Idorsia announces positive results of the two Japanese registration studies with clazosentan - Seite 4

Notes to the editor

Available data in Japanese patients
A Phase 2 study in Japanese and Korean patients showed that 10 mg/hr of clazosentan administered by continuous intravenous infusion significantly reduced vasospasm and vasospasm-related morbidity and mortality events. The results are published in Cerebrovascular Diseases (Fujimura M, et al. Cerebrovasc Dis 2017;44:59–67). On that basis, a registration program was initiated with clazosentan in Japan in May 2016.

About aneurysmal subarachnoid hemorrhage and cerebral vasospasm
Aneurysmal subarachnoid hemorrhage is a rare condition involving sudden life-threatening bleeding occurring in the subarachnoid space. It is caused by the rupture of an aneurysm – a weak, bulging spot on the wall of a cerebral artery. Emergency surgical repair (endovascular coiling or microsurgical clipping) is required to stop the hemorrhage.

The bleeding and the release of a vasoconstrictor (endothelin) by the neighboring vascular endothelium can lead to cerebral vasospasm (constriction of arteries in the brain) usually occurring between four and fourteen days after aSAH. This diminishes blood flow to the brain and about one third of patients consequently experience worsening of their neurological condition. Cerebral vasospasm is one of the leading secondary causes of disability and death in those that experience aSAH.

The prevalence of aSAH is estimated to be between 6 and 9 per 100,000 worldwide and is a significant problem in Japan with an incidence around twice as high as in many other countries of the world.

Available clinical data with clazosentan
Previously, clazosentan was investigated for the prevention of angiographic vasospasm in patients with aSAH in a Phase 2 study, CONSCIOUS-1, which demonstrated dose-dependent prevention of vasospasm.

This study was followed by two Phase 3 studies, CONSCIOUS-2 and CONSCIOUS-3, to assess the effect of clazosentan on the incidence of cerebral vasospasm-related morbidity and all-cause mortality. The dose of clazosentan (5 mg/h) used in CONSCIOUS-2 did not allow a statistically significant treatment effect to be observed, resulting in the premature termination of CONSCIOUS-3. However, an exploratory analysis of the data collected in CONSCIOUS-3 showed that a higher dose of clazosentan, i.e. 15 mg/h, significantly reduced cerebral vasospasm-related morbidity and all-cause mortality, with a 44% relative risk reduction (p=0.0074).