Experimental blood pressure drug takes natural approach

Dual-acting compound tests well in large group of people with mild to moderate hypertension

A new drug that enhances the body’s own blood pressure–lowering machinery has shown effectiveness in a large test, researchers reported online March 16 in the Lancet. The results have set the stage for a trial needed for regulatory approval in which the drug will be tested in heart failure patients, who are likely to benefit from its vessel-relaxing effects.

The drug is so new it still doesn’t have a name, having been dubbed LCZ696 by its maker, Novartis, which funded the study.

“We look at this drug as augmenting the body’s natural, intrinsically beneficial response” to circulatory disorders, whether caused by high blood pressure, stiff arteries or other problems, says study coauthor Martin Lefkowitz, a nephrologist at Novartis Pharmaceuticals in East Hanover, N.J.

Roughly 75 million U.S. adults have high blood pressure, according to the American Heart Association. The new findings could come as welcome news for many of them, says John Burnett, a cardiologist at the Mayo Clinic in Rochester, Minn., who didn’t participate in the study.

In the study, the drug tested well in people with mild or moderate hypertension. “This new class of drugs has the potential of increasing the ability to control blood pressure, not only in this type of patient but in others,” Burnett says. Researchers will need to test LCZ696 in people who have severe hypertension and those who are taking multiple medications, he says.

LCZ696 works in two ways. Part of it functions by blocking a protein called angiotensin-2 from binding to a receptor protein on cells, therefore lessening the ability of angiotensin-2 to constrict blood vessels and hike blood pressure.

In its other role, LCZ696 bottles up a compound called neprilysin that itself inhibits a natural protective substance called atrial natriuretic peptide. ANP is one of the body’s own blood pressure controllers, inducing the kidneys to flush out salt and water and ease pressure on blood vessels. “It’s the body’s own natural diuretic, without the adverse effects that diuretic drugs have,” Burnett says.

By inhibiting neprilysin, this portion of LCZ696 keeps more ANP in circulation, he says. “The heart makes ANP. This drug allows the heart to provide more of it.”

Inhibiting neprilysin has been tried before. Starting in the 1990s, researchers tested a drug called omapatrilat that combined a neprilysin inhibitor with a commonly prescribed blood pressure drug called an ACE inhibitor. ACE inhibitors directly lower levels of angiotensin-2. But that dual-strategy drug failed because it caused side effects such as swelling in various parts of the body including the throat.

In the new study, 1,215 people with slightly elevated blood pressure were treated for eight weeks in 18 countries. Some were randomly assigned to get LCZ696 while others got a standard hypertension medicine called valsartan (sold as Diovan). Valsartan makes up half of the LCZ696 compound. Some participants received an experimental drug called AHU377, which constitutes the other half of LCZ696. A fourth group got inert pills.

After eight weeks, volunteers’ blood pressure was recorded while they were sitting. LCZ696 and valsartan reduced blood pressure, but LCZ696 lowered diastolic blood pressure (the lower number) about two millimeters of mercury more on average than did valsartan and knocked about four millimeters more off the systolic blood pressure (the higher number). Those receiving the placebo or AHU377 showed no improvement.

A larger fraction of people getting LCZ696 experienced a decline in their systolic blood pressure greater than 20 millimeters compared with people getting valsartan. LCZ696 also worked better than valsartan in blood pressure measurements taken while upright and walking.

“The new drug LCZ696 … has great potential,” say Bernard Waeber and François Feihl of the University of Lausanne in Switzerland, writing in the same issue of the Lancet. In this study, people taking LCZ696 had no more side effects than those getting the placebo, they note.

Lefkowitz says Novartis will first seek regulatory approval for LCZ696 as a drug for heart failure patients, whether they have high blood pressure or not. In heart failure, the heart struggles to pump enough blood out to meet the needs of the body. LCZ696, by relaxing vessels, could ease that burden, he says.

The company is currently recruiting thousands of people with chronic heart failure for a trial testing the benefits of LCZ696 against other medications. Lefkowitz expects results in three or four years.

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