Gilead Sciences, Inc. (Nasdaq:GILD) today announced that data from
a Phase IIb study (DAR-201) of darusentan, an investigational
treatment for resistant hypertension, were published in the October
2007 edition of the Journal of Clinical Hypertension. In this study,
darusentan was evaluated as an add-on antihypertensive treatment in
patients who had not achieved goal blood pressure while being treated
with full doses of three or more antihypertensive medications,
including a diuretic. Gilead is currently conducting two follow-on,
pivotal Phase III clinical trials in resistant hypertension: DORADO
(DAR-311) and DORADO-AC (DAR-312).
"Despite aggressive lifestyle modifications and the use of
combination antihypertensive treatment regimens, a substantial number
of hypertensive patients fail to achieve the recommended blood
pressure goal, putting them at risk of stroke, heart failure, coronary
artery disease and other life-threatening conditions," said Henry R.
Black, MD, Director of Hypertension Research and Clinical Professor of
Internal Medicine at the New York University School of Medicine Center
for the Prevention of Cardiovascular Disease. "These preliminary study
results are encouraging in that darusentan, an investigational
therapy, appears to be effective at further lowering blood pressure as
add-on therapy in hypertensive patients classified as resistant based
on the strict criteria published by the Seventh Joint National
Committee on the Prevention, Detection, Evaluation and Treatment
(JNC7). Based on these results, Phase III clinical trials of
darusentan in resistant hypertension are warranted and are currently
underway."
DAR-201 was a randomized, double-blind, placebo-controlled trial
of 115 patients at approximately 30 investigative sites in the United
States. Patients underwent titration every two weeks through 10, 50,
100 and 150 mg of darusentan (n=76) or placebo (n=39) until the target
dose of 300 mg once daily was achieved. The treatment period was ten
weeks followed by a two week drug withdrawal period. The co-primary
endpoints were the changes from baseline through week 8 (150 mg) and
week 10 (300 mg) in trough sitting systolic blood pressure (SBP).
Darusentan (300 mg) significantly reduced placebo-corrected mean
trough sitting SBP from baseline by 11.5 mmHg (p=0.015) after ten
weeks of treatment. This effect was consistent across all pre-defined
subgroups, including age, race, gender and co-morbidity status. Change
from baseline to week 8 (150 mg) was also significant, with a
placebo-corrected mean reduction of 7.4 mmHg (p=0.048).
Darusentan also significantly reduced placebo-corrected mean
trough sitting diastolic blood pressure (DBP) by 6.3 mmHg (p=0.002).
Ambulatory blood pressure monitoring (ABPM) performed at week 10
revealed significant reductions from baseline in placebo-corrected
24-hour SBP and DBP in patients treated with darusentan. Reductions in
BP were maintained throughout the 24-hour monitoring period, with an
estimated trough-to-peak ratio of 96 percent. Fifty-one percent of
patients receiving darusentan achieved goal SBP, compared to 33
percent of patients on placebo (p=0.054) at week 10.
Seventy-eight percent of patients treated with darusentan were
able to successfully escalate to the maximum study drug dose of 300 mg
once daily. Adverse events were generally mild to moderate in
intensity. The most common adverse events occurring in patients on
darusentan were peripheral edema (17 percent), headache (11 percent),
sinusitis (8 percent), dizziness (7 percent) and nasopharyngitis (7
percent). One case of severe edema was reported in the darusentan arm.
Following randomization, five serious adverse events were reported
in four patients in the darusentan group (coronary artery disease,
aseptic meningitis, pneumonia, lung squamous cell carcinoma, and
pleural effusion) and one serious adverse event was reported by a
patient in the placebo arm (ischemic colitis). The cases of pneumonia,
pleural effusion and ischemic colitis led to study discontinuation by
the patients. None of these events were considered to be related to
study drug. No clinically significant changes in frequency or severity
of adverse events over time were observed and no deaths occurred
during the study. Liver function test results were comparable between
treatment groups and there were no observed serum aminotransferase
concentrations above two times the upper limit of the normal range in
either randomized group.
Darusentan is an investigational compound and has not yet been
determined safe or efficacious in humans.
About the Phase III DORADO Clinical Program
The primary objective of the DORADO program is to determine if
darusentan is a safe and effective treatment for reducing SBP and DBP
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 approximately 352
patients will be randomized to one of three doses of darusentan (50,
100 or 300 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.
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).
About Darusentan
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 is
selective for the endothelin type-A (ET(A)) receptor. Activation of
the ET(A) receptor by endothelin, a small peptide hormone, leads to
vasoconstriction (narrowing of blood vessels) and cell proliferation.
Elevated endothelin blood concentrations have been reported in some
patients with hypertension.
About Resistant Hypertension
The Seventh Report of the Joint National Committee on Prevention,
Detection, Evaluation and Treatment of High Blood Pressure (JNC7)
defines resistant hypertension 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 JNC7, a SBP
of less than 140 mmHg and a DBP 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.
Hypertension affects approximately one billion people worldwide.
While the exact number of patients classified as resistant by JNC7
criteria is unknown, estimates suggest a prevalence of anywhere
between two percent and five 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.
About Gilead Sciences
Gilead Sciences is a biopharmaceutical company that discovers,
develops and commercializes innovative therapeutics in areas of unmet
medical need. The company's mission is to advance the care of patients
suffering from life-threatening diseases worldwide. Headquartered in
Foster City, California, Gilead has operations in North America,
Europe and Australia.
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 risks
that safety and efficacy data from additional clinical studies may not
warrant further development of darusentan for the treatment of
resistant hypertension. In addition, feedback from regulatory
authorities or results from clinical trials might require
modifications or delays in later stage clinical trials or additional
trials to be performed. As a result, Gilead may make a strategic
decision to discontinue development of this product candidate if, for
example, it believes commercialization will be difficult relative to
other opportunities in its pipeline. 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 Annual Report on Form
10-K for the year ended December 31, 2006 and its Quarterly Reports on
Form 10-Q for the first and second quarters of 2007, filed with the
U.S. Securities and Exchange Commission. All forward-looking
statements are based on information currently available to Gilead, and
Gilead assumes no obligation to update any such forward-looking
statements.
For more information on Gilead, please call the Gilead Public
Affairs Department at 1-800-GILEAD-5 (1-800-445-3235) or visit
www.gilead.com.