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First Data to Show Addition of a Bile Acid Sequestrant (WelChol, colesevelam HCl) to Statin Therapy Significantly Reduces Median hs-CRP Levels

Adding WelChol to Stable Statin Therapy Further Improves Cardiovascular Risk Factors as Presented at the American Heart Association's Scientific Sessions 2005

Data presented today at the American Heart Association's Scientific Sessions 2005 in Dallas demonstrated that adding WelChol® (colesevelam hydrochloride) to stable statin therapy (i.e. Zocor® (simvastatin), Lipitor® (atorvastatin calcium) or Pravachol® (pravastatin sodium)) further reduced mean LDL-C, or "bad" cholesterol, and median high-sensitivity C-reactive protein (hs-CRP) levels. This is the first data to demonstrate that WelChol, a bile acid sequestrant (BAS), when added to statin therapy, reduces hs-CRP levels, which is a marker for inflammation and also a strong predictor of coronary heart disease (CHD) events(1)(2). Colesevelam HCl Added to a Statin: Effects on Lipid Profile and hs-CRP showed a substantial reduction in median hs-CRP. The addition of placebo to statin therapy led to a median hs-CRP percent increase of 17.2, while the addition of WelChol to statin therapy led to a median hs-CRP percent drop of 6.2 percent. The difference between treatment groups equates to a median hs-CRP percent change of -23.3 percent (p < 0.01).

The pooled study results also demonstrated that WelChol plus a statin significantly lowered mean LDL-C more than placebo (-15.7 versus -6.5 percent, p less than or equal to 0.001), while also significantly reducing mean total cholesterol and increasing mean apo A-1 versus placebo. In addition, of the 186 patients who had a baseline LDL-C level greater than or equal to 100 mg/dL, four times more patients reached the target LDL-C goal of < 100 mg/dL when WelChol was added to a statin, compared to placebo.

"Bile acid sequestrants were one of the first approved cholesterol-lowering drugs, having been studied in the 1970s, before hs-CRP was routinely measured," said lead study investigator Harold E. Bays, MD, FACP, Louisville Metabolic and Atherosclerosis Research Center Inc., Louisville, KY. "This analysis finally brings the past to the present, in that it is the first to show that a non-systemic agent, specifically WelChol, when added to a statin, statistically reduces hs-CRP, an important marker of arterial inflammation."

Elevated LDL-C is a major risk factor for CHD. Consequently, treatment guidelines identify LDL-C reduction as the primary aim of lipid-lowering treatment(3). Hs-CRP, a marker of arterial inflammation, is also a strong predictor of CHD events even after adjustment for traditional risk factors(1)(2)(3). The ability of statins to lower LDL-C accompanied by significant reductions in hs-CRP makes these agents the preferred treatment for the prevention of CHD in at-risk hypercholesterolemic patients.

About the Studies

Data were obtained from three randomized, double-blind, placebo-controlled, parallel, multicenter trials conducted in the United States between November 2002 and July 2003. All the patients tested had to be at least 18 years old, have an LDL-C level greater than or equal to 100 mg/dL and less than or equal to 250 mg/dL, triglycerides less than or equal to 300 mg/dL while on drug therapy and have taken stable doses of statin therapy (simvastatin, atorvastatin or pravastatin) for at least four weeks.

The studies involved a total of 194 patients between the ages of 18 and 75 with a mean age of 57, 55 percent of which were female. Pooled analysis of the three studies demonstrated mean baseline LDL-C levels in the active treatment group and placebo groups were 133+/-25 mg/dL and 130+/-21 mg/dL, respectively. The patients in each study were randomized 2:1 to receive either WelChol 3.8g/day or matching placebo for six weeks as add-on therapy to their usual dose of statin therapy. The primary endpoint of each of these studies was the percent change from baseline to endpoint in LDL-C while the secondary endpoints were the absolute change in LDL-C, absolute and percent changes in total cholesterol, triglyercides, apo A-I and apo-B, and the absolute change in hs-CRP. Each study was powered to specifically evaluate mean percent change in LDL-C, and therefore a pooled analysis of all three trials was set up to detect changes in the secondary endpoints.

WelChol added to a statin significantly lowered mean LDL-C more than placebo (-15.7 vs. -6.5 percent, p less than or equal to 0.001). WelChol also significantly reduced mean total cholesterol levels and non-HDL-C (p < 0.05) and increased mean apo A-I (4.8 vs. -0.2 percent, p less than or equal to 0.001). Median percent change in triglycerides was greater with active treatment compared to placebo (16.3 vs. 4.1 percent, p < .05). Of the 186 patients who had baseline LDL-C greater than or equal to 100 mg/dL, significantly more patients reached the target LDL-C of < 100 mg/dL with WelChol added to a statin, compared to placebo (39 vs. 9.5 percent, p < 0.0001). Finally, when WelChol was added to statin therapy it significantly reduced median hs-CRP compared to placebo (-6.2 vs. 17.2 percent), which equates to a median percent change between treatment groups of -23.3 percent, p < 0.01.

About WelChol

WelChol, a non-absorbed specifically engineered bile acid sequestrant (SE-BAS) indicated for LDL-C lowering approved by the U.S. Food and Drug Administration (FDA) for marketing in May 2000, is the top-selling branded drug in the bile acid sequestrant (BAS) class. Because WelChol is engineered for affinity, specificity and high capacity bile acid binding, it may have a lower drug-drug interaction potential than conventional bile acid sequestrants.

WelChol is different from most other cholesterol-lowering drugs on the market because it is non-systemic, meaning that the body does not absorb it and it is eliminated without traveling to the liver or kidneys. Systemic medications, which include the statin and fibrate classes, are those that are absorbed from the intestine into the bloodstream and travel throughout the body.

WelChol is a prescription drug indicated alone or in combination with a statin, as an adjunct to diet and exercise for the reduction of elevated LDL cholesterol in patients with primary hypercholesterolemia (Fredrickson Type IIa) when the response to diet and exercise has been inadequate. Liver-function monitoring is not required with WelChol when used as monotherapy, and in combination with a statin, no additional liver-function monitoring is required beyond that for the prescribed statin alone.

In clinical trials with patients with primary hypercholesterolemia, when WelChol was given alone in addition to a low-fat diet and exercise, it was shown to reduce LDL cholesterol by an average of 15 to 18 percent.

When WelChol is given in combination with a statin, the combination can lower cholesterol levels more effectively than using either therapy alone. In pivotal studies where WelChol was taken with a statin, WelChol 3.8g provided up to an additional mean 16 percent (32 mg/dL) reduction in LDL cholesterol. WelChol is the only non-systemic cholesterol-lowering agent approved by the FDA for combination with a statin. WelChol can be used in combination with any dose of any statin. It has been studied with four commonly prescribed statins -- Lipitor® (atorvastatin calcium), Zocor® (simvastatin), Pravachol® (pravastatin sodium) and Mevacor® (lovastatin).

WelChol is not for everyone, especially those with bowel blockage. Caution should be exercised when treating patients who have trouble swallowing or severe stomach or intestinal problems. Side effects may include constipation, indigestion and gas.

Like most prescription drugs, WelChol has not been studied in combination with all medications or supplements. Patients should always tell their doctor about all medications and supplements they are taking before starting any new therapy, including WelChol. WelChol has not been shown to prevent heart disease or heart attacks.

For more information on WelChol, call 877-4-SANKYO (877-472-6596), or go to the WelChol web site at www.WelChol.com.

About Sankyo Pharma

Sankyo Pharma Inc. is dedicated to developing and marketing important pharmaceutical products for the U.S. market. A national sales force of 615 representatives promotes WelChol®, and they are supported by dedicated managed care personnel. Sankyo Pharma also markets medications for the treatment of hypertension with its co-promote partner Forest Laboratories, Inc.

Sankyo Pharma launched WelChol, a non-systemic lipid-lowering agent, in September 2000. Currently, WelChol is the number-one prescribed branded agent in its category with 2004 sales in excess of $130 million dollars.

Sankyo Pharma's parent company, Sankyo Co., Ltd. of Tokyo, is one of Japan's largest pharmaceutical companies. Sankyo has a long history of discovering new classes of drugs, including the statin class of lipid-lowering drugs, with its discovery of the first statin, mevastatin, and the co-discovery of lovastatin, the first statin to be marketed. Additionally, Sankyo discovered, co-developed and manufactures pravastatin sodium.

For further information about Sankyo and its products, log on to www.sankyopharma.com.

Any trademarks not owned by Sankyo Pharma Inc. are the property of their respective owners.

References:

(1)Albert CM, Ma J, Rifai N, Stampfer MJ, Ridker PM. Prospective study of C-reactive protein, homocysteine, and plasma lipid levels as predictors of sudden cardiac death. Circulation 2002;105:2595-2599.

(2) Nissen SE, Tuzcu EM, Schoenhagen P, Crowe T, Sasiela WJ, Tsai J, Orazem J, Magorien RD, O'Shaughnessy C, Ganz P. Statin therapy, LDL cholesterol, C-reactive protein, and coronary artery disease. N Engl J Med 2005;352:29-38.

(3) Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) final report. Circulation 2002;106:3143-3421.

(4) Albert CM, Ma J, Rifai N, Stampfer MJ, Ridker PM. Prospective study of C-reactive protein, homocysteine, and plasma lipid levels as predictors of sudden cardiac death. Circulation 2002;105:2595-2599.

(5) Nissen SE, Tuzcu EM, Schoenhagen P, Crowe T, Sasiela WJ, Tsai J, Orazem J, Magorien RD, O'Shaughnessy C, Ganz P. Statin therapy, LDL cholesterol, C-reactive protein, and coronary artery disease. N Engl J Med 2005;352:29-38.

(6) Sakkinen P, Abbott RD, Curb JD, Rodriguez BL, Yano K, Tracy RP. C-reactive protein and myocardial infarction. J Clin Epidemiol 2002;55:445-451.

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