Results of phase III clinical trials with the investigational drug eplerenone, the first selective aldosterone blocker, were presented at the 17th Annual Scientific Meeting of the American Society of Hypertension (ASH).

The results of these studies showed that eplerenone provided significant blood pressure control both as initial therapy and in combination with other antihypertensive agents among a wide range of patient types, including those with low-renin hypertension, hypertension and diabetes, and hypertension and left ventricular hypertrophy (a condition in which cardiac muscle is enlarged and which is often a precursor of other hypertensive heart disease).

Despite the availability of several classes of antihypertensive compounds, hypertension remains significantly uncontrolled. Of the 50 million Americans with high blood pressure, 73% have not achieved the level of blood pressure control desired.

Hypertension increases the risk of heart attack, stroke, kidney failure, damage to the eyes, heart failure and atherosclerosis.

Eplerenone is the only compound designed to selectively block aldosterone and its effects. Preclinical and clinical research suggests a deleterious role of aldosterone in cardiovascular disease.

 The hormone aldosterone is a key component within the RAAS (renin angiotensin aldosterone system) and plays a significant role in the body’s regulation of the cardiovascular system.

The release of aldosterone is mediated through both RAAS and non-RAAS pathways. Currently available drugs such as angiotensin converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs) do not fully block the effects of aldosterone. “These studies are extremely encouraging in light of the emerging understanding about the need to address various pathways which contribute to cardiovascular disease,” said Goran Ando, M.D., Executive Vice President and President, R & D, Pharmacia Corporation. “As we understand more about the role of aldosterone, addressing its detrimental effects with eplerenone may become very important.”

Eplerenone in Essential Hypertension In one trial presented at ASH, eplerenone was evaluated using both clinic and ambulatory blood pressure measurements to determine efficacy, dose ranges and pharmacodynamic effects [ASH abstract # P243]. In this multinational trial that included 400 patients with mild-to-moderate hypertension, eplerenone doses of 50 to 200 mg once daily resulted in reductions in systolic and diastolic blood pressures ranging from 5.7-10.4/3.7-6.3 mmHg respectively. Headache was the most frequently reported adverse event and hyperkalemia was seen in one patient treated with eplerenone 200 mg once daily. Another study [ASH abstract # OR-51] in 499 mild-to-moderate hypertensive patients compared eplerenone and enalapril, a widely prescribed angiotensin converting enzyme (ACE) inhibitor. In the 12-month study, patients were randomly assigned to receive eplerenone or enalapril once a day. Study medication was titrated as needed, with doses ranging from 50 to 200 mg once daily for eplerenone and 10 to 40 mg once daily for enalapril. At week 24, blood pressure was reduced from baseline by 14.5/11.2 mmHg for patients treated with eplerenone and 12.7/11.3 mmHg for patients treated with enalapril.

These reductions were sustained over the duration of the trial. Additionally, in a subgroup of patients with baseline abnormalities in levels of urinary protein excretion, or microalbuminuria (n=64), reductions in microalbuminuria of 62% in the group treated with eplerenone compared with 26% in the group treated with enalapril were observed. Both eplerenone and enalapril were generally well tolerated, although cough was more common in the group treated with enalapril. Elevated potassium (greater than 5.5 mEq/L) was reported in less than one percent of patients in either group. Eplerenone in Special Populations More than half of patients with hypertension are salt-sensitive, and an estimated 25% of hypertensive patients have low plasma renin. Low plasma renin activity has been associated with an increased risk of cardiovascular disease. Previous clinical studies have demonstrated that hypertensive patients with low plasma renin, including African Americans, do not respond well to two widely used classes of antihypertensives — angiotensin converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs). The hypothesis that these patients might achieve significant blood pressure reductions with an aldosterone blocker was tested in the following clinical trials. Eplerenone and losartan, an ARB, were compared in a study of 168 patients [ASH abstract # OR-55] with low-renin hypertension. Patients were randomized to receive eplerenone or losartan once daily, with drug doses titrated as needed for blood pressure control to maximum doses of 200 mg and 100 mg for eplerenone and losartan respectively. A diuretic was added at week eight if blood pressure remained uncontrolled. This study demonstrated that eplerenone alone reduced systolic and diastolic blood pressures by 15.8/9.3 mmHg compared with reductions of 10.1/6.7 mmHg for losartan alone. Add-on therapy was required in 26% of patients treated with eplerenone and 45% of patients treated with losartan.

 No hyperkalemia was seen with either eplerenone or losartan in this trial, and both drugs were well tolerated with the overall incidence of adverse events similar between eplerenone and losartan. Results of another study [ASH abstract # P499] underscore these findings. This 16-week multicenter trial of 348 black and 203 white hypertensive patients, conducted in the United States and South Africa, compared the efficacy and safety of eplerenone, losartan and placebo. Patients were randomized to receive eplerenone or losartan once a day, with drug doses titrated as needed, again to maximum doses of eplerenone and losartan of 200 mg and 100 mg once daily respectively. This study demonstrated that in addition to providing significant reductions in blood pressure from baseline compared with placebo among all patients, in black patients eplerenone provided reductions in blood pressure of 13.5/10.2 mmHg compared with reductions of 5.3/6.0 mmHg with losartan. Elevated potassium was reported in only one percent of patients in the eplerenone treated group. Headache was the most commonly reported adverse event, occurring in approximately 13-14% of patients in each group. According to Dr. Ando, “Based on the caliber of clinical data presented at this meeting aldosterone blockade with eplerenone may confer immediate blood pressure lowering benefits as well as provide intriguing effects on markers of end organ damage.” In addition to providing evidence that eplerenone yields significant blood pressure reductions, data presented at the American College of Cardiology earlier this year explored the effects of eplerenone on urinary protein excretion in diabetics and left ventricular hypertrophy, both markers of hypertensive end organ damage. Eplerenone is currently under review by the U.S. Food and Drug Administration for the treatment of essential hypertension and is being studied for use in heart failure to determine its effect on morbidity and mortality in patients who have suffered a heart attack and have early complications of heart failure. Results from a number of clinical hypertension studies evaluating eplerenone alone or in combination with other antihypertensive agents and the EPHESUS trial in heart failure, in which eplerenone is being evaluated in combination with standard therapy, will be available in the coming year. Pharmacia (NYSE: PHA) is a top-tier global pharmaceutical company with a leading agricultural subsidiary. Pharmacia’s innovative medicines and other products save lives and enhance health and wellness. Pharmacia’s 59,000 people work together with many diverse stakeholders to bring these benefits to people around the world, and to create new health solutions for the future. This press release contains forward-looking or anticipatory statements about the company’s business and financial performance plans which are based on the information currently available and the expectations currently deemed reasonable by the company.

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