Dual receptor antagonist demonstrated to be effective in reducing SBP

An investigational first-in-class dual angiotensin and endothelin receptor antagonist lowered systolic blood pressure (SBP) in patients with stage 1 and 2 hypertension in a phase 2a trial, reported Joel M. Neutel, MD, associate professor of medicine, University of California, Irvine, and medical director of clinical pharmacology, Orange County Research Center, Tustin, California. These results were presented at the 23rd Annual Scientific Meeting of the American Society of Hypertension, New Orleans, May 14–17, 2008.

The compound, PS433540, was studied in 114 patients with mean daytime ambulatory SBP of 140 to 179 mmHg (and a diastolic blood pressure [DBP] <110 mmHg). Patients were either newly diagnosed with hypertension or had been treated for hypertension previously. After a 3- to 4-week placebo washout, patients were randomized to PS433540 200 or 500 mg once daily or placebo for 4 weeks.

The analysis presented here included 93 patients with ambulatory blood pressure analyses. The primary end point was mean 24-hour ambulatory SBP, and the secondary end points were mean 24-hour ambulatory DBP and seated office blood pressure.

The reductions in mean 24-hour blood pressure from baseline were 12.2/9.3 mmHg (P<.001) in the group randomized to 200 mg of active treatment and 14.8/10.1 mmHg (P<.001) in those randomized to 500 mg. Patients in the placebo group experienced a 0.4-mmHg decline in SBP and a 0.30-mmHg increase in DBP.

The reductions from baseline in mean seated office blood pressure were 16.9/10.5 mmHg (P<.001) in the PS433540 200-mg group and 17.3/9.8 mmHg (P<.001) in the 500-mg group. Placebo recipients had a 4.2-mmHg decrease in mean seated office SBP and a 1.6-mmHg increase in mean seated office DBP.

The effect of the 500-mg dose of PS433540 is equivalent to the effect achieved by adding a second antihypertensive drug to monotherapy, said Dr Neutel.

SBP reduction during the last 2 hours of the dosing interval was 14.4 mmHg with the 500-mg dose, “almost as good as what you see for the mean of the entire period, suggesting that it’s a truly once-a-day agent,” Dr Neutel said.

PS433540 was generally well tolerated, with no cases of peripheral edema reported in the group assigned to 200 mg and 1 case reported in those assigned to 500 mg.