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Title: Long-Term Data Show Once-Daily Investigational Compound Aliskiren, a Direct Renin Inhibitor, Safely Maintains 24-Hour Blood Pressure Reductions During 1 Year

"Long-Term Data Show Once-Daily Investigational Compound Aliskiren, a Direct Renin Inhibitor, Safely Maintains 24-Hour Blood Pressure Reductions During 1 Year"

• 12-month data show that aliskiren provides effective and well-tolerated blood pressure lowering in the long-term treatment of hypertension • Aliskiren provides sustained 24-hour blood pressure control without the effect of rebound hypertension after discontinuation of therapy • The study showed that aliskiren, when combined with the calcium channel blocker, amlodipine, provides blood pressure lowering without the increased incidence of swelling of the feet and ankles seen with higher doses of amlodipine alone • Aliskiren, if approved, would be the first in a new class called direct renin inhibitors EAST HANOVER, NJ -- September 12, 2006 -- New data show that once-daily aliskiren, the first orally effective direct renin inhibitor, provides safe, long-term, sustained, 24-hour blood pressure control without the risk of rebound hypertension. These data, presented today at the 15th World Congress of Cardiology (WCC) in Barcelona, Spain, add to the growing body of evidence that direct renin inhibition is an effective means to control high blood pressure. Aliskiren acts within the renin system, which is central to blood pressure regulation, by directly inhibiting the system's point of activation -- renin. If approved, aliskiren would be the first in a new class called direct renin inhibitors. In a study examining aliskiren as a monotherapy, and in combination with the commonly prescribed diuretic hydrochlorothiazide (HCTZ), aliskiren showed effective 24-hour blood pressure control, maintained over 1 year. This is the first study to demonstrate the long-term tolerability, safety and efficacy of aliskiren. Patients in the study taking aliskiren alone or in combination with HCTZ lowered their blood pressure substantially (17.4/13.3 mm Hg and 18.7/12.1 mm Hg, respectively), and these reductions were sustained over 24 hours. Many medicines fail to provide effective 24-hour blood pressure control, which is an important treatment consideration because patients typically experience early morning blood pressure surges. Therefore, sustained 24-hour blood pressure reductions are a potentially important benefit. The study also found that patients taking aliskiren avoided rebound high blood pressure, a potentially dangerous condition in which blood pressure rises quickly after antihypertensive therapy is stopped or a dose is missed. "Currently, 70% of people in the U.S. have uncontrolled blood pressure. Novartis is committed to helping physicians and patients get their blood pressure under control," said Marjorie Gatlin, MD, Vice President of Cardiovascular and Metabolic Clinical Development and Medical Affairs at Novartis Pharmaceuticals Corporation. "We are very encouraged by this long-term aliskiren data. If approved, aliskiren would be the first in a new class called direct renin inhibitors." Additional data released at WCC show that adding aliskiren to a low dose of the most commonly prescribed calcium channel blocker, amlodipine, significantly lowers blood pressure similar to higher doses of amlodipine alone, without the side effect of swelling that many people are unable to tolerate. This potentially uncomfortable swelling, also known as edema, can be limiting for people with high blood pressure and can often deter them from taking their medicines appropriately. Further, the study showed that adding aliskiren to low dose amlodipine provided the additive benefit of statistically significant blood pressure lowering in patients not at goal with low dose amlodipine alone (11.0/8.5 mm Hg and 5.0/4.8 mm Hg, respectively). Newly released aliskiren data highlights POSTER #797 "Aliskiren, a novel renin inhibitor, is well tolerated and has sustained BP-lowering effects alone or in combination with HCTZ during long-term (52 weeks) treatment of hypertension" Domenic Sica, MD, Medical College of Virginia Commonwealth University, Richmond, Virginia. The open-label study included 1,625 patients with mild to moderate high blood pressure who were followed for 12 months. Patients were randomized to receive once-daily treatment with aliskiren 150 mg or 300 mg. Patients taking aliskiren 300 mg whose blood pressure was not controlled were allowed to add HCTZ. After 11 months, 261 patients on aliskiren monotherapy were randomly assigned to continue on the drug or receive placebo during a four-week randomized, double-blind, placebo-controlled withdrawal phase. After 12 months of treatment with once-daily aliskiren as monotherapy or in combination with HCTZ, patients in both groups achieved similar significant reductions in blood pressure (17.4/13.3 mm Hg and 18.7/12.1 mm Hg, respectively). During a one-month withdrawal period, patients taking placebo experienced a gradual rise in blood pressure, while patients remaining on aliskiren maintained their blood pressure reductions. "High blood pressure is a chronic condition that, once diagnosed, requires effective and consistent long-term treatment to keep blood pressure at healthier and safer levels," said Domenic Sica, MD, Professor of Medicine and Pharmacology in the Division of Nephrology as well as Chairman of Clinical Pharmacology and Hypertension at the Medical College of Virginia Commonwealth University in Richmond, Virginia. "These long-term data highlight the efficacy and durability of aliskiren to safely help patients in their efforts to reach and maintain target blood pressure goals." In this study the most commonly reported adverse events include diarrhea, back pain, headache, dizziness and nasopharyngitis (cold symptoms). POSTER #784 "Aliskiren as add-on to amlodipine provides significant additional blood pressure lowering without increased oedema associated with doubling the amlodipine dose" Mark Munger, PharmD, Professor of Pharmacotherapy, College of Pharmacy, University of Utah, Salt Lake City, Utah. This six-week study included 762 patients with mild to moderate high blood pressure. All patients started treatment with amlodipine 5 mg. Patients with inadequate blood pressure control at this dose were randomized to receive aliskiren 150 mg plus amlodipine 5 mg or a double dose of amlodipine. After six weeks, patients taking the aliskiren/amlodipine combination had statistically significant reductions in mean sitting systolic blood pressure (P <.0001) and mean sitting diastolic blood pressure (P <.0001) compared to patients taking low dose amlodipine alone (11.0/8.5 mm Hg and 5.0/4.8 mm Hg, respectively). Significantly more patients taking the combination therapy responded to treatment and reached their blood pressure target than those taking low dose amlodipine. Outcomes were similar when comparing combination therapy to a double dose of amlodipine. However, 11.2% of patients in the high dose amlodipine group experienced edema versus 2.1% in the aliskiren/amlodipine group and 3.4% in the low dose amlodipine group. In this study the overall incidence of adverse events was similar across all treatment groups, although treatment-related adverse events were more frequent with amlodipine 10 mg than with amlodipine 5 mg or aliskiren 150 mg/amlodipine 5 mg. The overall incidence of adverse events was similar across the three groups. About High Blood Pressure Blood pressure is the amount of force blood puts on the walls of blood vessels as it goes through them. High blood pressure -- and its consequences -- is the world's number one killer and the number one risk factor for death. Despite extensive availability of current therapies, about 70% of all people with high blood pressure in the U.S. are not at target blood pressure levels. Many people require two or more medicines to control their blood pressure. Meanwhile, many existing treatments fail to provide sustained 24-hour blood pressure control, particularly during the early morning hours. About the Renin System The renin system is the body's key regulator of high blood pressure. It works by releasing proteins, such as angiotensin II (Ang II), that affect blood volume and blood vessel constriction. The renin system is activated by the enzyme renin. For this reason, hypertension research and drug development have long focused on controlling different points within the renin system. For more than 40 years, drug researchers have focused on controlling activation of the renin system. There are high blood pressure medicines and investigational compounds that can affect the renin system at various points. However, there are no currently approved treatments that directly address high blood pressure at its point of activation – renin. About Aliskiren The U.S. submission of aliskiren was accepted in April 2006. If approved, aliskiren, which was developed with Speedel, will represent the first new treatment approach for people with high blood pressure in more than a decade. It acts within the renin system, which is central to blood pressure regulation. By directly inhibiting the renin system's point of activation -- renin -- aliskiren decreases the system's activity. Sustained 24-hour blood pressure control is important, because blood pressure often surges during early morning hours. SOURCE: Novartis AG

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