Clazosentan is an endothelin receptor antagonist added to Actelion’s pipeline through the acquisition of Axovan in 2003.
Clazosentan is being developed as an intravenous infusion to treat cerebral vasospasm in patients post aneurysmal subarachnoid hemorrhage (aSAH). The product was granted orphan medicinal product status in Europe in 2003, and in the US in 2006.
REVERSE (REversal of Vasospasm with clazosEntan post-aneuRysmal Subarachnoid hEmorrhage), is a Phase II prospective, multi-center, open-label, single arm study to evaluate whether clazosentan has an early effect in reversing angiographically-confirmed cerebral vasospasm in patients with aneurysmal subarachnoid hemorrhage treated by endovascular coiling or surgical clipping. The study is expected to enroll approximately 25 subjects, and clazosentan will be administered at the dose of 15 mg/h for a maximum of 10 days.
Clazosentan has been investigated for prevention of angiographic vasospasm in patients with aSAH in the Phase IIb CONSCIOUS-1 (Clazosentan to Overcome Neurological ISChemia and Infarct OccUrring After Subarachnoid Hemorrhage) study. Clazosentan (1, 5, and 15 mg/h doses) dose-dependently prevented the occurrence of significant angiographic vasospasm, with a 65% relative risk reduction with the highest dose (P<0.0001); this suggests that endothelin-1 plays an important role in the pathogenesis of vasospasm. Compared with placebo, pulmonary complications, anemia, and hypotension were more common in patients receiving clazosentan.
On the basis of CONSCIOUS-1, two Phase III studies (CONSCIOUS-2 and CONSCIOUS-3) were designed to assess the effect of clazosentan on the incidence of cerebral vasospasm-related morbidity and all-cause mortality within 6 weeks post-aSAH. In CONSCIOUS-2, patients who had their aneurysm secured by clipping received placebo or clazosentan 5 mg/h; however, the treatment effect of clazosentan did not reach statistical significance. In CONSCIOUS-3, patients who had their aneurysm secured by coiling received placebo or clazosentan 5 or 15 mg/h. Recruitment into this study was halted prematurely after the results of CONSCIOUS-2 were known, because the 5 mg/h dose did not achieve its primary end point in clipped patients. However, analysis of the data collected in CONSCIOUS-3 showed that clazosentan 15 mg/h significantly reduced cerebral vasospasm-related morbidity and all-cause mortality, with a 44 % relative risk reduction (p= 0.0074 ). This dose also significantly reduced the incidence of delayed ischemic neurological deficit (DIND) with a 54% relative risk reduction (p= 0.0038 ). In addition, clazosentan reduced the need for rescue therapy for vasospasm. Clazosentan did not improve outcome, possibly due to the imbalance in the use of rescue therapy. The safety profile in CONSCIOUS 2 and 3 was similar to that observed in the CONSCIOUS 1 study.
2015 - Initiation of Phase II proof of concept to treat vasospasm in subjects with aSAH
2011 - Phase III CONSCIOUS-3 study discontinued
2010 - Phase III CONSCIOUS-2 study concluded - primary endpoint not met
2006 - Orphan status granted in US
2003 - Orphan status granted in Europe
2003 - Axovan acquisition
Macdonald R L, et al. Randomized Trial of Clazosentan in Patients With Aneurysmal Subarachnoid Hemorrhage Undergoing Endovascular Coiling. Stroke. 2012 Jun;43(6):1463-9. doi: 10.1161/STROKEAHA.111.648980.
Macdonald R L, et al. Clazosentan, an endothelin receptor antagonist, in patients with aneurysmal Page 7 of 8 Clinical Development subarachnoid haemorrhage undergoing surgical clipping: a randomised, double-blind, placebo-controlled phase 3 trial (CONSCIOUS-2). The Lancet Neurology, Volume 10, No. 7, p618–625, July 2011. DOI: http://dx.doi.org/10.1016/ S1474-4422(11)70108-9
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 experi¬mental cerebral vasospasm. J Pharmacol Exp Ther 283, 1110-1118; 1997.