In late December 2003, when Pfizer Inc. agreed to buy out Esperion Therapeutics Inc. for $1.3 billion - $35 per share, which amounted to a 54 percent premium to the average closing price during the previous 20 days - the pharmaceutical giant paid big for an opportunity that seemed even bigger.

Target: cholesterol.

Esperion's lead product is ETC-216 (ApoA-I Milano/phospholipid complex, also known as AIM), a variant of ApolipoproteinA-I (ApoA-I), the major protein component of high-density lipoprotein, or HDL, the "good" cholesterol. Because of its high density, the HDL form carries cholesterol away from the arteries and back to the liver, from which it's passed from the body. The process is called reverse lipid transport (RLT).

ApoA-I Milano is prevalent in a small population of northern Italians with paradoxically low levels of HDL cholesterol. Though that normally would correlate with high risk for cardiovascular disease, carriers of the ApoA-I Milano gene show a reduced risk - an effect believed to be due to enhanced RLT.

ETC-216 is the human recombinant version of ApoA-I Milano combined with a phospholipid to form a complex that mimics the structure and function of HDL. No wonder Pfizer wanted it. The Esperion buyout was completed in February of this year, and ETC-216 is in Phase III trials.

But what if a drug could do even better? Another pharmaceutical giant, AstraZeneca plc, believes it's found a candidate that might. Hence the potential $340 million deal last week with Avanir Pharmaceuticals Inc., which has a Reverse Cholesterol Transport program in the preclinical stage.

AstraZeneca is paying $10 million up front, with the rest due as milestones - described as "predictable" by Avanir - are met. Avanir, with an oral small molecule rather than a large molecule, calls its effort "the next step" beyond Esperion's bid, and claims that its compound can do more, although for competitive reasons the firm would not be more specific.

At the moment, the market is dominated by statins, among them AstraZeneca's Crestor, which works by inhibiting an enzyme known as 3-hydroxy-3-methylglutaryl coenzyme A reductase, responsible for making cholesterol in the body.

Crestor (rosuvastatin) has run into some trouble. Billed as a "super statin," Crestor seemed at first to be a sure winner, selling $908 million in 2004. Problems arose, and the activist group Public Citizen tried to get the drug removed from the market because of safety concerns, but the FDA called for a revised label instead, warning of potential muscle side effects and kidney problems in some patients.

Then, in May, the American Heart Association's journal Circulation published a rundown of side effect comparisons between the statins. Crestor's profile was worse than the others, though the class as a whole is low on adverse effects.

It's not the first time statins have hit bumps in the road. In 2001, Bayer AG withdrew Lipobay (cerivastatin) because of safety issues. The drug was linked to rhabdomyolysis, which leads to kidney failure, and caused 52 deaths, with 385 non-fatal cases among about 700,000 users in the U.S. Many of the worst instances involved Lipobay when taken with Lopid (gemfibrozil), Pfizer's lipid regulator.

Other statins are Lipitor (atorvastatin calcium) from Pfizer, Pravachol (pravastatin) from Bristol-Myers Squibb Co., Lescol (fluvastatin) from Novartis AG, and Zocor (simvastatin) and Mevacor (lovastatin), both from Merck & Co. Inc. There also is Zetia (ezetimibe), discovered by Schering-Plough Corp. and developed in a partnership with Merck, which also has Vytorin, a combination of simvastatin and ezetimibe.

Hyperlipidemia, long a focus of AstraZeneca, is a target of another deal recently disclosed between Merck and Metabasis Therapeutics Inc., which is taking aim at the liver enzyme AMP-activated protein kinase. The potential $74 million arrangement centers on a class of compounds believed to activate adenosine monophosphate, a protein kinase in the liver that regulates fat and cholesterol levels.

Reliant Pharmaceuticals Inc., which filed for a $300 million initial public offering in May, is another player in the blood-fats race. In February, the firm launched Antara for the management of cholesterol levels. Jointly developed with Ethypharm SA, Antara - a once-daily formulation of fenofibrate - was approved in November. Reliant's Omacor for high triglycerides also gained approval in November. The drug contains highly purified omega-3 acid ethyl esters, mainly eicosapentaenoic acid and docosahexaenoic acid, and is the first product in its class for the treatment of triglyceride concentrations in the blood 500 mg/dL and greater.

Reliant also has the statins Lescol and Lescol XL (an extended-release formulation), launched in November 2000, when the company signed a promotion agreement with Novartis that later was extended through 2007. The big push has been with the XL version, and Reliant earned promotion revenues of $105.1 million in 2004, down 13 percent from the previous year.

Days are numbered for statins' patent protection, particularly Pravachol and Zocor, whose patents expire next year. But the game, said Avanir - now with partner AstraZeneca - should be less about lowering cholesterol anyway, and more about strengthening the blood vessel walls.

That's what their program is focusing on. They hope to start clinical trials this year or early next, with AstraZeneca responsible for costs and both parties contributing scientific expertise.

Jagadish Sircar, vice president of drug discovery for Avanir, said its therapy could be used in conjunction with statins or as a monotherapy.

"People will try that first," he told BioWorld Financial Watch. "Our partner would like to do that, because they have Crestor." Sircar brushed aside the side effect drawbacks, saying "all statins" have such problems. "It's just a matter of how much."

It's too early to tell whether the Avanir compound will have any adverse interactions with statins, he added. "But I don't expect it, because we are acting on two different targets."

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