Basel, Switzerland - Phase 2b/3 results with a new renin inhibitor show that the drug lowers blood pressure effectively, similar to reductions seen with the angiotensin receptor blocker valsartan (Diovan^®, Novartis), with some hint that the two drugs may have additive effects.

Data from a randomized clinical trial of the renin inhibitor—called SPP100 or aliskerin—were disclosed January 20, 2005, during a report of the 2004 annual results of Novartis International AG by James Shannon (clinical development and medical affairs, Novartis).

The drug represents the first in a new class of agents called renin inhibitors, now under development by several companies. Phase 3 studies are ongoing in the US, Europe, and Japan, and more data are expected to be available later this year. Shannon reported that Novartis anticipates submission for FDA approval of aliskerin sometime in 2006.

Blockade of the renin angiotensin system is a proven strategy for reducing cardiovascular disease. Renin is the enzyme that cleaves angiotensinogen into angiotensin I, which in turn is acted on by angiotensin-converting enzyme (ACE) to form the vasoconstrictor angiotensin II. ACE inhibitors act by blocking the transformation of angiotensin I to angiotensin II, while ARBs block the action of angiotensin II that has already been formed, explained Dr Michael Weber (SUNY Downstate College of Medicine, Brooklyn, NY), who has consulted for Novartis in the development of this new drug. Renin inhibitors act further up the cascade, preventing the transformation of angiotensinogen to angiotensin I.

Both ACE inhibitors and ARBs have been shown to protect end organs like kidney and heart, but with these agents, there is a significant rise in plasma renin activity that may itself be an independent risk factor for both cardiovascular disease and renal injury. The increase in renin may prevent ACE inhibitors and ARBs from being as effective as they might be, Weber said. Plasma renin activity is reduced with aliskerin, suggesting that combining renin inhibitors with ACE inhibitors and ARBs might enhance their action.

Renin inhibitors have been known for many years, but the problem has been to make the compounds bioavailable orally and to manufacture them at an acceptable cost, Weber noted, hurdles that have apparently been overcome with the new agent, aliskerin.

Data presented in the Novartis annual results report were from a placebo-controlled phase 2b/3 trial of 1064 patients with essential hypertension, randomized to one of three doses of valsartan, three doses of aliskerin, or placebo. After eight weeks of treatment, systolic and diastolic blood pressure was reduced significantly by aliskerin vs placebo, and reductions were similar to those seen with valsartan.

In patients who received both drugs, there was some indication of additional reductions in systolic blood pressure vs either drug alone, suggesting a possible additive effect, which will be confirmed in a follow-up study. There was no significant difference in adverse events between treatment arms, Shannon noted in his presentation.

"I wouldn't want to make any claims for it as yet, other than to say that it's got blood-pressure efficacy that seems comparable to other classes of antihypertensive agents," Weber told heartwire. "As yet, we don't have any definitive evidence to show how it might be different from other currently available classes, but there are some potential ways in which it could be additive to other antihypertensive drug classes or even have some unique renal effects.

"This all has to be tested in appropriate clinical trials, but inevitably, there will be a fair amount of interest in the renin inhibitors because it's a new drug class for hypertension. A great many clinicians will be curious to see what happens as it's further developed."

Slides with these and other results are posted to the Novartis website.