Inhibition of endothelin-1 with darusentan: a novel antihypertensive approach for the treatment of resistant hypertension

Robert Weiss, Christopher A Graybill, Jennifer Linseman & Marshelle Warren

Darusentan is an ETA-selective endothelin receptor antagonist that is currently in Phase III clinical development for the treatment of resistant hypertension (RHTN). Current hypertension treatment guidelines describe RHTN as the failure to achieve goal blood pressure despite treatment with full or adequate doses of an appropriate three-drug regimen that includes a diuretic. The exact prevalence of RHTN in the hypertensive community is unknown; however, recent clinical trials suggest that as many as a third of enrolled subjects may demonstrate treatment resistance. While the mechanisms responsible for the development of RHTN are also unknown, one of the few vasoconstrictive signaling pathways that remain unopposed, even in the presence of aggressive treatment with currently available antihypertensive agents, is the endothelin pathway. The effi cacy and safety of darusentan, added on to full-dose background therapy including three or more medications, has recently been demonstrated in a randomized, placebocontrolled study in patients with guideline-defi ned RHTN. The ongoing development program will provide additional insight into the characteristics of patients with RHTN, in addition to providing key results on the effi cacy and safety of darusentan in this diffi cult-to-treat patient population.