DAR-311, a Phase III clinical trial evaluating the endothelin receptor antagonist ( ERA ) Darusentan 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 ).

In the DAR-311 study, reductions in mean trough sitting SBP 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 percent, 1.2 percent, 4.9 percent and 5.9 percent 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 g/dL, 0.92 g/dL, 0.93 g/dL and 1.08 g/dL in the placebo, Darusentan 50 mg, 100 mg and 300 mg, respectively ) and decreases in hematocrit ( 0.89 percent, 2.89 percent, 2.54 percent and 2.88 percent in the placebo, Darusentan 50 mg, 100 mg and 300 mg, respectively ) were also observed.
Liver function test results were comparable between treatment groups. 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.

The DORADO program is designed to evaluate the safety and efficacy of Darusentan for reducing systolic and diastolic blood pressure in resistant hypertension patients currently treated with full doses of three or more antihypertensive medications, one of which is a diuretic.

DORADO ( DAR-311 ) is an international Phase III double-blind, placebo-controlled parallel group trial, in which 379 patients were randomized to receive once-daily doses of Darusentan 50 mg ( n=81 ), 100 mg ( n=81 ), 300 mg ( n=85 ) or placebo ( n=132 ).

DORADO-AC ( DAR-312 ) is an international Phase III double-blind, placebo- and active-controlled, parallel group trial, in which approximately 770 patients will be randomized to receive Darusentan ( titrated to the optimal dose of 50, 100 or 300 mg once daily ), an active comparator ( Guanfacine 1 mg once daily ) or placebo. The co-primary endpoints of the trial are the changes from baseline to week 14 in trough sitting SBP and trough sitting DBP, as measured by sphygmomanometry.

For both studies, patients who complete the 14-week assessment period are eligible to enroll in long-term safety studies ( DAR-311E and DAR-312E ).

Darusentan is a propanoic-acid class endothelin receptor antagonist ( ERA ) being investigated in clinical trials as an add-on oral therapy for patients with resistant hypertension.
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.

Resistant hypertension is defined as the failure to achieve goal blood pressure in patients who are adhering to full doses of an appropriate three-drug regimen that includes a diuretic.
According to the Seventh Joint National Committee on the Prevention, Detection, Evaluation and Treatment ( JNC7 ), an systolic blood pressure of less than 140 mmHg and a diastolic blood pressure of less than 90 mmHg are recommended for patients with hypertension and no other serious conditions. For patients with diabetes and chronic renal disease, target systolic and diastolic blood pressures are more stringent - a SBP goal of less than 130 mmHg and a DBP goal of less than 80 mmHg.

Source: Gilead, 2009

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