Merck Sharp & Dohme (MSD) announced today that TREDAPTIVETM (nicotinic acid/laropiprant, MSD) 1 g/20 mg modified-release tablets, a new lipid-modifying therapy for patients with dyslipidemia and primary hypercholesterolemia, has been approved for marketing in the European Union (EU), Iceland and Norway.
TREDAPTIVE combines nicotinic acid (niacin) and laropiprant, a novel flushing pathway inhibitor. In clinical studies involving more than 4,700 patients, TREDAPTIVE reduced LDL-cholesterol (LDL-C, or "bad" cholesterol) levels, raised HDL-cholesterol (HDL-C, or "good" cholesterol) levels and decreased triglycerides (a type of fat in the blood). High LDL-C, low HDL-C and elevated triglycerides are risk factors associated with heart attacks and strokes.
TREDAPTIVE is approved for the treatment of dyslipidemia, particularly in patients with combined mixed dyslipidemia (characterized by elevated levels of LDL-C and triglycerides and low HDL-C) and in patients with primary hypercholesterolemia (heterozygous familial and non-familial).
TREDAPTIVE should be used in patients in combination with statins, when the cholesterol lowering effects of statin monotherapy is inadequate. TREDAPTIVE can be used as monotherapy only in patients in whom statins are considered inappropriate or not tolerated.
"The approval of TREDAPTIVE in the European Union further reinforces our long-standing commitment to the cardiovascular area by bringing novel and innovative therapies to patients. TREDAPTIVE provides comprehensive management of all three lipid parameters - LDL-C, HDL-C and triglycerides - for many patients," said Stefan Oschmann, president, MSD, Europe, Middle East, Africa and Canada.
The approval of TREDAPTIVE applies to the 27 countries of the EU, as well as Norway and Iceland.
TREDAPTIVE provided significant improvements in LDL-C, HDL-C and triglycerides
When added to ongoing statin therapy or alone, TREDAPTIVE 2 g/40 mg provided significant improvements in LDL-C, HDL-C and triglycerides when administered for a 24 week period. TREDAPTIVE 1 g (1 g/20 mg tablet) daily was initiated at the study start; at week 4 the daily dose of TREDAPTIVE was advanced to the maintenance dose of 2 g (2 x 1 g/20 mg tablets) through the remaining 20 weeks of the study. Across weeks 12 to 24 of the study, TREDAPTIVE 2 g significantly reduced LDL-C levels (-18 percent), increased HDL-C levels (20 percent) and reduced triglyceride levels (-26 percent) compared to placebo.
When TREDAPTIVE 2 g was coadministered with simvastatin (data pooled across 20 mg or 40 mg doses) LDL-C was reduced by 48 percent, HDL-C was increased by 28 percent and triglycerides were reduced by 33 percent following 12 weeks of treatment.
Flushing with TREDAPTIVE significantly less than modified-release nicotinic acid
In clinical studies, patients taking TREDAPTIVE experienced significantly less
moderate-to-extreme flushing than with modified-release nicotinic acid. Patients were initiated on either 1 g/20 mg of TREDAPTIVE, 1 g of modified-release nicotinic acid or placebo. After four weeks, patients were advanced to 2 g/40 mg of TREDAPTIVE or 2 g of modified-release nicotinic acid.
In patients who continued treatment with TREDAPTIVE after the dose advancement at week 5, the weekly frequency of moderate or greater flushing decreased and approached that of patients receiving placebo. In patients treated with modified-release nicotinic acid, the weekly flushing frequency remained constant after week six.
Fewer discontinuation rates due to flushing with TREDAPTIVE
In a pool of four active- or placebo-controlled clinical trials of more than 4,700 patients the percentage of patients taking TREDAPTIVE who discontinued therapy due to any flushing related symptom was 7.2 percent compared to 16.6 percent for the pooled modified release nicotinic acid groups.
Important information about TREDAPTIVE
TREDAPTIVE is generally well tolerated. Adverse reactions have usually been mild and transient. Flushing is the most common side effect of TREDAPTIVE and is most prominent in the head, neck and upper torso. Additional common clinical adverse reactions (≥ 1 percent to < 10 percent) reported by the investigators as possibly, probably, or definitely related to TREDAPTIVE in ≥1 percent of patients treated with TREDAPTIVE alone or co-administered with a statin for up to one year included elevations in ALT or AST (consecutive ≥ 3X ULN), fasting glucose, uric acid, dizziness, headache, paresthesia (a feeling of numbness, tingling, pricking, or burning of the skin), diarrhea, dyspepsia, nausea, vomiting, erythema (redness of the skin), pruritus (itching), rash, urticaria and feeling hot.
Impact of three major lipids on 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 but also high levels of triglycerides and low levels of HDL-C.
Cardiovascular disease is the main cause of death in Europe, accounting for over 4.9 million deaths (52 percent of all mortality) in 2002. Nearly half of all deaths from CVD are from CHD (48 percent) and nearly one-third are from stroke (29 percent). CHD by itself is the most common cause of death in Europe accounting for nearly 2.4 million deaths each year.1
About Nicotinic Acid (Niacin)
The mechanism of action of nicotinic acid (niacin) is not fully understood. Scientists do know that nicotinic acid inhibits the release of free fatty acids from connective tissue that stores fat in the body. This may contribute to reductions in LDL-C and triglycerides as well as elevations in HDL-C; all of which are associated with lower cardiovascular risk.
Specifically, nicotinic acid causes the distribution of LDL to shift from small, dense particles (most atherogenic) to larger particles. Nicotinic acid also elevates the HDL2 subfraction to a greater extent than the HDL3 subfraction, thereby increasing the HDL2:HDL3 ratio, which is associated with decreased cardiovascular disease risk. HDL is hypothesized to participate in the transport of cholesterol from the arteries back to the liver where it is eliminated from the body.
Treatment with nicotinic acid reduces the risk of death and cardiovascular events, and slows progression or promotes regression of atherosclerotic lesions. The Coronary Drug Project, a five year study completed in 1975, showed that nicotinic acid had statistically significant benefit in decreasing nonfatal, recurrent myocardial infarctions (MI) in men 30 to
64 years old with a history of MI. Though total mortality was similar in the two groups at five years, in a fifteen-year cumulative follow-up there were 11 percent fewer deaths in the nicotinic acid group compared to the placebo cohort.
Although nicotinic acid has been used for over 50 years for the treatment of cholesterol, its use has been limited by side-effects, including flushing. The improved flushing profile of TREDAPTIVE may allow more patients to reach and maintain a daily dose of 2 g of nicotinic acid through a simplified 1g to 2g dose advancement.
About Merck Sharp & Dohme
Merck & Co., Inc. (Whitehouse Station, N.J., U.S.A.), which operates in many countries as Merck Sharp & Dohme or MSD, is a global research-driven pharmaceutical company dedicated to putting patients first. Established in 1891, the Company currently 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 its medicines but help deliver them to the people who need them. Merck also publishes unbiased health information as a not-for-profit service.
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, 2007, and in any risk factors or cautionary statements contained in the Company´s periodic reports on Form 10-Q or current reports on Form 8-K, which the Company incorporates by reference.
1 The World Health Report 2004. Changing History. World Health Organization. 2004 Geneva, Switzerland.
TREDAPTIVETM is a trademark of Merck & Co., Inc., Whitehouse Station, NJ, USA
