Merck readies cholesterol drug Tredaptive for launch by 3rd quarter of 2009

Once-daily combination pill Tredaptive for cholesterol contains ER niacin and laropiprant.

Tredaptive, a high profile cholesterol buster combination pill from Merck is slated to be launched later this year.

Tredaptive contains extended release niacin and laropiprant (1000 mg nicotinic acid/20 mg laropiprant). Tredaptive is a lipid-modifying therapy for patients with mixed dyslipidemia and primary hypercholesterolemia.

Though Tredaptive is still an investigational drug in US, the cholesterol drug has already been approved in 39 countries outside the U.S.

Tredaptive is also known by the trade name Cordaptive in some places.

Merck & Co. Inc will begin launching Tredaptive in international markets including Mexico, the UK and Germany by the third quarter this year.

“Merck is pleased that we are now able to supply Tredaptive in approved markets and continue our long-standing commitment to help address unmet medical needs in cardiovascular care,” said Luciano Rossetti, MD, senior vice president and franchise head, Atherosclerosis and Cardiovascular, Merck Research Laboratories.

Niacin/Laropirant combination

Nicotinic acid is a lipid-modifying agent, and laropiprant, a potent, selective antagonist of the prostaglandin D2 (PGD2) receptor subtype 1 (DP1). Nicotinic acid lowers the levels of low-density lipoprotein cholesterol (LDL-C), total cholesterol (TC), very low density lipoprotein cholesterol (VLDL-C), apolipoprotein B (apo B, the major LDL protein), triglycerides (TG), and lipoprotein(a) (Lp(a), a modified LDL particle) and elevates the levels of high-density lipoprotein cholesterol (HDL-C) and apolipoprotein A-I (apo A-I, the major protein component of HDL).

Laropiprant suppresses PGD2 mediated flushing associated with administration of nicotinic acid. Laropiprant has no effect on lipid levels nor does it interfere with the effects of nicotinic acid on lipids.

The mechanisms by which nicotinic acid modifies the plasma lipid profile are not fully understood. Nicotinic acid inhibits release of free fatty acids (FFA) from adipose tissue, which may contribute to the reduced plasma LDL-C, TC, VLDL-C, apo B, TG, and Lp(a), as well as elevated HDL-C, and apo A-I, all of which are associated with lower cardiovascular risk.

Nicotinic acid causes a relative shift in the distribution of LDL subclasses from small, dense LDL particles to larger LDL 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 hypothesised to participate in the transport of cholesterol from tissues back to the liver, to suppress vascular inflammation associated with atherosclerosis, and to have anti-oxidative and anti-thrombotic effects.

Like LDL, cholesterol-enriched triglyceride-rich lipoproteins, including VLDL, intermediate-density lipoproteins (IDL), and remnants, can also promote atherosclerosis.

Elevated plasma TG levels are frequently found in a triad with low HDL-C levels and small LDL particles, as well as in association with non-lipid metabolic risk factors for coronary heart disease (CHD).

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 a 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 % fewer deaths in the nicotinic acid group compared to the placebo cohort.

Laropiprant has been shown to be effective in reducing flushing symptoms induced by nicotinic acid. The reduction in flushing symptoms (assessed by patient questionnaires) was correlated with a reduction in nicotinic acid-induced vasodilatation (assessed by measurements of skin blood flow).

In healthy subjects receiving Tredaptive, pretreatment with acetylsalicylic acid 325 mg had no additional beneficial effects in reducing nicotinic acid-induced flushing symptoms compared to Tredaptive alone.

Tredaptive was consistently efficacious across all prespecified patient subpopulations defined by race, gender, baseline LDL-C, HDL-C and TG levels, age and diabetes status.

Patients taking Tredaptive (2000 mg/40 mg) with or without a statin had significantly decreased all major “bad cholesterols” and also had significantly increased good cholesterols.

The effect on lipids was similar whether Tredaptive was given as monotherapy or was added to ongoing statin therapy with or without ezetimibe.

The anti-cholesterol responses appeared greater among women compared to men and appeared greater among elderly patients compared to younger patients .

Merck & Co., Inc, which operates in many countries including India as Merck Sharp & Dohme or MSD, is a  global research-driven pharmaceutical company. Established in 1891, Merck currently discovers, develops, manufactures and markets vaccines.