Endothelin antagonists in clinical trials: lessons learned

Over the past 20 years, a large number of endothelin receptor antagonists (ERAs) have been developed, many of which underwent clinical testing. Yet, today only two ERAs are approved for the treatment of only two clinical indications, namely pulmonary arterial hypertension and scleroderma-related digital ulcers. Clinical development of ERAs has been hampered by problems with dosing, with the makeup of study cohorts, and adverse events. More recently, a number of studies evaluated the potential of ERA treatment for proteinuric renal disease. Although several ERAs were found to reduce proteinuria in patients with nephropathy, clinical testing was stopped for all but one drug. The reasons for the failure of some of these studies and general considerations about how to move forward with clinical studies involving ERAs in renal disease are discussed in this chapter.