"There is a desire, I think, on the part of clinicians to have something that is more effective in helping us to get patients to goal rapidly," said lead investigator Dr Joel Neutel (University of California, Irvine) during a press conference here at the American Society of Hypertension 2008 Annual Meeting, where the findings were presented. "This reduction in the 24-hour ambulatory blood pressure recording is quite tremendous. I don't recall seeing such significant reductions in 24-hour systolic blood pressure before."

The compound, a dual-acting receptor antagonist known at the moment as PS433540 (Pharmacopeia, Princeton, NJ), blocks the angiotensin and endothelin receptors. Both angiotensin and endothelin, said Neutel, are powerful vasoconstrictors and appear to work hand-in-hand, with one stimulating the other to contribute to high blood pressure in patients. Blocking both physiological systems is one theoretical way of managing hypertensive patients, with the hope that dual blockade would bring about large reductions in systolic and diastolic blood pressure.

In this first-in-human phase 2a clinical trial, investigators randomized 93 patients to treatment with 200 mg of PS433540, 500 mg of PS433540, or placebo. Inclusion criteria were stringent, with patients having to meet baseline seated office blood-pressure criteria—150 mm Hg to 179 mm Hg systolic and diastolic <110 mm Hg—and then meet ambulatory blood-pressure criteria before randomization to treatment. This was done, said Neutel, in order to eliminate white-coat hypertension and include only patients with true high blood pressure.

After four weeks, treatment with both 200 mg and 500 mg of the dual-acting receptor blocker reduced systolic and diastolic blood pressure as measured by mean 24-hour ambulatory recording and traditional methods taken in the doctor's office. Both the 200-mg and 500-mg dose of PS433540 provided a reduction that was maintained throughout the 24-hour dosing interval.

The investigators report the drug to be safe and well tolerated, with the side-effect profile no different from placebo, even among those treated with the 500-mg dose. Previous concerns with endothelin antagonists have been edema and adverse effects on the liver, but in this study no red flags were raised. There was one reported case of edema in the 500-mg dosing arm and one case reported in the placebo group. Changes in liver enzymes were no different in the three treatment arms. Neutel said that this new compound includes a very specific endothelin antagonist that likely improves its overall side-effect profile.

It is becoming increasingly attractive to get patients more quickly to goal, said Neutel, and to find ways to improve compliance. One way to improve compliance and adherence might be to reduce the number of drugs or to prescribe agents that affect multiple pathways.

Commenting on the results of the study for heartwire, Dr Jackson Wright (Case Western Reserve University, Cleveland, OH), who was not affiliated with the study, said the 15-mm-Hg reduction in systolic pressure was credible and promising. Cautioning that the agent is still early in development, he said the dual mechanism of action is attractive, especially an agent that works on these two receptors.

"The combination of a [renin angiotensin system] RAS inhibitor with an agent that works at another receptor has been tried before, but this has advantages in the sense of using a RAS inhibitor that has a very low side-effect profile." A full safety signal, however, won't be revealed until larger studies are performed, he added.

During the press conference, Neutel said it is possible that the compound could be developed in combination with a hydrochlorothiazide diuretic or with a calcium-channel blocker. Company executives told heartwire that it is still too early to determine the exact direction they plan to go with the drug, but combining it with other agents is likely. The drug, however, would be available as monotherapy, leaving clinicians the option of combining it with hypertensive medications of their choice.

There is an ongoing phase 2b study with PS433540 in 400 patients using the 200-mg, 500-mg, and 800-mg doses and comparing the relative blood-pressure reductions against the angiotensin receptor blocker irbesartan. The trial is expected to be completed by the end of 2008.