Gilead Sciences, Inc announced that DAR-311 (Dorado), a phase-III clinical trial evaluating the company's 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). 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. The second study, DAR-312 (Dorado-AC), is approximately 90 per cent enrolled and is expected to be completed by the end of 2009.

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 per cent 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 per cent, 1.2 per cent, 4.9 per cent and 5.9 per cent of patients in the placebo, darusentan 50 mg, 100 mg and 300 mg groups, respectively, discontinued study drug due to edema. Decreases in haemoglobin (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 per cent, 2.89 per cent, 2.54 percent and 2.88 per cent 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. Full study results highlighting efficacy and safety will be submitted for presentation at a scientific meeting later this year.

"Failure to control blood pressure elevates the risk of a number of life-threatening cardiovascular conditions such as stroke, heart attack and heart failure, suggesting an unmet need for novel antihypertensive drugs with unique mechanisms of action that can be added to existing treatment regimens in patients with resistant hypertension. In this study, more than half of the patients treated with darusentan achieved goal blood pressure, as compared to approximately one quarter of patients receiving placebo," said Norbert Bischofberger, Gilead's executive vice president, Research and Development and chief scientific officer. "We look forward to presenting full results from this study and to completing our second phase-III study, which will further characterize darusentan's safety and efficacy profile."

Darusentan is an investigational compound and has not yet been determined safe or efficacious in humans.

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.

Gilead Sciences is a biopharmaceutical company that discovers, develops and commercializes innovative therapeutics in areas of unmet medical need.