Phase III clinical trial results of DAR-31 published

Sep 14 2009

Gilead Sciences, Inc. (Nasdaq:GILD) today announced the publication of data from DAR-311 (DORADO), a Phase III clinical trial evaluating the company’s once-daily oral endothelin receptor antagonist (ERA) darusentan as an add-on treatment for resistant hypertension, defined as the failure to achieve blood pressure goal while adhering to full doses of an appropriate three (or more) drug antihypertensive regimen that includes a diuretic. The results of the DAR-311 study, published online and in an upcoming edition of The Lancet, show that darusentan was effective at reducing trough sitting and mean 24-hour systolic blood pressure (SBP) and diastolic blood pressure (DBP) after 14 weeks of treatment in patients with resistant hypertension.

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>

“The addition of darusentan with optimized diuretic therapy has promise as a new strategy for treating patients with resistant hypertension, a condition for which no standard of care currently exists,” said Michael A. Weber, MD, Professor of Medicine at the SUNY Downstate Medical College of Medicine, Brooklyn, New York and lead study author. “These findings are important because patients with resistant hypertension are likely to be at increased risk of cardiovascular events including stroke, myocardial infarction and renal failure due to long-standing history of inadequately controlled hypertension, typically in conjunction with other risk factors like obesity, diabetes and chronic kidney disease.”

DAR-311 Results

Baseline Demographics

Baseline demographic and clinical characteristics were comparable across treatment groups. The mean patient age was 62 years old. There were nearly equal numbers of women and men in the study and 20 percent of patients were black. The mean body mass index (BMI) was 32 kg/m², an indication of obesity. Forty percent of patients were diabetic and 25 percent of patients had chronic kidney disease (CKD). At baseline, 58 percent of patients were on four or more antihypertensive medications. Mean baseline trough sitting SBP and DBP measures were 151 mm Hg and 86 mm Hg, respectively.

Primary Endpoint Results

Each of the three darusentan groups experienced statistically significant reductions (versus placebo) in trough sitting SBP and DBP. The mean reductions in SBP/DBP were 17/10 mm Hg with darusentan 50 mg, 18/10 mm Hg with darusentan 100 mg, 18/11 mm Hg with darusentan 300 mg and 9/5 mm Hg with placebo (p<0.0001 for comparison of each darusentan group versus placebo).

Similar numerical decreases in trough sitting SBP were observed in various subpopulations, including men and women, patients under or above age 65, patients with or without diabetes or CKD and patients on three background medications as compared to four or more. Not all responses in these subpopulation analyses achieved statistical significance.

Secondary Endpoint Results

According to guidelines, SBP of less than 140 mm Hg is recommended for patients with hypertension and no other serious conditions. For patients with diabetes and CKD, target SBP is more stringent, with a goal of less than 130 mm Hg. In DAR-311, 53 percent, 53 percent, 48 percent and 27 percent of patients achieved goal SBP in the darusentan 50 mg, 100 mg, 300 mg and placebo groups, respectively>

Ambulatory blood pressure monitoring (ABPM) performed at week 14 revealed similar highly significant reductions from baseline in 24-hour SBP and DBP in patients treated with darusentan and the reductions in ambulatory SBP were maintained throughout the 24-hour monitoring period.

Safety Profile

Edema and/or fluid retention was reported in 20 (25 percent), 26 (32 percent), 21 (25 percent) and 19 (14 percent) patients in the darusentan 50 mg, 100 mg, 300 mg and placebo groups, respectively. Four patients (2 percent) in the combined darusentan group discontinued the study due to fluid retention or edema. Almost all reports of clinical fluid retention occurred during the first six weeks of treatment. In approximately 70 percent of cases where diuretic therapy was altered, investigators subsequently reported that the edema or fluid retention prompting this additional diuretic therapy had resolved. Liver function test results were comparable between the groups and small mean decreases in hemoglobin (0.9-1.1g/dL), suggestive of hemodilution, were observed with darusentan.

Six patients had cardiac events during the trial that were reported as serious adverse events. There was one sudden death in a patient in the placebo group. Two darusentan patients had non-ST segment elevation myocardial infarctions, one in the darusentan 50 mg group and the other in the 100 mg group (but while receiving 50 mg during dose titration). Both of these events occurred in patients with prior coronary heart disease, and were associated with fluid retention and heart failure. There was one case of atrial fibrillation associated with symptoms of heart failure. This patient was receiving darusentan 100 mg and had prior left ventricular dysfunction, an exclusion criterion for the trial and thus was discontinued from further therapy following this incident. Lastly, there were two instances of fluid retention and heart failure, both randomized to the darusentan 300 mg group (one patient had two episodes: one on 100 mg and one on 300 mg). All episodes of fluid retention and heart failure responded promptly to diuretic therapy and with the exception of the patient with previous heart failure, the other four patients had left ventricular hypertrophy and left ventricular ejection fractions (measurements of heart pumping capacity) greater than 0.60.

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

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