Merck's "Good" Cholesterol Drug Meets Trial Goals
WHITEHOUSE STATION, N.J.--Merck & Co., Inc. announced today Phase III clinical study results with CORDAPTIVE(TM) (ER niacin/ laropiprant), an investigational compound containing Merck-developed extended-release niacin and laropiprant - a novel flushing pathway inhibitor, in which CORDAPTIVE reduced LDL-cholesterol (LDL-C) levels, increased HDL-cholesterol (HDL-C) levels and reduced triglyceride levels compared to placebo. Patients treated with CORDAPTIVE also reported significantly less flushing compared to those patients treated with extended-release niacin alone. CORDAPTIVE was administered as 1- and 2- gram doses alone or added to ongoing statin therapy in patients with dyslipidemia. These results were presented today at the 2007 European Society of Cardiology (ESC) Annual Congress in Vienna, Austria.
Across weeks 12 to 24 of the study, 2 grams (two 1-gram tablets) of CORDAPTIVE produced significant percent changes from baseline in LDL-C levels (-18 percent), HDL-C levels (20 percent) and triglyceride levels (-26 percent) relative to placebo. In addition, patients treated with CORDAPTIVE reported significantly less flushing both at the initiation of therapy and during maintenance therapy, compared to patients on extended-release niacin alone. In the study, a 1 gram tablet of CORDAPTIVE contained 1 gram of extended-release niacin and 20 mg of laropiprant. All of the comparative lipid efficacy and flushing side effect results presented from this study were statistically significant (p<0.001).
"Many LDL-C-lowering drugs have been shown to reduce the risk of heart attacks and stroke; however, the majority of these patients continue to be at risk for cardiovascular events. Niacin has been shown in previous outcome studies to reduce the risk of cardiovascular events, but its use has been limited as a result of the flushing side effect," said Anders Olsson, MD, Professor at the Faculty of Health Sciences of Linkoping University in Sweden, and a study investigator. "The results of this Phase III study support the development of the investigational compound CORDAPTIVE, which may result in fewer patients discontinuing therapy due to flushing."
About the study
The study was a double-blind, randomized trial that evaluated the lipid efficacy and flushing profile of CORDAPTIVE, as monotherapy or combined with a statin, in 1,613 patients with dyslipidemia (primary hypercholesterolemia or mixed dyslipidemia).
Patients - around 65 percent of whom were already on statin therapy - were initiated at either 1 gram of CORDAPTIVE per day (n=800), 1 gram of extended-release niacin alone per day (n=543), or placebo (n=270). After four weeks, patients in the group being treated with CORDAPTIVE and the group being treated with extended-release niacin doubled their respective doses to 2 grams per day for an additional 20 weeks.
The co-primary endpoints were the effects of 2 grams of CORDAPTIVE versus placebo on percent changes in LDL-C across weeks 12 to 24, and of 1 gram of CORDAPTIVE versus extended-release niacin on flushing symptom severity during the first week of treatment. Key secondary endpoints included the effects of 2 grams of CORDAPTIVE versus placebo on HDL-C levels, triglyceride levels and other lipid parameters, and the flushing frequency and intensity of 2 grams of CORDAPTIVE compared to extended-release niacin alone.
In the study, patients who advanced to 2 grams of CORDAPTIVE reduced their LDL-C levels from baseline by an average of 19 percent (versus a reduction of 0.5 percent with placebo), raised their HDL-C levels by an average of 19 percent (versus a reduction of 1.2 percent with placebo), and reduced their triglyceride levels by an average of 22 percent (versus an increase of 3.6 percent with placebo). The 2-gram dose of CORDAPTIVE also significantly reduced both "non-HDL-C" (another measure of lipids which includes a broader spectrum of atherogenic lipoproteins) and Apolipoprotein B (also called Apo B, a component of LDL-C), and raised Apolipoprotein A-I (also called Apo A-I, a component of HDL-C). These effects were observed from weeks 12 to 24 and occurred irrespective of concomitant statin therapy.
As measured by the Global Flushing Severity Score (GFSS), 69 percent of patients treated with 1 gram of CORDAPTIVE reported either no flushing symptoms or mild flushing symptoms during the first week of treatment, compared to 44 percent of those who received extended-release niacin alone. Nearly half of the patients in the extended-release niacin group (49 percent) reported moderate or greater flushing symptoms during week 1, compared to 27 percent treated with CORDAPTIVE. By week 24, the frequency of moderate or greater flushing was 0.7 days/week among those treated with 2 grams of extended-release niacin, versus 0.2 days/week for patients taking 2 grams of CORDAPTIVE or a placebo. More than twice as many patients on extended-release niacin discontinued treatment because of flushing than patients taking CORDAPTIVE (22 percent versus 10 percent).
CORDAPTIVE was generally well-tolerated in this study. Reported side effects of interest included: liver enzyme elevations =>3x ULN in ALT and/or AST (1.4 percent in the group treated with CORDAPTIVE, 1.0 percent in the group treated with extended-release niacin, and 0.0 percent in the placebo group (p=0.610 for CORDAPTIVE vs. extended-release niacin)) and increased median fasting plasma glucose (FPG) values (increase of 4.0 mg/dL in the group treated with CORDAPTIVE, increase of 4.0 mg/dL in the group treated with extended-release niacin, and increase of 0.5 mg/dL in the placebo group). 0.4 percent of patients treated with CORDAPTIVE had =>10x ULN increases in creatine kinase (CK) levels but none had associated muscle symptoms (p=0.276 for CORDAPTIVE vs. extended-release niacin). All elevations resolved upon discontinuation of study therapy. There was no statistically significant difference seen between the patient group treated with CORDAPTIVE vs. the patient group treated with extended-release niacin for liver enzyme elevations =>3x ULN and for CK levels =>10x ULN. There were no reports of hepatitis, myopathy or rhabdomyolysis observed in this study.
Bothersome side effect of flushing
Flushing is the dilation of blood vessels causing redness of the skin coupled with warming or burning on the face and neck. It is believed that niacin induces the flushing response by triggering the release of prostaglandin D2 (PGD2), a chemical that causes vasodilation in the skin and flushing symptoms. CORDAPTIVE contains laropiprant, an investigational PGD2-receptor antagonist that is designed to reduce flushing associated with niacin by selectively blocking the binding of PGD2 to its receptor.
"In this Phase III study, CORDAPTIVE reduced niacin-induced flushing at both the initiation of treatment - week 1 - and during the maintenance phase of weeks 2 through 24. Such reduction has the potential to allow physicians to start at the 1-gram dose of niacin and advance to a 2-gram dose, which increases the likelihood that patients will not discontinue treatment due to flushing," said John Paolini, M.D., Ph.D., Clinical Research, Cardiovascular Disease, Merck Research Laboratories.
About dyslipidemia
Dyslipidemia is the elevation of LDL-C and/or triglycerides or a low HDL-C level that contributes to the development of atherosclerosis, the number one cause of death among men and women and the primary reason for loss of quality of life in Western countries. Major modifiable risk factors for atherosclerotic disease include hypertension, diabetes, obesity, smoking and high levels of total cholesterol or LDL-C. Low levels of HDL-C also increase a person's chances of developing atherosclerosis. In fact, epidemiologic studies have shown that for every 1 mg/dL rise in HDL-C, the risk of developing cardiovascular disease decreases by two percent to three percent.
About cardiovascular risk factors
Cardiovascular disease (CVD) is a general term referring to diseases that affect the heart or blood vessels. Coronary heart disease (CHD), also known as coronary artery disease (CAD), is one of the most common forms of CVD and is the leading cause of death globally. Major risk factors for CVD include abnormal blood lipids, meaning not only high LDL-C ("bad" cholesterol) and triglyceride levels, but also low levels of HDL-C ("good" cholesterol). Researchers hypothesize that HDL-C takes part in the reverse transport of LDL-C from peripheral tissues in the body back to the liver for elimination. It is also theorized that HDL-C suppresses vascular inflammation associated with atherosclerosis and may potentially reduce the risk of injury to blood vessels through an anti-oxidative effect.
About Merck
Merck & Co., Inc. is a global research-driven pharmaceutical company dedicated to putting patients first. Established in 1891, Merck discovers, develops, manufactures and markets vaccines and medicines to address unmet medical needs. The Company devotes extensive efforts to increase access to medicines through far-reaching programs that not only donate Merck medicines but help deliver them to the people who need them. Merck also publishes unbiased health information as a not-for-profit service. For more information, visit www.merck.com.
Forward-looking statement
This press release contains "forward-looking statements" as that term is defined in the Private Securities Litigation Reform Act of 1995. These statements are based on management's current expectations and involve risks and uncertainties, which may cause results to differ materially from those set forth in the statements. The forward-looking statements may include statements regarding product development, product potential or financial performance. No forward-looking statement can be guaranteed, and actual results may differ materially from those projected. Merck undertakes no obligation to publicly update any forward-looking statement, whether as a result of new information, future events, or otherwise. Forward-looking statements in this press release should be evaluated together with the many uncertainties that affect Merck's business, particularly those mentioned in the risk factors and cautionary statements in Item 1A of Merck's Form 10-K for the year ended Dec. 31, 2006, and in its periodic reports on Form 10-Q and Form 8-K, which the Company incorporates by reference.