Pivotal Data Demonstrating Efficacy Of Darusentan In Treating Resistant Hypertension Published In The Lancet

Main Category: Hypertension
Also Included In: Regulatory Affairs / Drug Approvals
Article Date: 15 Sep 2009 - 0:00 PDT

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Gilead Sciences, Inc. (Nasdaq:GILD) 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 (n=81), 100 mg (n=81), 300 mg (n=85) or placebo (n=132) for up to 14 weeks as an add-on to existing antihypertensive regimens. The co-primary efficacy endpoints were change from baseline to week 14 in trough sitting SBP and DBP. Secondary endpoints included change from baseline in mean 24-hour SBP and DBP and percent of patients reaching SBP goal. The most common patient-reported adverse events were edema and/or fluid retention, dizziness, headache and fatigue. Results from this study were presented at the American Society of Hypertension, Inc. Twenty-Fourth Annual Scientific Meeting and Exposition (ASH 2009) in May 2009.

"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 (p=0.0002, p<0.0001 and p=0.0007 for darusentan doses compared to placebo, respectively). In patients with diabetes, approximately 34 percent, 45 percent, 30 percent, and 16 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.

About the Phase III DORADO Program

DAR-311 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. The second study, DAR-312 (DORADO-AC), is fully enrolled and is expected to be completed with data available by the end of 2009.

DAR-312 is an international Phase III double-blind, placebo- and active-controlled, parallel group trial, in which approximately 849 patients were 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).

About Darusentan

Darusentan is an oral, once-daily 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 (narrowing of blood vessels) and cell proliferation.

About Resistant Hypertension

Resistant hypertension is defined as the failure to achieve goal blood pressure in patients who are adhering to full doses of an appropriate three (or more) drug regimen that includes a diuretic. Hypertension affects approximately one billion people worldwide. While the exact number of patients classified as resistant is unknown, estimates suggest a prevalence of anywhere between 2 percent and 5 percent of hypertensive patients in general practice settings in the United States, with significantly higher rates in specialty referral clinics. Failure to control hypertension elevates the risk of stroke, coronary artery disease, myocardial infarction, heart failure, kidney disease and cardiovascular mortality. Currently, there is no accepted standard of care for treatment of patients with resistant hypertension.

Source
Gilead Sciences