Darusentan, an endothelin receptor antagonist ( ERA ) for the treatment of resistant hypertension, met its co-primary efficacy endpoints of change from baseline to week 14 in trough sitting systolic blood pressure ( SBP ) and trough sitting diastolic blood pressure ( DBP ).

DORADO is one of two ongoing Phase III clinical trials evaluating the safety, efficacy and tolerability of Darusentan as an add-on treatment for resistant hypertension, defined as the failure to achieve goal blood pressure while adhering to full doses of an appropriate three-drug regimen that includes a diuretic.

In the DORADO, reductions in mean trough sitting systolic blood pressure from baseline of 8.6 mmHg, 16.5 mmHg, 18.1 mmHg and 18.1 mmHg were observed for the placebo, Darusentan 50 mg, 100 mg and 300 mg groups, respectively, after 14 weeks of treatment.
Reductions in mean trough sitting DBP from baseline of 5.3 mmHg, 10.1 mmHg, 9.9 mmHg and 10.7 mmHg were observed for the placebo, Darusentan 50 mg, 100 mg and 300 mg groups, respectively, after 14 weeks of treatment.
These results were statistically significant for all Darusentan groups ( p<0.001 ).

The most common treatment-emergent adverse event was peripheral edema/fluid retention, which was reported in 17, 32, 36 and 29 percent of patients in the placebo, Darusentan 50 mg, 100 mg and 300 mg groups, respectively. Most cases were mild to moderate in severity. Across all study groups, 0%, 1.2%, 4.9% and 5.9% of patients in the placebo, Darusentan 50 mg, 100 mg and 300 mg groups, respectively, discontinued study drug due to edema.
Decreases in hemoglobin ( 0.19, 0.92, 0.93 and 1.08 g/dL in the placebo, Darusentan 50 mg, 100 mg and 300 mg, respectively ) and decreases in hematocrit ( 0.89, 2.89, 2.54 and 2.88% in the placebo, Darusentan 50 mg, 100 mg and 300 mg, respectively ) were also observed.
Observed serum aminotransferase concentrations above three times the upper limit of the normal range were reported in three patients, one each in the placebo, 100 mg and 300 mg Darusentan groups. One death ( sudden cardiac death ) occurred during the study; this patient was receiving placebo.

. Darusentan selectively blocks the endothelin type-A ( ETA ) receptor, which if activated by endothelin-1 ( ET-1 ), leads to vasoconstriction and cell proliferation. Elevated ET-1 blood concentrations have been reported in some patients with hypertension, including several subgroups of hypertensive patients that have been historically difficult to treat.

Source: Gilead, 2009

XagenaMedicine_2009