From a Blockbuster to a Generic: Lipitor

York College
Abstract
Once a new chemical entity is licensed as a drug, it is usually protected by patent rights for a period of up to twenty years. Patent protection gives the developing pharmaceutical company exclusive rights to manufacture and market the product. This is how companies in the pharmaceutical industry recoup the costs of researching and developing a new drug; such costs may reach more than one billion US dollars. However, once the patent expires, any competitor can manufacture and market the drug as a generic product, which is subject to a much shorter and less costly approval process for licensing. Thus, the generic drugs are much cheaper than the corresponding brand name drugs. Twenty drugs are scheduled to come off patent between 2011 and 2016. One of the major drugs in this category is Lipitor, Atorvastatin calcium, a statin class of lipid-lowering agents. It has been a blockbuster drug, i.e. its sales have generated more than one billion US dollars per year. This life-saving drug was developed in 1997 by Parke-Davis Research, a division of Warner-Lambert (now known as Pfizer). The sales of Lipitor have exceeded US $10 billion per annum and accounted for approximately 25% of Pfizers revenue for the past decade; in fact it is the most profitable drug ever developed. With the expiration of Lipitors patent in November 2011, the U.S. Food and Drug Administration (FDA) approved the first generic version of Lipitor in December of 2011. The generic Lipitor is currently being produced and distributed in the U.S. This drug works by decreasing the amount of unhealthy cholesterol, i.e. the Low-Density Lipoprotein (LDL) or triglycerides that are produced by the liver, and increasing the healthy cholesterol High-Density Lipoprotein (HDL) in the blood. In effect, Lipitor reduces the risk of heart attack and stroke. Although Lipitor can decrease the unhealthy cholesterol, patients still need to maintain a healthy diet.

Lipitor (Atorvastatin Calcium)

Atorvastatin calcium is chemically described as [R-(R*, R*)]-2-(4-fluorophenyl)-, -dihydroxy-5-(1methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoic acid, calcium salt (2:1) trihydrate. Its empirical formula is (C33H34FN2O5)2Ca3H2O and its molecular weight is 1209.42 g/mol. Its structural formula is:

Generic Lipitor
Atorvastatin Calcium is the generic equivalent of Pfizer's Lipitor drug. Two companies were entitled to sell generic Lipitor for six months after the U.S. patents for the drug expired. U.S.-based Watson Pharmaceuticals Inc. was authorized by Pfizer to sell a generic version of Lipitor; it did not need regulatory approval and started selling the drug as of November 30, 2011. Ranbaxy Pharmaceuticals Inc. had also gained approval to make generic Atorvastatin calcium tablets and six months exclusivity to Lipitor; however,a final clearance from the FDA is still needed, so that the generic version could be launched in the U.S. For the first six months after 11/30/11, Ranbaxy shared part of the profit with Teva Pharmaceuticals, USA.

How much does it cost to produce a new drug?

Atorvastatin calcium is a white to off-white crystalline powder. It is insoluble in aqueous solutions of pH=4 and below. But it is soluble in distilled water, pH=7.4. A new drug undergoes an extensive research and development (R&D) process and is initially protected by patents. An estimated of 1.2 billion dollars over a period of ten to fifteen years are needed for a pharmaceutical company to develop and gain approval for a single new drug. The pharmaceutical industry spent 67.4 billion dollars in R&D (Research and Development) during 2011, including phase IV clinical trials, which are conducted after a drug is approved for market distribution. A generic drug is chemically equivalent to a brand name drug, which has lost its patent protection; it is sold at significantly lower prices. A generic drug can cost 20% to 80% less than a brand name one.

Mechanism of Lipitor (Atorvastatin Calcium)

The first statin to be approved in the 1970s was Lovastatin. The generic Atorvastatin was the 5th statin approved by the FDA. Lovastatin is a fungal metabolite with a complex molecular structure. Whereas atorvastatin is a synthetic compound similar to the fungal one. Atorvastatin can inhibit 3-hydroxy-3-methyl-glutaryl-CoA reductase (HMGCoA) that plays an essential role in the production of cholesterol in the liver.
Figure A: A normal artery with normal blood flow with a crosssection of a normal artery. Figure B: An artery with plaque with a cross-section of an artery with plaque buildup.

Introduction
What is cholesterol? Cholesterol and triglycerides are lipids that are produced in your body and can also be found in some foods. We need some cholesterol to be healthy, however, the problem comes when we have too much of it. The cholesterol and triglycerides can block up the blood vessels, which increase the chance of getting coronary heart disease. Coronary heart disease is formed when plaque (compose of calcium, cholesterol, fat) clog up in the coronary arteries. There is no symptom for people with high blood cholesterol. Consequently, many people are unaware that their cholesterol levels are high. What causes high levels of cholesterol? There are many causes that can affect the cholesterol levels in your blood. We can control some causes but not all of them. o People can manage their food intake as well as the physical activities and weight. o However, high cholesterol can run in families, men often have lower levels of HDL good cholesterol than women. As we age, the LDL bad cholesterol levels often rise. Before age 55, women generally have lower LDL cholesterol levels than men. But after age 55, women can have higher LDL levels than men. How can high cholesterol level treated? Maintain a healthy weight, have regular physical activity, eat more whole-grain, fruits and vegetables. Beside the lifestyle changes, the doctor can prescribe some cholesterol lowering drugs such as Lipitor. Lipitor works by lowering the LDL bad cholesterol and triglycerides in your blood. Lipitor can also increase the HDL good cholesterol.

Patents
A patent is a right granted by a government for any device, substance, method or process that is new, inventive and useful. The patent period lasts 20 years, starting from the registration date; it may include the clinical trials. In 2010, the pharmaceutical industry registered sales of $860 billion worldwide. There were 133 blockbuster drugs (with annual sales exceeding $1 billion), which accounted for $295 billion of those sales about 34% of the market. 13 blockbusters are expected to lose patent protection by the end of 2013. The generic industry will benefit in the short run; however, fewer blockbusters will be coming off patent for them to replicate for some time to come.

HMG-CoA reductase catalyzes the reduction of 3-hydroxy-3-methylglutarylcoenzyme A (HMG-CoA) to mevalonate. This is the rate-limiting step in hepatic cholesterol biosynthesis. Inhibition of the enzyme decreases de novo cholesterol synthesis, increasing expression of low-density lipoprotein (LDL) receptors on hepatocytes. This increases LDL uptake by the hepatocytes, decreasing the amount of LDL-cholesterol in the blood. Atorvastatin also reduces levels of triglycerides and slightly increases levels of HDL-cholesterol.

Conclusion
The discovery of the statins mechanism enabled the advent of Lipitor, a revolutionary breakthrough with respect to cholesterol problems and the most profitable medicinal drug ever discovered. After atorvastatin calcium, more drugs aiming at the same target, HMG-CoA reductase, were developed and produced. One of them is Crestor (rosuvastatin calcium), which is not to come off patent until January 2016. The worlds best selling blockbuster drug, Lipitor, went off patent in 2011 and subsequently its generic version entered the market. This constituted a multimillion loss from the standpoint of the pharmaceutical company which held its patent. Today the companies producing the generic version benefit enormously but, most importantly, it is the patients who benefit the most and can now obtain the drug at an affordable price. Thus, Lipitor reaches more patients who necessitate it. Reference
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Development of Lipitor (Atorvastatin Calcium)

The molecule (atorvastatin), which became Lipitor was synthesized in 1982 at Parke-Davis division of Warner-Lambert Company (now Pfizer) by Bruce D. Roth. This was part of a project attempting to discover drugs inhibiting the body's production of cholesterol. The key for inhibition of cholesterol synthesis came from previous studies on complex fungal products, called Statin (1985). Lipitor was introduced in the market in 1997. In order to become accessible for the general public, the drug had to follow all the standard procedures or stages: 1. 2. 3. 4. 5. 6. Conduct preclinical research File investigational new drug (IND) application with FDA Perform clinical trials, toxicology testing, and establish manufacturing and control procedures File the new drug application (NDA) with FDA Market the drug product Keep on post-marketing surveillance of the product
Cholesterol's biosynthesis

Lipitor & its generic version Watson and Ranbaxy.

Lipitors Profitability
Warner-Lambert entered into a co-marketing agreement with Pfizer in 1996 to launch Lipitor. Lipitor is the largest-selling medicinal drug of any kind worldwide. Pfizer and Warner-Lambert merged in June 2000, creating the world's most valuable and fastestgrowing pharmaceutical company. Lipitor is taken by 4.3 million Americans. Lipitor revenues formed 15.8% of the companys total revenues. Lipitor revenues brought more than $10 billion annually in worldwide sales for its manufacturer, Pfizer, and more than $130 billion over the past 14 years.