Clazosentan (DB06677): A Comprehensive Monograph

1.0 Executive Summary

Clazosentan is a potent, highly selective, intravenously administered small molecule antagonist of the endothelin-A (ETA) receptor.[1] It was developed as a targeted therapy to prevent cerebral vasospasm and its ischemic consequences following aneurysmal subarachnoid hemorrhage (aSAH), a life-threatening form of stroke.[3] The drug's mechanism is rooted in its ability to block the action of endothelin-1, the body's most powerful endogenous vasoconstrictor, which is released in large quantities after aSAH and is a key mediator of arterial narrowing in the brain.[2]

The clinical development of Clazosentan is characterized by a significant and persistent paradox: while the drug has unequivocally demonstrated a powerful, dose-dependent ability to reduce the incidence and severity of angiographic vasospasm, this success on a key pathophysiological marker has not consistently translated into improved long-term neurological function or reduced all-cause mortality in large, global clinical trials.[4] This disconnect highlights the multifactorial nature of delayed cerebral ischemia (DCI) after aSAH, suggesting that large-vessel vasospasm is only one component of a more complex secondary injury cascade.