• Diabetes (Issue 1) HTML | PDF
• Biogenerics (Issue 2) HTML | PDF
• Obesity (Issue 3) HTML | PDF

Cholesterol Management

Competitor Analysis: Cholesterol Management

Index

Hypercholesterolemia:

1- Who is at risk?

2- Why should I care?

3- Today’s therapeutic options

4- The Cholesterol Management Market

5- New drugs in development

Download a PDF version of Biotech Features: Cholesterol Management

---

Hypercholesterolemia: Who is at risk?

Cholesterol is a soft, fat-like, waxy substance found in the bloodstream and in all the body's cells. It is used by the body for making the cells membranes, for protecting nerves, for digesting dietary fats and for producing certain hormones, such as the sexual hormones of men and women. Around 75% of the cholesterol the body needs is made naturally by the liver and other cells of the body and can be affected by heredity, while the other 25% comes from foods such as eggs, meats, butter, and dairy products.

Would you like to learn more about the Cholesterol Management field?

People are used to say that there exist two different types of cholesterol commonly named “good” and “bad”, thus, making it important to understand the difference between them and the normal levels of each one in the blood. Despite cholesterol itself is not bad for the human body, too much cholesterol in the blood of one type (bad), or not enough of the other one (good), represents a major risk of suffering from coronary heart disease, heart attack or stroke.

Cholesterol can't be dissolved in the blood and it has to be transported to and from the cells by carrier particles called lipoproteins which deliver cholesterol to different body tissues to be used, stored or excreted.

The lipoprotein known as “bad” cholesterol is a low-density lipoprotein named LDL; and the lipoprotein known as “good” cholesterol is a high-density lipoprotein called HDL. These two lipids, along with triglycerides and Lp(a) cholesterol, make up the total cholesterol count, which can be determined through blood test . The most complete laboratory blood test to determine cholesterol levels is the “lipoprotein profile” which is conducted after a 9 to 12 hour fast and gives information about the:

• Total cholesterol
• LDL (bad) cholesterol
• HDL (good) cholesterol
• Triglycerides--another form of fat in the blood

Normal cholesterol blood levels are different according to family history (heredity), gender, age, dietary habits and exercise and lifestyle habits of the patient.

Normal levels for the different “lipoprotein profile” parameters are listed below and are expressed in milligrams per deciliter of blood (mg/dL).

Total Cholesterol Level	Category
Less than 200 mg/dL	Desirable
200-239 mg/dL	Borderline High
240 mg/dL and above	High

LDL Cholesterol Level	Category
Less than 100 mg/dL	Optimal
100-129 mg/dL	Near optimal/above optimal
130-159 mg/dL	Borderline high
160-189 mg/dL	High
190 mg/dL and above	Very high

HDL Cholesterol Level	Category
Less than 40 mg/dL	Low
40-59 mg/dL	Normal
60 mg/dL and above	Optimal

Triglycerides Level	Category
Less than 150 mg/dL	Normal
150-199 mg/dL	Borderline high
200 mg/dL and above	High
500 mg/dL	Very High

---

Hypercholesterolemia: Why should I care?

High circulating cholesterol levels are not good for health. Cholesterol and particularly LDL (bad) cholesterol can be accumulated as cholesterol-laden "plaque” into inner blood vessel’s wall Biologics under development for Cholesterol Management.clogging the arteries. The plaque is a thick, hard deposit that can narrow the arteries and make them less flexible. This condition is known as atherosclerosis (from the Greek words athero: gruel or paste, and sclerosis: hardness). If a clot forms and blocks a narrowed artery, heart attack or stroke can result. This injury occurs especially in coronary and brain arteries causing a decrease of the blood supply, increasing the risk of heart attack and stroke. When blood flow to the heart is impeded, the heart muscle becomes starved for oxygen, causing chest pain (angina). If a blood clot completely obstructs a coronary artery affected by atherosclerosis, a heart attack (myocardial infarction) or death can occur.

Considering the different types of lipoproteins, LDL and HLD are directly involved and they are main factors in heart disease risk:

• Low-density lipoprotein (LDL): Is the form in which cholesterol is carried into the blood and is the main cause of harmful fatty buildup in arteries. The higher the LDL cholesterol levels in the blood, the greater the heart disease risk.
• High-density lipoprotein (HDL): Carries blood cholesterol back to the liver, for its elimination. HDL helps prevent a cholesterol buildup in blood vessels. Low HDL levels increase heart disease risk.

Different factors can affect cholesterol levels:

• Diet. Saturated fat raises LDL levels more than anything else in the diet. This kind of fat is present mostly in animal products. Another fat intake with diet is cholesterol, found only in animal products. Reducing the amount of saturated fat and cholesterol in the diet helps lower the blood cholesterol level.
• Weight. Overweight is a risk factor for heart disease and it also tends to increase cholesterol. Losing weight can help lower LDL and total cholesterol levels, as well as raise HDL and lower triglyceride levels.
• Physical Activity. Not to do exercise is a risk factor for heart disease. Regular physical activity may not only lower LDL cholesterol, but it may increase levels of desirable HDL. It’s recommended to exercise at least 30 minutes a day. If this is not possible it would be appropriate try to do some physical activity several times a week.
• Age and gender: Before menopause, women tend to have total cholesterol levels lower than men at the same age. Cholesterol levels naturally rise as men and women age. Menopause is often associated with increases in LDL cholesterol in women.
• Heredity: High cholesterol often runs in families. Even though specific genetic causes have been identified in only a minority of cases, genes still play a role in influencing blood cholesterol levels.

Other risk factors that increase the risk of heart disease include cigarette smoking, high blood pressure, diabetes and obesity. If any of these is present in addition to high blood cholesterol, the risk of heart disease is even greater. Controlling those risk factors it is possible to decrease risk of suffering heart disease.

---

Today’s therapeutic options

Risk factors can be brought under control either by changes in lifestyle, such as diet, losing weight, or an exercise program, or quitting a tobacco habit. Drugs also may be necessary in More than 16 clinical stage CETP Inhibitors and RCT Activators to raise HDL some people. There are non-pharmacology measures which can help to bring several risk factors under control. For example, weight loss can reduce blood cholesterol levels, help control blood glucose, and lower high blood pressure. But there are situations which require a pharmacological treatment to reduce cholesterol to normal levels and lower risk of heart failure without giving up the lifestyle changes.

The main goal of cholesterol-lowering treatment is to lower LDL level enough to reduce risk of developing heart disease or having a heart attack. Thjere exist several kinds of drugs designed for different targets that are available and currently in use for cholesterol lowering. These drugs are statins, resins, nicotinic acid, fibrates, and cholesterol absorption inhibitors, and they are shortly described in the following table:

Drug Type	General characteristics	Drug Name ( Commercial name)	Commentaries
Statins . Also called HMG-CoA reductase inhibitors	Slow down body's production of cholesterol. These drugs also remove cholesterol buildup from your arteries (blood vessels).	Atorvastatin (Lipitor) Fluvastatin (Lescol) Lovastatin (Altocor, Mevacor) Pravastatin (Pravachol) Rosuvastatin (Crestor) Simvastatin (Zocor)	Are very effective in lowering LDL levels and are safe for most people
Resins. A lso called bile acid sequestrants	Help to lower LDL cholesterol level.	Cholestyramine (Prevalite, Questran) Colesevelam (Welchol) Colestipol (Colestid)	It can be used alone or in combination with statin drugs
Nicotinic acid. Also called Niacin	When given in large doses, it can lower your levels of triglycerides and LDL cholesterol, and increase your HDL cholesterol level	Is a B vitamin (Advicor, Niaspan, Niacor)	Lowers LDL and triglycerides and raises HDL
Fibrates . Also called fibric acid derivatives	Help to lower cholesterol by reducing the amount of triglycerides (fats) in the body and by increasing the level of HDL	Fenofibrate (Antara, Lofibra, Tricor) Gemfibrozil (Lopid)	Although fibrates lower LDL they are used mainly to treat high triglyceride and low HDL levels
Cholesterol absorption inhibitors	Help to lower cholesterol by reducing the amount that is absorbed by intestines	Ezetimibe (Zetia)	Reduces total cholesterol level by 15%-20%. combination of ezetimibe and simvastatin is commercialized under Vytorin

There is a chance to improve out­ come beyond statins monotherapy by trying to increase HDL-C levels . Fibrates and niacin are primarily used as single agents but their use in combination with statins is in­ creasing in an attempt to lower triglycerides and raise HDL-­ C levels. L ike all medicines, these drugs can cause side effects. However, the side effects usually are not severe and are not experienced very often. Common side effects of cholesterol-lowering drugs include the following:

• Diarrhea or constipation
• Abdominal pain, cramps, bloating or gas
• Nausea and/or vomiting
• Headache
• Drowsiness or dizziness
• Muscle aches or weakness Flushing (skin turning red and warm)
• Sleep problems

Almost half of the patients given statins discontinue treatment before the end of the first year of therapy, and 5%-30% of patients suf­ fer intolerable side effects from statins and fibrates.

---

The Cholesterol Management Market

Drug Class	Branded Product	Company	Sales 2006
Statins	Lipitor; atorvastatin	Pfizer	12,866 (+ 6 %)
	Zocor; simvastatin	Merck & Co.	2,802 (- 64 %)
	Crestor; rosuvastatin	AstraZeneca	2,028 (+ 59 %)
	Pravachol; pravastatin	Bristol-Myers Squibb	1,197 (- 47 %)
	Mevalotin; pravastatin	Daiichi-Sankyo	774
	Lescol; fluvastatin	Novartis	725 (- 5 )
			Total: 20,394
Cholesterol Absorption Inhibitors	Zetia; ezetimibe	Schering-Plough & Merck & Co (JV)	1,925
	Vytorin; ezetimibe + simvastatin	Schering-Plough & Merck & Co (JV)	1,933
			Total: 3,858 (+ 48 %)
Fibrates (fenofibrate)	Tricor; fenofibrate	Abbott (from Solvay)	1,048 (+ 13.1 %)
	Lipanthyl; fenofibrate	Solvay Pharmaceuticals (via Fournier Pharma acquisition)	564 (+ 123 %)
	Antara; fenofibrate	Oscient Pharma-ceuticals	35
	Lipidil; fenofibrate	Kaken	29.3
			Total: 1,676.3
Niacin	Niaspan; Nicotinic acid ER	Abbott (from Kos Pharmaceuticals acquisition)	473.8
	Niaspan; Nicotinic acid ER	Merck Serono	9.6
	Advicor; niacin + lovastatin	Abbott (from Kos Pharmaceuticals acquisition)	121.5
			Total: 604.9
Bile Acid Sequestrants	WelChol; colesevelam	Daiichi-Sankyo	198 (+ 48 %)
	Colestid; coelstipol	Pfizer	20
			Total: 218

---

New drugs in development

It is interesting to note that statins reduce cardiovascular events by only 30-40%. Epidemiological New targets for Cholesterol Management. analyses clearly indicate that a significant portion of risk is linked to other particles such as low high-density lipoprotein cholesterol (HDL-C), high triglycerides and others. Several new drugs are be­ ing investigated which affectmore than the traditional LDL-C pathways. They include:

Agents that re­ duce LDL-C levels by mechanisms other than HMG-CoA inhibition such as:

• Intestinal cholesterol absorption inhibitors
• Acyl-CoA cholesterol acyl transferase inhibitors
• Squalene Synthase Inhibitors
• Sterol-regulating binding protein cleavage activating protein ligands
• Microsomal triglyceride transfer protein inhibitors
• Synthetic Apolipoprotein E Peptides
• Famesoid X receptor antagonists
• LDL-C receptor activators

And agents that raise HDL-C cholesterol or improve cholesterol efflux such as:

• Cholesterol ester transfer protein inhibitors
• Reverse cholesterol transport activators
• Retinoid X re¬ceptor selective agonists
• Secific peroxisome proliferator-activated receptor (PPAR) agonists
• Estrogen like com¬pounds

AGENTS TO REDUCE LDL-C CHOLESTEROL

Intestinal Cholesterol Absorption Inhibitors: A promising target for LDL-C reduction is the Learn more about innovative fibrates and PPAR agonists in Cholesterol Management. prevention of intestinal cholesterol absorption. About 25% of the circu­ lating cholesterol is derived through intestinal uptake. Plant stanol esters provide a novel approach to lowering plasma low-density lipoprotein (LDL-C) cholesterol by die­ tary means. They competitively inhibit the absorption of cholesterol thus lowering its level in plasma.

Acyl-CoA cholesterol acyl transferase inhibitors: Another potential target for LDL-C reduction is the acyl­ coenzyme A cholesterol acyltransffrase (ACAT) enzyme. The ACAT enzyme is responsible for a critical step in atherosclerosis development, since it catalyzes the conversion of free cholesterol into cholesterol esters readily up-taken by macrophages. Indeed, inhibition of the ACAT enzyme reduces foam cell formation and leads to atherosclerosis regression in animals models . Although partial inhibition of the ACAT enzyme results in anti­ atherogenic effects, complete inhibition of the enzyme exac­ erbates atherogenesis in animal experiments.

Squalene Synthase Inhibitors: These agents inhibit the enzyme squalene synthase that catalyzes which participate in an important step of cholesterol biosynthetic pathway . One agent, zaragozic acid, induced a reduction in LDL-C level as high as 70-80% in animal models but was associated with hepatotox­ icity and myopathy.

Sterol-regulating binding protein cleavage activating protein ligands. Increased Expression of LDL-C Receptors: The proteins are responsible for the upregulation of LDL-C receptors in the liver's cells known as hepatocyte, which results in an increased expression of LDL-C receptors with an increase in the ab­ sorption of circulating LDL-C cholesterol particles and re­ duction in serum LDL-C level.

Inhibitors of Microsomal Triglyceride Transfer Protein: The Microsomal Triglyceride Transfer Protein (MTP) is a protein that contributes to formation of LDL-C in liver cells. A number of small molecules that are capable of inhibiting MTP have been studied in animal models with varied success. One such agent, implitapide suppressed the extent of atherosclerosis by 83% in a particular animal model.

Synthetic Apolipoprotein E Peptides: When these agents were administrated to a special animal model ( ApoE knock-out mice) , results shown a large reduction in cholesterol levels within hours.

Farnesoid X Receptor Activators: The Farnesoid X receptor/bile acid receptor (FXR) is a recently discovered member of the nuclear hormone super­ family. It is highly expressed in various tissues. For more than a decade, the resin extract of the Indian Guggul tree has been in use as a cholesterol-lowering agent. Its active ingredient, guggul­sterone, inhibits hepatic cholesterol synthesis by selectively modulating the Farnesoid X receptor . In addition, gug­gulsterone lowers lipids through its thyroid stimulating activ­ ity . It is available in the United States as a dietary sup­ plement called Guggulipid, although at least one study chal­ lenged its cholesterol lowering effect.

LDL-C Receptor Stimulants: Agents such as Lifibriol are under study for their ability to activate the LDL-C receptor. The exact mechanism of action of lifibriol is not known.

AGENTS TO INCREASE HDL-C CHOLESTEROL

Direction of new re­ search has switched to increasing the levels of HDL-C. The HDL-C metabolic pathway provides an excellent example of multiple targets that can be potentially aimed at to induce atherosclerosis regression. HDL-C metabolism is very complex, but the main mechanisms by which HDL-C impacts atherosclerosis are; reverse cholesterol transport, protection of LDL-C from oxidation and reduction of expression of endothelial adhesion molecules.

Reverse Cholesterol Transport Targets: In this hypothesis, HDL-C interacts with cells within the vessel wall. It pro­ motes the efflux of cholesterol that is therefore transferred to the liver for excretion in the bile . In theory, the accelera­ tion or facilitation of this process promotes atherosclerosis regression, and this could be obtained even in the absence of an increase in blood levels of HDL-C or ApoAl.

Cholesterol Ester Transfer Protein Inhibitors (CETP): The most recent approach to increasing HDL-C level is the alteration of HDL-C metabolism. Ongoing research is investigating the HDL-C raising effect of CETP inhibition and its anti-atherogenic effects. Of interest, moderate alcohol intake increases HDL-C levels and reduces atherosclerosis related events likely through the inhibition of CETP . In addition, patients lacking CETP due to genetic defects have very high levels of HDL-C and low levels of LDL-C choles­ terol , although some concerns remains that complete absence of CETP may induce rather than inhibit develop­ ment of atherosclerosis. In a rabbit atherosclerosis model, however, CETP inhibition resulted in atherosclerosis regres­ sion .

HDL-C Related Proteins and Peptides: An additional focus of research relating to reverse cho­ lesterol transport involves Apolipoprotein-Al (ApoAl), the principal protein component of HDL-C. Infusion of purified ApoA-1 shows no benefit, as it is degraded in the kidneys. Several investiga­ tors have engaged in developing peptides modeled on the amphipathic helix of ApoA-1 that are functional and not cleared by the kidneys.

Additional agents in development include nonfibrate peroxisome proliferative activated receptor a agonists, and rimonabant.