Up and down with cholesterol management

The Business Intelligence firm La Merie S.L. reported today that the US$ 20.392 bln branded statin market in 2006 has reached a plateau before the imminent implosion in 2010 by patent expiry of atorvastatin which posted 2006 sales of US$ 12.9 bln. Combinations of a potent statin with a cholesterol absorption inhibitor such as ezetimibe may capture a significant portion of this market, but therapies targeting at LDL cholesterol reduction have matured. Future directions in cholesterol management aim at increasing HDL cholesterol due to its inverse relation with cardiovascular and stroke events. Approved drugs with a modest effect on HDL such as niacin are being improved while innovative HDL targeting therapies are in development. It has to be seen whether inhibitors of cholesterol ester transport protein recover from the fallout of torcetrapib, but alternatives such as apoA-I mimetics are available which induce cholesterol efflux by reverse transport to the liver. These results and more were found in a competitor analysis conducted by La Merie Business Intelligence. The competitor analysis of Cholesterol Management can be acquired at www.pipelinereview.com, La Merie’s News Center and Online Store.

Combining the most potent HMG-CoA reductase inhibitor rosuvastatin and cholesterol absorption inhibitor (CAI) ezetimibe leads to > 70 % reduction of LDL cholesterol. Both drugs showed a growth of 2006 sales of 59 % or 48 %, while the US$ 20.4 bln branded statin market in 2006 suffered from patent expiry of Zocor and of Pravachol with sales reductions of 64 % or 47 %, respectively. Ezetimbe products represent the second largest drug class for cholesterol management with 2006 sales of US$ 3.858 bln. Cholesterol absorption inhibition is an area of ongoing R&D activitities with special promise in combination with a potent statin. The classical PPAR alpha agonist fenofibrate from Abbott and Solvay (originating from Fournier Pharma) posted combined 2006 sales of US$ 1.612 bln and benefits from an additional modest increase of HDL cholesterol. The next generations of PPAR agonists represent the largest R&D field in cholesterol management. The most advanced are fixed dose combinations of fenofibrate or novel PPAR alpha activators with a statin in phase III trials followed by novel PPAR alpha activators as montherapy in early clinical trials. Innovative research is aimed at the ideal profile of PPAR alpha and gamma activation in one molecule or PPAR delta agonism. Stimulation of the thyroid hormone beta receptor is in its early clinical stage with preliminary proof of concept without affecting the cardiovascular system.

The inverse relation of HDL cholesterol to the incidence of coronary heart disease and stroke explains the increasing interest in high HDL cholesterol levels as a therapeutic target. Together with the industry’s interest in novel patent protected drugs it has spurred R&D regarding HLD targeting drugs. Available approved niacin based drugs lead to an increase of HDL of up to 26 (15 – 35 %) %, but suffer from flushing as side effect. Advanced developments are ongoing to abolish flushing by a flushing pathway inhibitor in a fixed dose combination and to offer single pill treatment of niacin plus a statin. Enthusiasm about cholesterol ester transfer protein (CETP) inhibitors has suffered from a drawback after Pfizer had to terminate its phase III drug torcetrapib due to significant cardiovascular side effects. It has to be seen whether the side effects are to be attributed to the chemical class or to the mechanism of action. A number of small molecule CETP inhibitors is in early clinical development. Variants or fragments of apolipoprotein A-I (apoA-I) and small molecules or lipids serve for reverse cholesterol transport to the liver. At least nine projects are in early clinical development and further are soon to enter.
Other new directions in R&D of modern cholesterol management include the reduction of apolipoprotein B100 and antagonizing the effect of oxidized LDL.

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SOURCE: La Merie Business Intelligence