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February 01, 2011 (Vol. 31, No. 3)

Finding a Blockbuster Successor to Lipitor

As Patent-Protected Statins Fade Into Sunset, One Major Failure Hovers Ominously Over Contenders

  • Back in 2008, Pfizer strategically delayed generic competition for its blockbuster statin product Lipitor (atorvastatin) by some 20 months until November 2011. By settling global patent disputes with Ranbaxy Laboratories, a generic drug maker in India that had threatened to market its own version of Lipitor, Pfizer hung on to the majority of the cholesterol-lowering market.

    Although most statin drugs already have generic versions, Lipitor remains widely used, especially among patients who don’t respond to the generic formulations or require a higher dose than Lipitor’s competitors offer. Lipitor became the best-selling pharmaceutical in history with 2009 sales of $11.4 billion and retained this status in 2010. The drug thus dominates the $20 billion statin market.

    Statins comprise a class of drugs that lower cholesterol by inhibiting HMG-COA reductase, an enzyme that synthesizes cholesterol in the liver. By the end of 2010, branded statins remaining on the market included: Lipitor; fluvastatin (Novartis’ Lescol); lovastatin (Merck & Co.’s Mevacor and Watson Pharmaceuticals’ Altocor and Altoprev); pitavastatin (Kowa Company’s Livalo); pravastatin (Bristol-Myers Squibb’s Pravachol); rosuvastatin (AstraZeneca’s Crestor); and simvastatin (Merck’s Zocor).

    Several combination preparations of a statin and another agent, such as Merck’s Vyotrin, which couples ezetimibe and simvastatin, are also available.

  • CETP Inhibition

    So what might the next wave of successful anticholesterol agents look like? Will any achieve the therapeutic success of statins? One new class of drug candidates is cholesterol ester transfer protein (CETP) inhibitors, but there has already been one major clinical failure, with Pfizer’s torcetrapib failing in Phase III. The firm spent $800 million developing the drug, which was dubbed one of pharma’s biggest flops.

    CETP normally moves cholesterol from high-density lipoproteins (HDL) to very low density or low density lipoproteins (VLDL or LDL). Inhibition of this transfer process is expected to increase HDL levels, the good cholesterol, and reduce the bad cholesterol, or LDL levels.

    While Pfizer was expected to win approval for torcetrapib in 2008 and assuage declining Lipitor sales, it was forced to stop development in 2006 after the occurrence of major cardiovascular events among trial participants. The study called Illuminate involved 15,067 patients with coronary heart disease (CHD) or CHD risk equivalent (type 2 diabetes) given torcetrapib and atorvastatin or only atorvastatin.

    The primary endpoint of the trial, a composite of first major cardiovascular event defined as CHD death, nonfatal myocardial infarction, stroke, or hospitalization for unstable angina, diverged between the treatment groups early in the trial. At termination, the torcetrapib group showed a 25% increased risk over the groups that received atorvastatin alone. Overall, 82 patients taking the combination of torcetrapib and atorvastatin died compared with 51 deaths among those taking only atorvastatin.

    In a post-hoc analysis of the halted trial, investigators concluded that the reasons for the adverse outcome were uncertain. They said that torcetrapib administration was associated with undesirable off-target effects that could have contributed to and increased mortality/morbidity. These included heightened blood pressure, increased sodium bicarbonate and aldosterone levels, and decreased potassium levels.

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