain.
``Vasospasm is a major problem in patients with aneurysmal subarachnoid hemorrhage. Vasospasm is both unpredictable and the leading treatable cause of disability and death,'' said Neal Kassell, M.D; Distinguished Professor and Co-Chairman, Department of Neurosurgery at the University of Virginia, Charlottesville, and chairman of the CONSCIOUS-2 Steering Committee (Clazosentan to Overcome Neurological iSChemia and Infarct OccUrring after Subarachnoid hemorrhage).
Dr Kassell concluded: ``A reduction in the occurrence of vasospasm is expected to result in measurable clinical benefit. The CONSCIOUS-2 trial is specifically designed to demonstrate this benefit.''
Each year over 80,000 people in the EU, U.S. and Japan have an aSAH with a sudden bleeding into the compartment surrounding the brain(1). Two out of three patients who suffer an aSAH are at risk of developing vasospasm2. Prevention and treatment options for vasospasm are limited and if left untreated, 1 in 5 patients will subsequently suffer permanent disability or death(2). In earlier studies, the use of Pivlaz(r) was associated with a significant reduction in the incidence of vasospasm.(3)
Previous studies supporting CONSCIOUS-2
The CONSCIOUS-2 study follows the earlier phase IIb dose-finding study CONSCIOUS-1. CONSCIOUS-1 showed that clazosentan, in a dose dependent fashion, significantly reduced the occurrence of moderate or severe cerebral vasospasm(3). CONSCIOUS-2 will subsequently measure the clinical benefits of Pivlaz(r) through the primary endpoint of vasospasm-related morbidity and all-cause mortality which includes neurological deterioration, new brain infarcts, introduction of vasospasm rescue therapy or death from any cause.
CONSCIOUS-2 is a global study, and will include a minimum of 765 patients from more than 100 centers, randomized 2:1 to receive either 5 mg/h of Pivlaz(r) or placebo. The centers represent over 25 countries in EU, Canada, Asia, Australia and New Zealand. Discussions with the U.S. Food and Drug Administration (FDA) are ongoing; it is planned to include an additional 24 additional centers in the United States. Study results may become available as early as the second half of 2009.
To enable a clear evaluation of the beneficial effect on vasospasm-related morbidity and all-cause-mortality, the patients enrolled into CONSCIOUS-2 will be a well-defined, homogenous population consisting of those who have had their aneurysm clipped (securing the aneurysm by surgical means).
The CONSCIOUS-2 trial will also investigate the effect of Pivlaz(r) on the extended Glasgow Outcomes Scale (GOSE) at three month as a secondary endpoint. Evaluating the potential impact of Pivlaz(r) on the established and recognized GOSE will provide additional support for the clinical relevance of the chosen primary endpoint.
Full evaluation of benefit and risks
In earlier studies in patients with aneurysmal subarachnoid hemorrhage (aSAH), the use of clazosentan was associated with a higher incidence versus placebo of adverse events such as fluid retention, also evidenced by excess cases of pulmonary complications, and hypotension versus placebo and especially when clazosentan was used concomitantly with nimodipine
Consequently, next to the standard evaluation of adverse events in general, the study has special protocols in place to fully assess the safety of Pivlaz(r) including class-specific effects, for example, fluid retention observed previously with selective-A endothelin receptor antagonists. In addition, special patient management guidelines have been put in place to adequately address these potential adverse events.
Study initiation triggers non-P&L effective milestone payment
The commencement of the phase III development of Pivlaz(r) in this indication triggers a milestone payment of CHF 15 million to former Axovan shareholders. Actelion acquired Axovan in 2003. Accordingly, the milestone payment to be payable in Q4 2007 is booked through the balance sheet as goodwill.
Notes to editors:
About aneurysmal SAH (aSAH)
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). 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 re-bleed and a further 20% become disabled. Intravascular coiling or surgical clipping is usually required to secure the aneurysm to stop the bleeding and prevent further episodes.
About cerebral vasospasm following aSAH
Vasospasm (uncontrollable tightening) of the brain blood vessels is a feared complication after aSAH, because a shortage of brain blood supply can lead to cerebral ischemia and infarction. Vasospasm is unpredictable and seen in over 67% of untreated patients with angiography at the time of maximum spasm around the end of the first week. Symptomatic vasospasm, or delayed ischemic neurological deficit (DIND), affects nearly one third. The amount of blood seen on the CT-scan at hospital admission is the most powerful prognostic factor for vasospasm.
About endothelin and vasospasm
After the initial bleeding episode the blood progressively breaks down in the brain acutely up-regulating the release of endothelin in the subarachnoid space. Endothelin is a potent and persistent vasoconstrictor and pro-inflammatory mediator produced by the endothelium in the vascular wall of the cerebral arteries. Endothelin mediates vasospasm in the cerebral vasculature and provides the rationale for the use of Pivlaz, an intravenous endothelin receptor antagonist, for the prevention of vasospasm. Post aSAH, increased endothelin levels have been demonstrated in the cerebrospinal fluid (CSF), especially in those patients developing vasospasm.
About Pivlaz(r) (clazosentan)
Pivlaz(r) is an intravenous endothelin receptor antagonist (ERA). Pivlaz(r) was developed for acute short-term intravenous use and has the ability to cross the blood brain barrier. Pivlaz(r) blocks the binding of endothelin to its receptors. By blocking endothelin in pre-clinical models, Pivlaz(r) prevents both the inflammation and vasoconstriction which is known to induce vasospasm following aSAH.
CONSCIOUS-2 (Clazosentan to Overcome Neurological iSChemia and Infarct OccUrring after Subarachnoid hemorrhage) is a large multi-centre, international, double-blind, randomized, placebo-controlled trial to evaluate clazosentan and show clinical benefit. Clazosentan will be administered at 5mg/h continuously for 14 days following an aSAH. The primary endpoint of the trial is morbidity related to vasospasm and all cause mortality. The Glasgow Outcomes Scale Extended (GOSE) is one of several secondary endpoints, assessed at three months. Around 765 patients from more than 100 centers in 25 countries worldwide will be enrolled.
CONSCIOUS-1 was a multi-centre, international, double-blind, randomized, placebo-controlled, parallel group, dose-finding study to evaluate the efficacy of three 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(3). Clazosentan significantly reduced angiographic vasospasm at all tested doses with a relative risk reduction compared to placebo of 65 percent at the highest dose. As a secondary endpoint (post hoc analysis), the study also evaluated the ability of clazosentan to reduce the occurrence of early morbidity/mortality. Clazosentan showed a trend in favor of reducing morbidity/mortality related to vasospasm, when the events were centrally assessed. The trend was most pronounced with 5 mg/h with a relative risk reduction of 28 percent(3). The use of clazosentan was associated -- as observed previously with other selective-A endothelin receptor antagonists in different indications -- with 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. 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(4).
(1) Linn, F. H., Rinkel, G. J., Algra, A., and van Gijn, J. Incidence of subarachnoid hemorrhage: role of region, year, and rate of computed tomography: a meta-analysis. Stroke 1996 27, 625-629.
(2) Dorsch NWC Therapeutic approaches to vasospasm in subarachnoid hemorrhage. Curr Opin Crit Care. 2002;8:128-133.
(3) Macdonald, RL; Kassell, N; Mayer S; Schmiedek, P; Weidauer, S; Pasqualin, A; Randomized Trial of Clazosentan, an Endothelin Receptor Antagonist, for the prevention of Vasospasm after Aneurysmal Subarachnoid Hemorrhage, EANS, 2007, 3rd-8th Sept, Glasgow
(4) 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
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 1,200 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).
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