About Clazosentan

Clazosentan (Pivlaz®) is an intravenous endothelin receptor antagonist added to Actelion’s pipeline through the acquisition of Axovan in 2003. Clazosentan is currently evaluated for the prevention of vasospasm following aneurysmal subarachnoid hemorrhage (aSAH). In 2003, orphan status was granted for clazosentan in Europe. For the US, orphan drug status was granted in 2006.

Current Status

Clazosentan is currently 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 will include a minimum of 765 patients with aSAH and aneurismal surgical clipping from more than 100 centers, randomized 2:1 to receive either 5 mg/h of clazosentan or placebo. The centers represent over 25 countries in the EU, Canada, Asia, Australia and New Zealand. As of the end of 2007, discussions with the US Food and Drug Administration (FDA) are ongoing; it is planned to include an additional 24 centers in the United States. Study results may become available in the second half of 2009.

Supporting Studies

Clazosentan has shown promising results in the prevention and treatment of vasospasm in preclinical models of aSAH. Phase I trials in healthy volunteers have shown that infusions of clazosentan are generally well tolerated. A proof-of-concept phase IIa placebo-controlled study of vasospasm in patients with SAH was published in 2005 [1]. Fewer cases of vasospasm and less severe vasospasm were observed in the clazosentan group compared with the placebo group. This was accompanied by fewer patients with new cerebral infarcts in the clazosentan treated group.

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 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. The trend was most pronounced with 5 mg/h with a relative risk reduction of 28%.

References

1. Vajkoczy P. et al. Journal of Neurosurgery. 103, 9-17, 2005