About clazosentan in clinical development
Clazosentan (Pivlaz®) is an intravenous endothelin receptor antagonist added to Actelion’s pipeline through the acquisition of Axovan in 2003. It is currently being evaluated in a Phase III program looking at its impact on vasospasm-related morbidity and mortality following aneurysmal subarachnoid hemorrhage (aSAH). The product was granted orphan medicinal product status in Europe in 2003, and in the US in 2006.
Clazosentan in development for the prevention of vasospasm-related morbidity/mortality post aneurysmal subarachnoid hemorrhage
Current status
Clazosentan is currently being investigated in the pivotal Phase III study CONSCIOUS-2 (Clazosentan to Overcome Neurological iSChemia and Infarct OccUrring after Subarachnoid hemorrhage). The study will measure the clinical benefits of clazosentan 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 which has concluded enrollment with over 1,150 patients with aSAH and aneurysmal surgical clipping, from more than 100 centers, randomized 2:1 to receive either 5 mg/h of clazosentan, or placebo. CONSCIOUS-2 results are expected to become available in October 2010. If successful, Actelion will approach health authorities for filing.
Enrollment is ongoing in another Phase III study with clazosentan, CONSCIOUS-3. This 1,500 patient study evaluates the efficacy and safety of two doses (5 or 15 mg/h) of clazosentan versus placebo in patients post-aSAH treated by endovascular coiling. The primary endpoint is identical to that of CONSCIOUS 2.
Available clinical data
Clazosentan has been studied in a Phase II program consisting of two studies.
The first was a proof-of-concept Phase IIa placebo-controlled study of prevention of vasospasm after clipping for aSAH, published in 2005. Fewer cases of vasospasm and less severe vasospasm were observed in the clazosentan group compared with the placebo group. There were also fewer patients with new cerebral infarcts in the clazosentan-treated group.
CONSCIOUS-1 was a multi-center, 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 aSAH in patients who underwent either clipping or coiling to stop the initial bleed, assessed by angiography.
CONSCIOUS-1 showed a strong treatment effect on the primary endpoint. Clazosentan significantly reduced moderate/severe vasospasm at all tested doses, with a relative risk reduction compared to placebo of 65% at the highest dose. A post-hoc analysis showed a trend in favor of reducing morbidity/mortality related to vasospasm using central assessment.
Milestones
2009 – Phase III CONSCIOUS-3 study initiation
2007 – Phase III CONSCIOUS-2 study initiation
2006 – Orphan status granted in US
2005 – Proof-of-concept published
2003 – Orphan status granted in Europe
2003 – Axovan acquisition
Key scientific literature
Macdonald R L, Kassell N F, Mayer S et al. Clazosentan to Overcome Neurological Ischemia and Infarction Occuring After Subarachnoid Hemorrhage (CONSCIOUS-1). Stroke 39: 3015-3021; 2008.
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 103, 9-17; 2005.
Roux S. et al. Ro-61-1790, a new hydrosoluble endothelin antagonist: general pharmacology and effects on experimental cerebral vasospasm. J Pharmacol Exp Ther 283, 1110-1118; 1997.
