September 13, 2009
Pivotal Data Demonstrating Efficacy of Darusentan in Treating Resistant Hypertension Published in The Lancet
Important Findings From First of Two Phase III Studies of Darusentan for 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
“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
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.
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).
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
This press release includes forward-looking statements, within the
meaning of the Private Securities Litigation Reform Act of 1995, that
are subject to risks, uncertainties and other factors, including the
risk that we may not obtain data from the DAR-312 clinical study in the
currently anticipated time frame. Further, safety issues may arise or
the results from the DAR-311 or DAR-312 clinical studies may be
otherwise inadequate to support regulatory approval of darusentan, which
may cause us considerable expense and may lead to delays or cause us to
abandon further development of darusentan. These risks, uncertainties
and other factors could cause actual results to differ materially from
those referred to in the forward-looking statements. The reader is
cautioned not to rely on these forward-looking statements. These and
other risks are described in detail in Gilead’s Quarterly Report on Form
10-Q for the first and second quarters, as filed with the
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