Emerging developing markets on small molecules

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PHARMACEUTICAL INDUSTRY: AN INTRODUCTION

The pharmaceutical industry is responsible for developing through innovation; producing through formulations (such as tablets, capsules, injections, creams, lotions, etc.) and marketing drugs that are used as medications to treat various diseases. Amongst all businesses contributing to the global economy, pharmaceutical industry is considered to be very complex. As there is a multitude of factors involved in the pharmaceutical industry, it is also one of the most regulated industries in the world. The main focus of the pharmaceutical industry is to come up with drugs that are excellent in terms of quality, safety and efficacy.

HISTORY OF DRUG REGULATION: During the transition phase from 19th to 20th century, pharmacy was a science still in its juvenile stages. The most common method of manufacturing drugs was by processing them with hands in the local pharmacy units. It was very difficult to ensure consistency in design and composition of the drugs because advance technologies and equipment to ascertain and assess the uniformity of content were non-existent. The most important challenge faced by the 19th and 20th century pharmaceutical practices was to provide a concrete definition for DRUG was and to define acceptable standards of composition, purity, and strength. The most important development in this direction was marked by the creation of the US Pharmacopoeia (USP) in 1820 (FDAReview.org, 2008).

Two main events led to strategic initiatives in the field of regulating drugs. These were the Sulphanilamide disaster and the Thalidomide tragedy. The first one i.e. Sulphanilamide disaster occurred in 1937 in the US. The main cause was an elixir of the medicine sulfanilamide that was not prepared properly and the consumption of which led to mass poisoning in the US causing a loss of more than 100 lives. This mishappening prompted the USA Food, Drug and Cosmetic Act in 1938, which required pre-approval before distribution of a new drug. The Food, Drug and Cosmetic Act, also introduced the New Drug Application (NDA) although at that time there was no requirement for proof of safety, only efficacy needed to be demonstrated. This law continued until the next milestone i.e. the Thalidomide tragedy which occurred in the early 1960s. In 1950s, Thalidomide was introduced as a sedative (narcotic tranquilizer). In 1961, it was withdrawn from the market owing to widespread severe birth defects reported in newborn babies due to the consumption of this drug by pregnant women. This tragedy is still termed as "one of the biggest medical tragedies of modern times" with the number of deformed babies ranging from 10,000 to 20,000 (Anon, 2010). This was a particularly sensational event and led to a much stricter and rigorous testing regime for drugs before they could be marketed to the general public. In 1948, the US Food & Drug Administration (FDA) first introduced Good Manufacturing Practice (GMP) Regulations but these guidelines more or less remained a concept. It was only after a few tragedies as mentioned above FDA gave decisive powers of the GMP and the pharmaceutical companies were required to maintain strict adherence to these. Since those days, the requirements for the manufacture and testing of medicinal products, and product license applications have changed drastically.

PHARMACEUTICAL COMPANIES: Most of the pharmaceutical companies came into effect in the 19th and the early 20th century but the field still remained small scale in scope. The major development and expansion work in the field of pharmaceuticals started only after 1970. Few key milestones in the history of pharmaceuticals occurred during the 1920s and 1930s when key drug discoveries in terms of insulin and penicillin were made. These were the first drugs that were manufactured on a large scale and distributed. During this period, the European countries developed particularly strong pharmaceutical industries and this is the main reason why most of the pharmaceutical giants are headquartered in the European countries. In the 1940s, government regulations were released to label drugs as prescription medicines (available only with a physician prescription) and non-prescription drugs (available as over the counter drugs). 1950s saw a drastic development in the biotechnology domain of the scientific approaches such as researches on human biology and DNA. In 1970s, there were several initiatives to start a mass expansion in the field of pharmaceuticals. During this era, the pharmaceutical industry witnessed patents coming in to force in most countries. Mid-1980s were marked by small biotechnology firms coming in to existence but these were still not a dominant force.

Two main areas where all pharmaceutical companies delve into are the Core Pharmaceutical Business that involves patented molecules and new chemical entities and Biotechnology based Pharmaceutical Products that involve drugs and molecules that are biotechnology derived products. Biotechnology derived products is an umbrella term used for a collection of products that have been prepared by a large number of specialized technologies and processes that involve the use of living organisms or their units to prepare and develop products that have an added-value and are pharmacologically viable i.e. they can produce a desired medicinal effect in the human beings or animals and can be used as medicines for the betterment of the human race. Pharmaceutical companies that utilize these processes and techniques extensively on the industrial and commercial scale are referred to as biotechnology based companies.

GLOBAL SCENARIO OF PHARMACEUTICAL & BIOTECHNOLOGY INDUSTRY

SALES AND REVENUE: The main predictors of the global scenario for these industries remain company's annual and quarterly reports and overall state of affairs (market as well as economic). In 2006, global pharmaceutical sales totaled US$643 billion with a growth of 7% from the previous year (IMS Health, Feb 2007). Strongest growth in pharmaceutical sales since 1998 was reported by North America (12.6% per year) compared to 9.3% in Europe and 2.9% in Japan (Office of Fair Trading [UK], Feb 2007). The three major markets i.e. North America, Europe (including the UK) and Australia represent 45%, 23% and 1% of total global sales (IMS Health MIDAS, 2007).

However, predictions of high growth for the recently introduced products or sales loss could not be predicted always with absolute certainty due to frequent challenges encountered in the pharmaceutical industry viz. patent expiry, generic entry, labeling restrictions or black box warnings etc. For example best seller drugs of 2008 like Risperdal, Fosamax, Prevacid, Protonix, Norvasc and Nexium faced further loss of sales due to patent expiry. Regulatory action by FDA (black box warning, restricted use and labelling changes) resulted in loss of sales for Avandia as well as Aranesp and other erythropoietin brands.

Based on the IMS health Projections (Feb 2007), the global pharmaceutical market was $815 billion in 2009 and biotechnology drugs/biologics accounted for $130 billion and generics for $90 billion of the global market. The major therapeutic areas with huge sales were CNS, Cardiovascular, and Cancer having sales $125 billion, $ 110 billion and $75 billion respectively.

Although the major pharmaceuticals are, now, engaged in conducting research for new biopharmaceuticals (active ingredients), biopharmaceuticals is now an indispensible and highly focused area, with successful products in various therapeutic areas like Neurology, Infectious Diseases, Cardiovascular, Oncology etc. The main therapeutic segments covered by the biopharmaceuticals include Erythropoietin (EPO), Monoclonal Antibodies, Granulocyte-Colony Stimulating Factor (G-CSF), Vaccines, Insulin, Interferons and Human Growth Hormones. Top 3 categories in biotech products were monoclonal antibodies ($40 billion), vaccines ($25 billion) and TNF inhibitors ($22 billion) sales in 2009. In terms of market revenue, biopharmaceuticals accounted for 10% of the total pharmaceutical market. This figure is projected to rise to approximately 15% by 2015(Knol Beta, 2010).

However, Lipitor still remains the world best selling drug ($12.4 billion projected sales) followed by Plavix (sales of $9 billion) and Enbrel.  In 2009, of the top ten best selling drugs, 5 products were biologicals and of the top twenty best selling drugs, 8 products were biological. Tamiflu was the most famous and talked about antiviral of 2009 with sales of $3.1 billion. Eleven brands had blockbuster sales of more than $5 billion and all drugs listed in the 20 top drug lists category experienced sales of more than $4 billion in the year 2009 (Knol Beta, 2010).

The global market for biopharmaceuticals is projected to reach US$182.5 billion by 2015, registering a CAGR of 12.4% during the period 2006-2015 (Piribo projections).

Table 1 shows the list of 12 largest pharmaceutical and biotechnology companies also called as the BIG PHARMA ranked by healthcare revenues in 2009. As is evident from the table, of the 12 big pharma by revenues, 6 companies are US based and another 6 are UK based. The table clearly depicts the dominance of the US and the UK in the pharmaceutical sector.

Table . Top 12 Pharmaceutical Companies by Revenues (2009)

Rank

Company

Country

Total Revenues (USD millions)

R&D Expenses (reported currency in millions)

Fortune 500 Ranking

1

Johnson & Johnson

USA

61,897

6,986

103

2

Pfizer

USA

50,009

7,845

152

3

Roche

Switzerland

45,304

SFr9,874

171

4

GlaxoSmithKline

UK

44,421

£4,106

168

5

Novartis

Switzerland

44,267

$7,469

183

6

Sanofi-Aventis

France

40,870

€4,583

181

7

AstraZeneca

UK

32,804

$4,409

268

8

Abbott Laboratories

USA

30,765

2,744

294

9

Merck & Co.

USA

27,428

$5,800

378

10

Bayer HealthCare

Germany

22,297

€1,845

154

11

Eli Lilly

USA

21,836

N/A

455

12

Bristol-Myers Squibb

USA

18,808

3,647

435

Source: Various Annual Reports. Available as a separate bibliography for Table 1 in the end.

Table 2 shows the top 15 pharmaceutical companies by sales in 2008. As is evident, of the 15 top companies, 7 pharmaceutical companies are US based and 6 are UK based. Along with the trends depicted by Table 1, Table 2 emphasizes again the dominance of the US and the UK in the pharmaceutical sector.

Table . Top 15 Pharmaceutical Companies by Sales (2008)

Rank

Company

Sales ($M)

Based/Headquartered in

1

Pfizer

43,363

US

2

GlaxoSmithKline

36,506

UK

3

Novartis

36,506

Switzerland

4

Sanofi-Aventis

35,642

France

5

AstraZeneca

32,516

UK/Sweden

6

Hoffmann-La Roche

30,336

Switzerland

7

Johnson & Johnson

29,425

US

8

Merck & Co.

26,191

US

9

Abbott

19,466

US

10

Eli Lilly and Company

19,140

US

11

Amgen

15,794

US

12

Wyeth

15,682

US

13

Teva

15,274

Israel

14

Bayer

15,660

Germany

15

Takeda

13,819

Japan

Source: IMS Health, 2008. Top 15 Global corporations

Table 3 shows a list of the top 20 pharmaceutical products in terms of sales in billion USD in 2008. Lipitor remained the top selling drug, followed by Plavix and Enbrel.

Table . Top 20 Pharmaceutical Products in Terms of Sales in Billion USD in 2008

Revenue Rank 2008

Generic Name

Brands

Companies

Indications

Sales $ billion

2008       2009    

1

Atorvastatin

Lipitor

Pfizer, Astellas

Cholesterol

13.35      12.45

2

Clopidrogel

Plavix

Bristol Myers Squibb, Sanofi Aventis

Atherosclerosis

9.4          9.29

3

Etanercept

Enbrel

Amgen, Pfizer Takeda

RA, JRA,  Ps, PsA, AS

7.66        8.0

4

Fluticasone Salmetrol

Advair

Glaxo Smith Kline

Asthma

7.65        7.764 

5

Infliximab

Remicade

J&J, Merck, Mitsubishi Tanabe

RA, UC, CD, Ps, PsA, AS

6.2          6.91

6

Valsartan

Diovan

Novartis

Hypertension

5.74        6.01

7

Bevacizumab

Avastin

Roche

Colon cancer

4.82        5.92

8

Rituximab

Rituxan

Roche

 NHL, RA

5.4          5.80  

9

Aripiprazole

Abilify

Otsuka, BMS

 

Schizophrenia

4.75        5. 6

10

Adalimumab

Humira

Abbott

RA, Ps, JIA, PsA, AS, CD

4.5          5.49

11

Trastuzumab

Herceptin

Roche

Breast Cancer

4.72       5.02

12

Nexium

Esmoprazole

Astra Zeneca

Ulcer

5.2          4.95

13

Olanzapine

Zyprexa

Lilly

Schizophrenia

4.69        4.91

14

Quetiapine

Seroquel

Astra Zeneca

Astellas

Schizophrenia

4.64        4.89

15

Rosuvastatin

Crestor

Astra Zeneca,

Shionoggi

Cholesterol

  3.6        4.74

16

Ontelukast

Singulair

Merck

Asthma

4.33        4.66

17

Venlafaxine

Effexor

Pfizer

Depression

3.90        4.3

18

 Insulin glargine

 Lantus

 Sanofi Aventis

 Diabetes

                4.22

19

Enoxaparin      

Lovenox

Sanofi Aventis

Anticoagulant DVT   

3.99        4.17

20

Pioglitazone

Actos

Takeda

Diabetes

3.86        4.11

All Sales figures are actual sales figures from different companies

Source: Knol Beta, 2010. Top Ten/Twenty Best Selling Drugs 2009

DEFINITIONS

In general terms a DRUG is a substance which when absorbed into the body of a living organism, alters normal bodily function in some way. In pharmacological context, a drug is "a chemical substance used in the treatment, cure, prevention, or diagnosis of disease or used to otherwise enhance physical or mental well-being." (Dictionary.com, 2010). AN ACTIVE PHARMACEUTICAL INGREDIENT (API) is any biologically active substance present in a pharmaceutical drug. It is sometimes also referred to as active substance, active entity or moiety. A FORMULATION also called as a DOSAGE FORM or DRUG PRODUCT of a drug has two main ingredients. These are, the API which is the active part of the drug itself causing the desired pharmacological effect and an excipient that is pharmaceutically and pharmacologically inert and is added to the API in order to balance the API and also in order to keep the final dosage form intact.

All medicinal substances that have pharmacological properties are called pharmaceutical substances and these can be classified within a number of terminologies as described under.

NEW CHEMICAL ENTITIES or SMALL MOLECULE DRUGS: A new chemical entity (NCE) or new molecular entity (NME) is defined as a new compound with new chemical structure, different interaction with biological targets and say a better therapeutic response when compared to already present products / formulations. In other words this is a molecule or a pharmacologically active moiety that has not been previously approved by drug regulatory authorities for medicinal use in general public. An NCE is produced during the drug discovery phase and can later on undergo clinical trials after which it will be approved for marketing in humans. The company that produces the NCE is known as the innovator company.

GENERICS: A drug with the same active ingredients and equivalence as the original small-molecule pharmaceutical (API) produced by using chemical synthesis. A generic must contain the same active ingredients as the original formulation. Generic drugs should be identical or within an acceptable range to the branded product (innovator product) with respect to the pharmacological effect produced. Generics are also expected to be identical in dose, strength, route of administration, safety, efficacy, and intended use with the innovator product.

BIOPHARMACEUTICALS (Accenture research, 2009) is a general term referred to products that are biotechnology-derived pharmaceuticals or products that are produced by using processes and techniques specific to the field of biotechnology. Biopharmaceuticals is a broad term that covers several sub-terms such as biological, biosimilars, biogenerics. BIOLOGICAL PRODUCTS or BIOLOGICALS are defined by the US FDA as "pharmaceuticals that include a broad range of products such as vaccines, blood and blood components, allergenic products, somatic cells, gene therapy, tissues, and recombinant therapeutic proteins generally composed of sugars, proteins, or nucleic acids or complex combinations of these substances, or may be living entities such as cells and tissues". Biologicals can be isolated from a wide range of natural sources such as human, animal, or microorganism or maybe produced using various other technologies such as gene-based and cellular techniques. When compared to the conventional small molecules or APIs, biological are very different. This is due to the fact that that biological have a huge complex structure against small molecules whose structure is comparatively simple and very well known. Due to this reason, biological cannot be easily identified and isolated. Also because these products are heat labile and can be easily infected by microorganisms, it is relatively difficult to prepare these products and hence there are fewer companies that are extensively biotech based in the world.

The synthetic small molecules are simple, small, easily characterized and clean entities.

Figure 1 shows the structure of Aspirin

A biotech molecule has complex production site, a very large product, heterogeneous structure, is difficult to characterize and is difficult to clean.

Figure 2 shows the structure of Human Insulin

http://images.google.com/images?q=tbn:Zr6sJa8imE4J:www.worldofmolecules.com/drugs/aspirin.gif

http://www.lightsources.org/images/pressreleases/2006/pruch061_1.jpg

Figure . Structure of Aspirin

Figure . Structure of Human Insulin

Source: http://home.cc.umanitoba.ca/~joneil/aspirin.gif

[Accessed 25 June, 2010]

Source: http://www.lightsources.org/images/pressreleases/2006/pruch061_1.jpg [Accessed 25 June, 2010]

BIOSIMILARS (European EMEA) or FOLLOW-ON BIOLOGICS (US FDA) are approved drugs, produced by using biotechnology, referencing an originator biologic. These are follow-on or copies or different versions of the already approved and manufactured biotech products. There is always difficulty in establishing similarity amongst these products because it is almost impossible to compare one protein with another protein and hence there safety and efficacy cannot be easily established with already approved counterparts. Thus, unlike we have generics for the small molecules or APIs it is very difficult for any company to have a biogeneric for a generic product. Hence, these products are commonly called as Biosimilars. BIOGENERICS is a term used to refer to interchangeable Biosimilars which are very difficult to figure out.

DRUGS & MECHANISM OF ACTION

Pharmacology is a branch of science dealing with the study of drug action. It studies the interactions that occur in organisms when a chemical substance (in this case the drug substance) interacts with the biochemical functions of the body. Pharmacology encompasses the study of specific aspects related to pharmaceuticals such as the drug properties determined by its composition, drug-body and drug-drug interactions, toxicology, therapeutic efficacy, and medicinal benefits accomplished.

Whenever a drug substance is administered to a patient it initiates a specific biochemical interaction in the body to produce its pharmacological effect. In pharmacology, this dynamic action - reaction is called as the Mechanism of Action (MOA). Generally, a mechanism of action includes one or the other molecular targets or selectivity site to which the drug binds to produce an effect. When the drug binds to the receptor or the target (such as an enzyme) it produces an irreversible change to the receptor initiating further biochemical reactions in the cell. These reactions are responsible for the targeted pharmacological effect desired.

Figure . Mode of Action of Various Antiplatelet Drugs

http://www.australianprescriber.com/upload/issue_files/3004_f1_antiplatelet.gif

Source: McCann, A., 2007. Antiplatelet therapy after coronary occlusion

Key: ADP: Adenosine diphosphate; GP IIb/IIIa: Glycoprotein IIb/IIIa complex; COX: Cyclo-oxygenase

Figure 3 demonstrates the MOA of various antiplatelet drugs that are a group of powerful medications that prevent the formation of blood clots. Whenever a person gets wounded, platelets arrive and aggregate on the site of wound and club together to form a clot that stops the bleeding. Usually this is a very useful phenomenon and helps our body to prevent excessive blood loss. Problem occurs when these platelets start aggregating inside an injured blood vessel in diseases such as atherosclerosis and prevent the smooth blood flow through the blood vessel. Antiplatelet medications are the drugs administered to prevent this process from occurring. The most common antiplatelet drug is Aspirin, others being Plavix (clopidogrel bisulfate) and Ticlid (ticlopidine hydrochloride) (Cleveland Clinic, 2009).

As is clear from the diagram, the various modes of actions of antiplatelet drugs (that do not allow platelets to aggregate) can be described as:

Aspirin inhibits the enzyme cyclo-oxygenase 1 and in turn inhibits platelet activation. This prevents the synthesis of thromboxane A2 that causes platelet aggregation

Clopidogrel prevents adenosine diphosphate from binding to a platelet receptor and in turn inhibits the activation of the glycoprotein IIb/IIIa complex. This inhibits platelet aggregation.

Dipyridamole inhibits platelet aggregation by increasing the production of prostacyclin that causes platelet aggregation

Thus, it is clear from this discussion that various drug molecules act on various sites in the same cell with various mechanisms of actions to produce similar pharmacological effects.

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