Dyslipidemia refers to an abnormal concentration of lipids or lipoproteins (special lipid-protein particles that transport lipids) in the blood. Cholesterol is a lipid that has been a major health concern because of its link to atherosclerosis, the fat containing plaques that can narrow arteries and rupture, leading to heart attack, stroke, and other conditions. Cholesterol found in low-density lipoproteins (LDL), the predominant carrier of cholesterol in the blood, has been the major target identified by treatment guidelines.

Triglycerides are another type of lipid associated with atherosclerotic diseases. Much of their risk is thought to come from their influence on other factors, though it is possible they have a direct effect as well. Elevated triglyceride production by the liver is coupled with increased secretion of very-low-density lipoproteins (VLDL), which after delivering their triglycerides to peripheral tissues, are metabolized to smaller particles that are richer in cholesterol and atherogenic. High triglycerides are also often associated with more atherogenic, smaller LDL particles and low levels of high-density lipoproteins (or HDL, particles that carry cholesterol from peripheral tissue back to the liver), in a syndrome called the atherogenic dyslipidemia. HDL found in isolation is a risk factor as well.

Dyslipidemia is a common problem in developed countries. Based on recently updated recommendations, we estimate the number of patients in the US eligible for treatment is 42 million, with an additional 19 million for whom treatment is optional.

The dominant drugs in the dyslipidemia market are the statins, which block the synthesis of cholesterol by the liver and are the most effective for lowering LDL-C. They have demonstrated a strong clinical track record for lowering the risk of CHD events in patients with and without prior heart disease. Lipitor (Pfizer – PFE) is the market leader, due to higher potency and efficacy at the time it was introduced, as well as other marketing factors. However, over the next several years until it loses patent protection in 2010, its lower doses are likely to lose significant market share to recently introduced generic Zocor (simvastatin). At the same time, more potent drugs, Crestor (AstraZeneca – AZN) (a statin, which had had negative safety publicity) and Vytorin (Merck – MRK and Schering-Plough – SGP) (a combination of Zocor and the cholesterol absorption inhibitor Zetia), have been gaining share, a trend that is likely to continue, with Vytorin remaining ahead. An outcomes study for Crestor may expand treatment to a new group of patients, though results may not be considered unique to Crestor.

A novel Phase III drug, TAK-475 (Takeda), blocks the same pathway as the statins, but may avoid their side effect of muscle aches and weakness, that can lead to a more serious condition. However, it has potential safety issues of its own, and unless it can demonstrate superior clinical outcomes, it will likely be used in conjunction with the statins. ISIS 301012 (Isis - ISIS), in Phase II, blocks production of the protein in LDL. Though it has not shown as striking a reduction in LDL-C as high dose statins, higher doses are being tested. While it is encouraging that this antisense drug does appear to have an effect on lipid levels, we do have some concerns regarding the potential risk-benefit profile of this drug. Since it is an injectable agent, ISIS 301012 is planned to target patients who cannot reach LDL-C goals with statins alone, including those with a genetic disorder.

The fibrates and the niacins are groups of drugs that are most effective at raising HDL-C and lowering triglycerides. While the fibrates have some supporting clinical outcomes studies, the evidence is not as robust as for the statins, and there have been some safety concerns. They also have a variable effect on LDL-C. Tricor (Abbott – ABT, Solvay – SVYSY and Elan - ELN) has been the more popular branded fibrate, and while it has had mixed results in an outcomes study in diabetics (FIELD), which also raised possible safety concerns, we do not see it losing significant share until new competitors enter. Abbott and Solvay are also developing a next-generation fibrate, ABT-335 (Phase III), and with AstraZeneca, a combination drug of either Tricor or ABT-335 with Crestor (Phase I). Given Crestor’s potency, the combination drug is likely to be quite appealing.

There have been fewer outcomes studies for the niacins, and while they offer an attractive combination of effects on various lipids, they suffer from an annoying side effect of flushing (warmth and itching, along with some more serious effects), and are used less frequently in diabetics because they can modestly raise blood sugar. Niaspan (KOS Pharmaceuticals– KOSP, Merck KGaA, and Barr - BRL) is the dominant branded drug, but over-the-counter preparations are also used. A lower flush formulation of Niaspan has an NDA submitted, but we do not see it growing Niaspan’s share substantially. Simcor (KOS Pharmaceuticals – KOSP), in Phase III, combines Niaspan with simvastatin, but is likely to be strongly challenged by MK-0524B (Merck – MRK), a combination of an extended release niacin, a flushing inhibitor, and simvastatin. The latter, however, still needs to overcome formulation issues. Similarly, we think MK-0524A, the drug without the simvastatin and also in Phase III, will take a majority of new patients away from Niaspan (if it is indeed effective – there has been little data available), though we do not think most existing Niaspan users will switch, due to their tolerance for flushing.

The CETP inhibitors, Torcetrapib (Pfizer – PFE) in Phase III, and R1658 (Roche - RHHBY and Japan Tobacco) in Phase II, have a novel mechanism of action that raises HDL-C, but only has modest effects on LDL-C and little if any on triglyceride levels. Nevertheless, there is evidence that CETP is involved the process whereby elevated triglycerides leads to smaller LDL particles and lower HDL-C in the atherogenic dyslipidemia. Though we think the weight of preclinical evidence supports the efficacy of this mechanism, there has been mixed epidemiologic evidence, with some studies finding increased CHD in CETP deficient patients. Pfizer plans to submit the NDA for Torcetrapib next year after results from atherosclerosis progression studies are available, but we think it is more likely approval will be delayed pending results from a large clinical outcomes study. Additional outcomes trials for the fibrates and niacins, focusing on their potential benefit when added to statins, will have data around the same time as Torcetrapib, or soon thereafter. We believe that Torcetrapib will be ultimately successful, and take a large share from the niacins and fibrates, in addition to expanding treatment in this segment. R1658 is later in development, and while it may avoid the side effect of mild blood pressure elevation seen with Torcetrapib, preliminary data has not demonstrated as strong HDL-C raising effects. Pending more data, we are projecting it to take a lower share of the two.

Finally, there are several drugs in early-stage development that act as mimics of the HDL lipoprotein. Hence their purpose is not to alter the body’s usual lipid levels, but rather to treat atherosclerotic plaques. Examples include intravenous drugs in development by Pfizer (ETC-216, ETC-642) and an oral drug under development by Novartis (D-4F). If such drugs could be developed as subcutaneous formulations that are more convenient for regular use, or if the oral drug is successful, these could be potential competitors for the CETP inhibitors. These HDL mimics will be evaluated in a separate indication report.

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