Darusentan Data Encouraging But "Very, Very Early"

June 16, 2009

June 16, 2009 (Milan, Italy) — Results of a phase 3 trial with darusentan (Gilead Sciences, Foster City, CA) in patients with resistant hypertension were reported during a late-breaking trials session at the European Meeting on Hypertension 2009 this weekend [1]. Presenting the findings, Dr Lars Lindholm (Umea University, Sweden) said they were encouraging but stressed, "These are very, very early data."

Lindholm said, "It was very nice to be able to show there was an effect on systolic BP as well as diastolic BP" with darusentan, adding that the drug enabled many patients to attain their treatment goals. But he pointed out an "interesting" placebo effect: almost a quarter of the patients on placebo in the trial who had resistant hypertension and were on "so-called optimum treatment" had reductions in both systolic and diastolic blood pressure. Also, he acknowledged there were adverse events with the drug, in particular edema, which could prove problematic.

One of the chairs of the late-breaking session, Dr Michael H Alderman (Albert Einstein College of Medicine, Bronx, NY), commented to heartwire that the darusentan data are "certainly interesting--these are patients whose blood pressure is not easy to control, so new and better therapies to achieve that goal would be desirable. But this is a preliminary study, and I wonder how significant [the BP-lowering] effect was after one corrects for the fall in BP achieved among subjects given placebo. The second thing is the fluid retention . . . and as I recall there were a few cases of heart failure. It's early days, but I certainly think it justifies more work."

Darusentan Groups Achieved Significant Reductions in BP

The new data--from the DAR-311 (also known as DORADO) study--were first reported by Gilead Sciences in a press release in April; they were also presented at the American Society of Hypertension meeting last month, as well as by Lindholm at the European meeting.

DAR-311 examined the safety, efficacy, and tolerability of darusentan, an endothelin antagonist, as an add-on treatment for resistant hypertension--defined as the failure to achieve blood-pressure goals while adhering to full doses of an appropriate three-drug antihypertensive regimen that included a diuretic. In the double-blind, placebo-controlled, parallel-group international trial, 379 patients with resistant hypertension received a once-daily dose of darusentan 50 mg (n=81), 100 mg (n=81), or 300 mg (n=85) or placebo (n=132) for 14 weeks in addition to their existing drug regimen.

The trial met its co-primary efficacy end points of change from baseline to week 14 in trough sitting systolic blood pressure (SBP) and trough sitting diastolic blood pressure (DBP), with results being significant for all darusentan doses, even after adjustment for the reductions in BP seen in the placebo group (p<0.001). A higher proportion of darusentan-treated patients achieved SBP goals by week 14 than placebo patients (53.1%, 53.1%, and 48.2% for the 50-mg, 100-mg and 300-mg doses compared with 27.3% for placebo).

Lindholm noted that there did not appear to be a dose-response effect with darusentan; "they seem to get almost [all the benefits] with a 50-mg dose," he noted.

Reductions in SBP, DBP With Placebo and All Darusentan Doses After 14 Weeks of Treatment

Patient group Reduction in SBP, mm Hg Reduction in DBP, mm Hg
Placebo -8.6 -5.3
DAR 50 mg -16.5 -10.1
DAR 100 mg -18.1 -9.9
DAR 300 mg -18.1 -10.1

Would a Reduction in Dose Solve the Edema Problem?

The most common treatment-emergent adverse events were peripheral edema and fluid retention, which were reported in around a third of patients taking all doses of darusentan. No one in the placebo group discontinued treatment due to edema, compared with 1.2%, 4.9%, and 5.9% of those in the three darusentan groups, respectively.

Another side effect seen with darusentan was anemia, although this did not appear to be a major problem, said Lindholm, adding that "we showed the data to hematologists, and they said it was nothing to be concerned about." Liver-function test results were also comparable across the groups, "nothing much to write home about," he said.

One cardiac death occurred in a patient on placebo. There were cardiovascular events in five patients taking darusentan: two had MIs (with a prior history of CAD), one had recurrence of congestive heart failure (CHF) present at baseline, and two developed CHF with preserved ejection fractions that responded well to loop diuretics, said Lindholm.

In answer to a question at the end of the session as to whether doses of darusentan lower than 50 mg might still reduce blood pressure but with lower incidences of edema, he said this was quite possibly the case.

It was shown in early work that 50 mg was better than 10 mg, he said, "but between 10 mg and 50 mg, we don't know; 25 mg might have done the trick. This is what it's like when you are early out."

In a second phase 3 study, DAR-312, around 770 patients are being randomized to darusentan (titrated to the optimal dose of 50, 100, or 300 mg once daily), an active comparator (guanfacine 1 mg once daily), or placebo for 14 weeks, with the same co-primary end points as DAR-311.