FDA Okays First Direct Renin Inhibitor for Hypertension

The FDA has approved aliskiren (Tektuma), the first oral direct renin inhibitor for treatment of hypertension. The drug is the first in a new class of agents known as oral renin inhibitors and is approved for the treatment of high blood pressure as monotherapy or in combination with other antihypertensive medications Unlike angiotensin converting enzyme inhibitors that attack the middle of the renin-angiotensin cascade, or angiotensin receptor blockers (ARBs) that target the bottom of the cascade, aliskiren interferes at the top of the renin-angiotensin cascade — before any disruption of blood pressure regulation.

A once-daily oral tablet, aliskiren blocks the action of renin at the top of the renin-angiotensin-system cascade. A pooled data analysis of antihypertensive treatment with the drug in more than 8000 patients, presented by Dr Matthew R Weir (University of Maryland School of Medicine, Baltimore) at the World Congress of Cardiology in Barcelona in September, suggested that it reduces blood pressure effectively regardless of age or gender, is well tolerated, and appears to be additive to most other antihypertensive agents, with the exception of angiotensin-receptor blockers.

In clinical trials reported at the American Society of Hypertension meeting in 2006, the drug was also touted for its ability to smooth out the daily peaks and troughs of blood pressure. Variations in blood pressure during the day are thought to increase the risk of end organ damage.

In clinical trials, the drug demonstrated efficacy across all demographic groups, but African Americans reported smaller reductions in blood pressure.  As with other blood pressure medications, the drug was most effective when used in combination with a thiazide diuretic.

"Clearly, a new drug with a unique mechanism of action is a welcome addition," Dr Franz Messerli (St Luke’s-Roosevelt Hospital, New York, NY) stated that,  "However, there are several questions coming to mind. Is there a need for triple blockade of the renin angiotensin system, and if so, what is the risk/benefit ratio? If the prorenin story plays out–and that’s a big if–conceivably aliskiren will have distinct advantages in the diabetic patient. From a purely antihypertensive point of view, I cannot conceive that a drug that has a very similar shallow dose-response curve as the angiotensin-receptor inhibitors but seems to have more adverse effects will confer a distinct advantage."

Where aliskiren might be advantageous, said Messerli, is in patients who cannot take ACE inhibitors because of cough or angioedema or those who need a double blockade of the renin angiotensin system, such as diabetic patients with albuminuria. He added that while there seem to be many unanswered questions, "this is not unusual when a new compound is introduced, because our vision of efficacy and safety is still narrow because of the lack of data."

The FDA said aliskiren was evaluated for safety in more than 6,460 patients, including 1,740 who were treated longer than six months, and more than 1,250 for over one year.  Side effects were usually mild and brief. The most common side effect experienced by patients taking aliskerin was diarrhea, which was reported by about 2% of patients randomized to it.

Rarely patients experienced allergic reactions characterized by swelling of the face, lips, or tongue and difficulty breathing.
Aliskiren and other drugs that act directly on the renin-angiotensin system should not be used during pregnancy, said the FDA, because they can cause injury and even death to the developing fetus. It will be sold in the United States in March in doses of 150 milligram and 300 mg.       

Aliskiren was developed by Novartis.