bishwjit final thesis

TO STUDY THE GLOBAL MONOCLONAL ANTIBODY MARKET AND

ITS POTENTIAL IN INDIA

A THESIS

Submitted in partial fulfilment of the requirements for the degree of

Master of Business Administration (Pharm.)

BY

BISHWJIT GHOSHAL

Batch 2014-16

DEPARTMENT OF PHARMACEUTICAL MANAGEMENT

National Institute of Pharmaceutical Education and Research

Sector-67, S.A.S. Nagar, Mohali-160062

Punjab, India

June 2016



Punjab, India

CERTIFICATE

This is to certify that the work entitled, “To study the global monoclonal

antibody market and its potential in India” has been carried out by Mr.

Bishwjit Ghoshal under my direction and supervision.

Date: ___________________ Signature: ___________________________

Place: S.A.S. Nagar, Mohali Name: Dr. Anil Kumar Angrish

Designation: Associate Professor

Department: Pharmaceutical Management



Punjab, India

DECLARATION

I hereby declare that the present work embodied in this thesis entitled, “To study the

global monoclonal antibody market and its potential in India” has been

carried out by me under the direct supervision of Dr. Anil Kumar Angrish, NIPER.

This work has not been and will not be submitted in part or in full in any other

university or institution for any degree or diploma or to any other organization for

commercial purpose.

Date: ________________ Bishwjit Ghoshal

Place: S.A.S. Nagar, Mohali Department of Pharmaceutical Management

NIPER, Sector-67

S.A.S. Nagar, Mohali-160062

Punjab, India

ACKNOWLEDGEMENT

With immense pleasure, I am deeply grateful to my esteemed guide Dr. Anil Kumar Angrish

(Associate Professor, NIPER) under the guidance of whom this project has been done. He has

been very generous with both his time and his patience in providing inputs for effectiveness of

the project, generosity with which information & ideas were shared and for displaying

confidence in my ideas and potential. I acknowledge his advice and guidance throughout the

year.

I wish to thank Dr. Anand Sharma (Professor, NIPER) and Dr. Sunil Gupta (Associate

Professor, NIPER) for being my advisor. I appreciate their assistance and feedback on my

thesis.

I owe a very special word of thanks to my friends for helping me immensely throughout this

work and supporting me morally without which it would have been highly difficult to

complete this work.

I am also thankful to all other faculties, staff members and my colleagues who have in anyway

have been helpful to me in this project.

Above all, I am thankful to my parents for helping me attain this position in life. I owe all my

love and affection to them.

-BISHWJIT GHOSHAL

List of Abbreviations

ALCL Anaplastic Large Cell Lymphoma

AMD Acute Macular Degeneration

CAPS Cryopyrin Associated Periodic Syndrome

CD Cluster Differentiation

cDNA Copy Deoxyribonucleic Acid

CDR Complimentarity Determining Region

CLL Chronic Lymphocytic Leukemia

CTCL Cutaneous T-Cell Lymphoma

CTLA Cytotoxic T-lymphocyte Antigen

Dabs Domain Antibodies

DME Diabetic Macular Edema

DNA Deoxyribonucleic Acid

DPP-4 Di-peptidyl peptidase 4

EGF Epidermal Growth Factor

EpCAM Epithelial Cell Adhesion Molecule

Fab Antigen binding fragment

Fc Constant fragment

HAMA Human against Mouse Antibody

HHV Human Herpes Virus

HIV Human Immunodeficiency Virus

HLA Human Leukocyte Antigen

IL Interleukins

IV Intravenous

MAb Monoclonal Antibodies

MCD Multicentric Castleman’s Disease

PD-1 receptor Programmed Death receptor

RANK Receptor Activator of Nuclear factor Kappa-B ligand

RNA Ribonucleic Acid

RSV Respiratory Syncytial Virus

RVO Renal Vein Occlusion

SJIA Systemic Juvenile Idiopathic Arthritis

TNA-α Tumor Necrosis Factor alpha

VEGF Vascular Endothelial Growth Factor

Executive Summary 2016

1 National Institute of Pharmaceutical Education and Research, S.A.S. Nagar

Executive Summary



Executive Summary

Global pharmaceutical market is a highly dynamic entity. The demands of the patients change

which leads to a change in the products manufactured. There was a time when the whole

market was dominated by the chemically derived products. But, the problems of side effects,

hypersensitivity and adverse reactions of these drugs made the patients to look for safer

alternatives.

This search for alternatives paved way for new types of products including herbal products,

biologics, etc. Out of these classes, biologics are the one that have become the most preferred

class of drugs in the market. Biologics include blood and blood products, cells and tissues,

recombinant proteins, vaccines, etc.

The class of biologics discussed in this report is monoclonal antibody, which includes

recombinant proteins synthesized by fusing antibody secreting plasma cells and myeloma

cells. The source of protein decides the type of monoclonal antibody. Based on this, there are

four types of monoclonal antibody products in the market viz. Murine, chimeric, humanized

and human monoclonal antibodies. These products have developed with time.

In 1986, the first monoclonal antibody product came into the market, Orthoclone OKT3 which

was a murine monoclonal antibody. With time, developments took place in the products

reducing the portion of murine proteins making it less antigenic to the patient and thus

increasing the tolerance.

Today, monoclonal antibodies have a lot of diagnostic as well as therapeutic applications.

Their specificity to a particular antigen make them a perfect candidate for diagnostic purposes

to identify and separate a particular antigen or protein. In therapeutics, monoclonal antibody

products have been widely used in cancers, auto-immune diseases and hypersensitivity

disorders with a lot of new indications being identified for the application of monoclonal

antibodies.

The monoclonal antibodies are used against cell specific antigens owing to their high

specificity for them. Usually, their mechanism of action is based upon blocking of receptors

mainly responsible for growth including Epidermal Growth Factor (EGF) and Vascular

Endothelial Growth Factor (VEGF). In auto-immune diseases, they act by inhibition of

interleukins and human immunoglobulins that are responsible for causing auto-immune

reaction.

After the arrival of first monoclonal antibody product in the market, this field has seen a

tremendous growth in years. In 2013, a global sale of around 75 million USD was generated

by these products. The monoclonal antibody market is expected to show a considerable

expansion both in terms of products and the diseases covered by these drugs.



A total of 58 drugs have been approved for commercial sale but 11 of them were removed

from the market for various reasons leaving 47 approved drugs for commercial sale. There is

an average approval rate of 4-5 drugs for these products. At this rate, we can look at a number

of seventy monoclonal antibody products in the market by 2020.

Out of the products present in the market, monoclonal antibodies have made a special place for

themselves. This statement is strengthened by the fact that out of top 10 selling products of

2014 globally, six were monoclonal antibody products i.e. Humira (Adalimumab), Enbrel

(Etanercept), Remicade (Infliximab), Rituxan (Rituximab), Avastin (Bevacizumab) and

Herceptin (Trastuzumab). Out of top 50 products of 2014 by sale, seventeen are monoclonal

antibody products. This just showcases the impact that these products have and the place these

products have made in the market.

The companies have a strong pipeline of products that ensures rich supply of new products

into the market. Around 400 monoclonal antibody products are under clinical trials that are to

come into the market upon approval in the coming years. This also shows the scope of

expansion the monoclonal antibody market has in the future.

So, this study has been conducted to analyze the global scenario of monoclonal

antibody products in terms of products, companies and competitive therapies.

Secondary analysis of monoclonal antibody market has been carried out to analyze the

market scenario and position that these products hold.

Detailed description of the top monoclonal antibody products have been given in the

report.

The present study will give details about the inline as well as pipeline products and

their features.

Introduction 2016


Chapter 1

Introduction

Introduction 2016


1. Introduction

New products and novel treatment methods have evolved from time to time. For many years

now, the use of monoclonal antibodies in therapeutics have been identified and realized

leading to innovation in the products ultimately giving new and improved products.

Antibody related products have not only found use in therapeutics but also in diagnosis as in

imaging and scanning. The reason for the emergence of monoclonal antibodies as an important

therapeutic category is that when a human cell or tissue, is treated with original antibody

product leads to therapeutic benefit with maximum patient safety and less side effects.

1.1 Types of Immunity

There are two ways of classifying immunity:

(a) Characteristic of adaptability- Innate immunity and Acquired immunity

(b) Types of cells involved- Cellular immunity and Humoral immunity

1.1.1 Innate immunity

Innate immunity is the immunity that a person has by birth with no requirement of prior exposure. It provides the host with a fast acting response that helps him to survive. It is

involved with slowing the infection at an early stage and the elimination is done by the immune system.

Includes different components:

Anatomic Barriers: Skin and Mucous membrane

Physiologic Barriers: Febrile responses, gastric pH, chemical mediators such as lysozyme, interferon and complements

Endocytic Barriers: Cells that internalize and destroy the foreign material

Inflammatory Barriers: Phagocytic cells and Serum proteins

Cytokines: Macrophages, Neutrophils, Basophils, Eosinophils and others

1.1.2 Acquired Immunity

It is often referred to as adaptive immunity. It includes immunity components that react to new

antigens and the response gets stronger with re-exposure to antigens. This immunity is stronger, more specific and accurate when compared to innate immunity. The only problem

with this immunity is that it requires time to work and without prior exposure to the antigens, the response elicited is not strong.

Introduction 2016


1.1.3 Cellular Immunity

Cellular immunity refers to the cells of the activated immune system. The cellular immune

system’s main function is to survey and remedy intracellular irregularities, such as intracellular bacteria, viruses and cancer. The cells involved include:

Effector T cells- responsible for direct actions against antigens

Cytotoxic T cells- destroy irregular cells directly

Helper T cells- overlapping action between cellular and humoral immunity

1.1.4 Humoral Immunity

This includes the cells which circulate in humor, extracellular fluids such as plasma, lymphatic

system and tissue fluids. The cells involved include:

B-cells Plasma Cells: secrete antibodies

Memory Cells: keep a memory of the encounter with antigen and elicit

a stronger response on next encounter

1.2. What is an Antibody?

1.2.1 Genesis of Antibodies

The lymphoid progenitor of B-cell produces in the vicinity of 106 antigen-compatible preliminary B-cell lineages each day. During maturation, B-cell undergoes many changes,

including the appearance of cell surface bound immunoglobulin of µ and δ isotypes.

When a B-cell is contacted upon by an antigen, this leads to the formation of progeny clones, originating from particular B-cell. As it expands, it produces memory B cells and plasma B cells that mediates the immune response.

Figure 1: Genesis of Antibodies

Lymphoid

Stem Cell

Memory

B-Cell

Antibody

Secretion

Activated

B-Cell

Pro-B-

Cell

Immature

B-Cell

Naïve B-

Cell

Mature B-

Cell

Plasma

Cell

Surface Immunoglobulin

In Periphery In Bone Marrow

Introduction 2016


1.2.2 Structure of an Antibody

Each antibody is composed of two heavy polypeptide chains and two light polypeptide

chains which are identical in nature. These chains are held together by disulfide bonds.

Each heavy and light chain is composed of folds which are called domains.

Light chains contain one variable region and one constant region while Heavy chains

contain one variable region and three or four constant regions depending on the

antibody type

Variable regions are called so because the amino acid sequences in these areas differ in

different B-cell lines. Constant regions are invariant for different classes of antibodies.

All antibodies are hinged between constant region 1 and constant region 2 to provide

flexibility to the antibody structure.

The paired variable and constant regions above this hinge are referred to as antigen

binding fragment (Fab) of antibody. The paired constant regions below the hinge are

called constant fragment (Fc) of the antibody.

Figure 2: Structure of Antibody

Introduction 2016


1.3 Polyclonal and Monoclonal Antibodies

1.3.1 Polyclonal Antibodies

Polyclonal antibodies are a class of antibodies produced from B cell clones activated by an immunized animal

Traditionally, animals like goat, sheep, horse are used for the purpose. They are injected with a specific antigen that elicits a primary immune response. This is then

followed by secondary and tertiary immunization that produces further higher amounts of antibodies which are then collected and purified to obtain specific antibodies.

There is a high chance of variability in production of polyclonal antibodies. Since they

cannot be stored for a long time, several animals are to be injected at the same time to produce antibodies. Due to the differential immune response of animals, the antibodies

developed are highly variable in nature. Polyclonal antibodies represent a heterogeneous set of antibodies that are able to

recognize various epitopes of antigen and can do so with varying affinities making

them advantageous for various biological assays.

1.3.2 Monoclonal Antibodies

Monoclonal antibodies are the antibodies that recognize a single epitope within an antigen. They are usually generated from a single B cell of an immunized mouse

leading to the formation of identical antibodies recognizing a particular epitope of antigen.

Monoclonal antibodies, due to their special characteristics of antigen specificity, limited cross reactivity and long life finds use in both diagnostic as well as therapeutic applications.

Figure 3: Comparison of monoclonal antibody and polyclonal antibody binding

Introduction 2016


1.4 Types of Monoclonal Antibodies

Based on relative contents of murine (rat) and human antibodies, the monoclonal antibodies

can be divided into four categories:

Murine Antibodies

Chimeric Antibodies Humanized Antibodies

Human Antibodies

1.4.1 Murine Monoclonal Antibodies

In 1975, Kohler and Milstein discovered that antibody secreting plasma cells of murine and immortal murine myeloma cells can be fused together with the benefits of each of them

retained. This led to the emergence of first monoclonal antibody that was wholly murine based.

Preparation of murine monoclonal antibodies:

Fusion of a cancerous mouse B-cell myeloma with an immunized mouse plasma cell.

The fusion leads to the formation of a hybrid cell or hybridoma containing the characters of both plasma cells and myeloma cells.

The myeloma cells provide immortality to the hybrid cell while plasma cells provide the antibody secreting function.

Disadvantages:

Reduced plasma half-life of murine vs human IgG

A human IgG has a half-life of about three weeks while a murine IgG has a half-life of only a few hours.

Human against Mouse antibody (HAMA) response

Murine monoclonal antibodies tend to evoke a HAMA response that not only further reduces the half-life of murine antibodies but also elicits an anaphylactic

hypersensitivity reaction owing to their foreign nature.

Examples:

Muromonab CD-3- immunosuppressant used in organ transplant

Y-90 Ibritumomab tiuxetan- radioimmunotherapeutic agent used as anti-neoplastic agent in Non-Hodgkins lymphoma

Introduction 2016


1.4.2 Chimeric Monoclonal Antibody

With the emergence of recombinant DNA technology, the monoclonal antibodies with more

amounts of human sequences were developed. The first advancement in this field was development of Chimeric monoclonal antibodies.

Chimeric antibodies contain proteins from two sources: human and marine. Where murine monoclonal antibodies contained 100% of murine proteins, chimeric antibodies contains 33%

murine proteins and remaining human proteins. In chimeric antibody, the variable region providing antigen specificity contains murine proteins while the constant region dictating

antibody isotype are replaced with human proteins.

Preparation of chimeric monoclonal antibody:

The variable region genes from a murine hybridoma are isolated and amplified using the Polymerase Chain Reaction leading to the formation of a copy-DNA of the murine

variable region.

This Variable copy-DNA is then ligated into a plasmid for transfer to a host.

In a similar sequence cDNA of human heavy chain constant regions is also amplified and ligated into a separate plasmid producing heavy chain copy DNA.

The last step is the fusion of variable cDNA from murine and Heavy Constant cDNA from human using co-transfection.

Disadvantages:

Human against Chimeric antibody (HACA) response

In spite of the modifications in the original murine antibody sequence, still, immune response is elicited to the murine portion i.e. the variable sequence of the antibody.

Examples:

Abciximab- used as platelet aggregation inhibitor in coronary artery procedures

Infliximab- Destroys B-cells and used to treat auto-immune diseases

Rituximab- Binds with tumor-necrosis factor and used in treatment of non-Hodgkins

lymphoma

Cetuximab- Inhibits epidural growth factor and used to slow growth of metastatic

diseases

1.4.3 Humanized Monoclonal Antibody

This is the next level of the development of monoclonal antibodies whereby the murine protein

content was further reduced.

Humanized monoclonal antibodies retain only the hypervariable region or complementary

determining region of the murine antibody while the remaining portion is human. Thus, these antibodies contain 5-10% of murine content.

Introduction 2016


Preparation of Humanized monoclonal antibody:

Using r-DNA technology, the light and heavy chains genes of human antibody can be

amplified using polymerase chain reaction. The resultant cDNA can be used as template for the in-vitro synthesis of humanized monoclonal antibody except the CDR fragment which is provided by murine.

Murine CDRs are grown in parallel.

The respected CDR genes and cDNA from humans can be spliced into vector DNA

and incorporated into bacteria for growth.

Through co-transfection i.e. incorporating human cDNA and murine cDNA into the

same bacterial cell, an intact humanized monoclonal antibody can be produced.

Drawbacks:

Improper or no-existent glycosylation

The synthesis process of humanized monoclonal antibody can lead to improper or non-existent glycosylation. Glycosylation of the Fc part of antibody is crucial in determining the solubility, serum clearance and general pharmacokinetics of the

antibody.

Examples:

Palivizumab- Prevention of respiratory syncytial virus infections in infants

Trastuzumab- Treatment of HER-2 positive metastatic breast cancer

Alemtuzumab- Treatment of chronic lymphocytic leukemia (CLL), cutaneous T-cell

lymphoma (CTCL) and T-cell lymphoma

1.4.4 Human Monoclonal Antibody

Human Monoclonal Antibodies are fully or nearly 100% human proteins in composition. This is the newest and most developed category of monoclonal antibodies.

Preparation of Human Monoclonal Antibody:

There are two techniques of producing human monoclonal antibodies. These are:

Genetically engineered, transgenic or knockout mice

Use of phage display libraries 1.) Genetically engineered, transgenic or knockout mice

Knockout mice are prepared by harvesting early stage embryonic stem cells from early stage fertilized mouse embryo. An existing gene is “knocked out” or replaced by an artificial gene.

The altered stem cells are grown in the mice with a foreign gene. Since, the stem cells of the mouse are altered, they are not able to synthesize murine

immunoglobulins and corresponding B-cells. The replaced human germ line DNA can cause the mouse to produce human B-cells that can then produce human monoclonal antibodies.

Introduction 2016


2.) Use of phage display libraries

Phages are the viruses that infect bacteria. They have hollow heads that contain phage

DNA or RNA and tails which help the phage to bind to specific sites on host bacteria.

The viral DNA is injected into the host cell causing the rapid production of identical

progenies. The rapid division ultimately bursts the cell and leads to infection of ore

bacteria.

Specific human antibody fragments are fused into the phage DNA structure. The

introduction of altered phage DNA leads to rapid division generating a large population

of antibody fragments specific to a certain antigen.

Each resulting phage has a functional antibody protein on its surface and contains the

gene encoding the antibody incorporated into the phage genome.

Examples:

Panitumumab- Treatment of Epidermal Growth Factor expressing metastatic

colorectal cancer

Golimumab- Blocks TNF-α and used in treatment of rheumatoid arthritis

Canakinumab- Blocks interleukin-1β and used in treatment of Cryopyrin-Associated

periodic syndrome

Ustekinumab- Blocks interleukin 12 & 23 and is used in treatment of plaque psoriasis

Figure 4: Types of therapeutic monoclonal antibody

Introduction 2016


1.5 Monoclonal Antibodies in Therapy and Diagnostics

Figure 5: Types of therapies used for treatment of Ailments

As depicted above, all the products used for therapy and diagnosis can be classified into 3

major sections, i.e. Chemical, Herbal and Biologic. The topic of interest, Monoclonal

Antibodies form a subclass of Biologics derived products.

Monoclonal Antibodies find a lot of applications in the field of diagnostics and therapeutics.

Some of the applications of Monoclonal Antibodies can be listed as follows:

A. Diagnostic Applications

In research and laboratory MAbs can be used to detect the presence of antigens. Different technologies that employ MAbs are Western blot, Enzyme linked radio-immuno-assay, Radioimmuno assay, fluorescence microscopy, electron microscopy, etc.

Gene cloning With gene cloning, it is a difficulty to identify the cells containing the desired genes. If a MAb is available that can identify the desired gene, then that can be used to detect the cells and ultimately the gene for treatment.

Medicinal Products

(Pharmaceuticals, Drugs)

Chemically Synthesized

Pharmaceuticals

Biological Medicine Products

(from Humans or Animals)

Herbal

Pharmaceuticals

Blood and Blood

Products

Cells and

Tissues

Advanced Therapy

Medicinal Products

Extracellular

Vesicles

Recombinant

Proteins Vaccines Others

Hormones (Insulin,

Erythropoietin)

Monoclonal

Antibodies

Fusion

Proteins

Introduction 2016


Protein purification MAbs have unique specificity for a particular protein. This specificity can be exploited to separate the desired protein from a mixture. MAb affinity columns are used for the purpose.

Identification of cell surface markers Cluster differentiation (CD) and human leukocyte antigen (HLA) are expressed as antigens on several immune cells. Flow cytometry is used to find out the number of these antigens on the cells using MAbs directed against a specific cell antigen. If the number of CD markers come out to be low, immunodeficiency disease is expected while overproduction indicates cancer. Thus, MAbs may be used for understanding, diagnosing, and managing immune system-related diseases.

Analysis of Cell function Cells are majorly made of proteins. Monoclonal antibodies can be used to analyze functions of different parts of cells. These can be used to purify, remove or destroy various subpopulations

of cells which can then be analyzed.

B. Therapeutic Applications

Cancer Therapy MAbs are used against cancer cell specific antigens that will induce an immunological reaction against the cancer cells. There are several mechanisms through which monoclonal antibodies act in the body.

Binds to complement proteins of the tumor cells leading to direct toxicity to the cells Blocks the growth factors released by the cells leading to inhibition of the growth of

the cells. The growth factors generally targeted are Vascular Endothelial Growth

Factor (VEGF) and Epidermal Growth Factor (EGF)

Autoimmune Diseases Monoclonal Antibodies find a great deal of use in autoimmune diseases due to their antigen specific nature of action. Crohn’s disease, ulcerative colitis, macular degeneration are some of the disorders in which MAbs find use. These are also used in graft rejection in organ transplant. The mechanisms by which monoclonal antibodies act are:

Ability to identify and bind to Tumor Necrosis Factor-alpha Inhibition of Interleukins on activated T-cells

Inhibition of Human immunoglobulins e.g. IgE, IgG

Other diseases Apart from autoimmune and tumors, MAbs also find use in the treatment of other disease. For example, Prolia (denosumab) is used to increase the bone mass in the patients; Synagis (pelivizumab) is used to treat lower respiratory tract infections caused by Respiratory syncytial virus.

Introduction 2016


1.6 Shift from conventional therapy to monoclonal antibodies

Since time, chemically derived products have ruled the pharmaceutical market. All the

research has been focused on coming up with new chemical entities, improvement in the

existing molecular entities and development of new formulations. But, the biggest problem

encountered with these products has been the safety issues, since all the chemical products

have side effects which in some cases become life threatening.

With the coming up of biologics derived products in the market, the pharmaceutical market

has seen a considerable shift of pharmaceutical firms as well as patients to the Biologics.

Monoclonal Antibodies, a type of biologics derived products since its arrival in 90s has seen a

rapid growth.

The reasons that can explain this shift from conventional therapy to monoclonal antibodies

include:

1. High specificity, low risk

Monoclonal antibodies are known for their high specificity for a particular antigen.

Due to this unique feature, the risks of cross reactions with unwanted antigens or other

molecules is negligible which make it a much safer option compared to other

therapeutic products. Moreover, when these products are in clinical trial phase, the

unexpected risk to the subjects is very low making it more attractive for the firms.

2. Increasing understanding of diseases at molecular level

With the advancement of technology and knowledge about the diseases, the researchers

are not only able to identify and classify the disease at physiological level, but also at

molecular level. The technology has helped the researchers to understand the anatomy

of disease which ultimately helped them to come up with more focused and specific

medicines for treatment. Monoclonal antibody products often provide the most rapid

route to a clinical proof-of-concept for activating, inhibiting or blocking the new

molecular targets. This is the reason that when any novel target comes into light,

monoclonal antibodies are usually the first type of products advancing to clinical trials.

3. Aging population and increased purchasing power in emerging countries

The people in the emerging countries are getting old. This has led to an increase in the

demand for healthcare products in these countries which ultimately has increased the

demand for monoclonal antibodies as well. Moreover, with the improvement of global

economy and standard of living in the emerging countries, more people are now able to

afford the expensive monoclonal antibody products leading to the expansion of the

reach of these products to different economic strata which were earlier out of reach.

Introduction 2016


4. Improvement in MAb production technology

The biopharmaceutical industry is maturing with time and the technologies for

production of monoclonal antibody products are improving making them more cost

efficient and improved process yields. As a result, there is an ever-increasing

opportunity for these products to penetrate more cost sensitive indications and markets.

5. Emergence of Biosimilars

With the expiry of patents of prominent monoclonal antibody products, the companies

are coming up with the Biosimilar version of these blockbuster products. Examples

include Remsima and Inflectra that have been approved in the European Union for

commercial sale as biosimilars. Although, the impact of these biosimilars on the overall

sale of the MAb products cannot be tracked at such an early stage, but, it is expected

that the expectance of these biosimilars in the market will lead to a gradual increase in

the sale of the monoclonal antibody products.

Introduction 2016


1.7 Biosimilars- An alternative

According to WHO, a biosimilar is a biotherapeutic product which is similar in terms of

quality, safety and efficacy to an already licensed reference biotherapeutic product. People

confuse the tern biosimilar to generic versions of biologics, but this is not so. The generics are

bioequivalent and identical to the reference products whereas biosimilars are similar to, and

not identical to the reference product.

As we have seen, monoclonal antibodies have gained a special position in pharmaceutical

industry owing to a tremendous growth. Out of the 47 marketed products, a considerable

fraction of sales come from six products namely, Humira (adalimumab); Enbrel (etanercept);

Rituxan (rituximab); Remicade (infliximab); Avastin (bevacizumab) and Herceptin

(trastuzumab). These products face loss of exclusivity over the coming years.

Figure 6: Best-selling biologics and their patent expiry dates

Source: www.news.mims.com

Literature Review 2016


Chapter 2

Literature Review



2. Literature Review

There has been a lot of work done by many researchers covering many aspects related to the

monoclonal antibodies. The aspects include their composition, manufacturing, marketing, regulation, etc.

2.1 The therapeutic monoclonal antibody market: (Dawn M Ecker, Susan Dana Jones, and

Howard L Levine, January/February 2015; © 2015 BioProcess Technology Consultants,

Inc.)

The authors in the report gave a detailed description about the market scenario of the

monoclonal antibodies in the therapeutics. The first commercial monoclonal antibody came into the market as Orthoclone OKT3 for prevention of kidney transplant rejection in 1986. After the arrival of this product, this class of biopharmaceutical products has grown

significantly and by November 2014, forty seven products are being marketed in US or Europe for the treatment of a variety of diseases.

The first monoclonal antibody to arrive in the market was a murine antibody consisting of murine proteins. This class had problems of hypersensitivity and anaphylactic reactions in

patients due to the foreign nature of the antibody. In the late 1990s, the first chimeric antibodies were produced which was a development in the existing product. This was then followed by humanized antibodies and fully human antibodies.

In 2013, the global sale of monoclonal antibody products was nearly $75 billion, half of the

total sales of all the biopharmaceutical products. There has been a rapid growth in the market and with a good amount of products in the pipeline, this market is trusted to give good returns to the pharmaceutical sector.

2.2 Monoclonal Antibodies- Key to unlocking the Biosimilars market (Cynthia A. Challener, April 01, 2014, Biopharm International)

Monoclonal Antibodies belong to a class of products known as Biologics. It is considered to

be one of the most complicated sections of Biologics derived drugs. On the other hand, we have Biosimilars which according to FDA is a biological product that is highly similar to a United States licensed reference biological product not withstanding minor differences in

clinically inactive components, and for which there are no clinically meaningful differences between the biological product and the reference product in terms of the safety, purity and

potency of the product.

In the article, author has tried to show the positive impact that monoclonal antibodies will have

on the biosimilar market. The growth can be ascribed to the fact that a lot of monoclonal antibody biosimilars are to be expected to be launched in the coming years. Some of the examples include infliximab (currently marketed as Remicade by Johnson & Johnson);

trastuzumab (currently marketed as Herceptin from Roche); adalimumab (currently marketed as Humira from Abbott).



The article further covers other aspects including complexity in development of monoclonal antibodies biosimilar. Compared to the relatively small protein molecules for which biosimilars are approved, MAbs are comparatively very complex and hard to characterize. The

complexity thus requires more complex manufacturing process increasing the cost ultimately. The article also talks about the need for a clear regulatory framework and a precise approval

procedure for MAb biosimilars.

Earlier, developed countries used to be the main focus of the companies for their products.

But, with time, the focus has shifted to the developing or emerging countries. The author has talked about the alterations that the companies need to make in their product to make it

feasible and affordable for the customers in the emerging markets. It also talks about the marketing and strategic decisions that the company will have to take to gain a strong hold in these markets. Strategic alliance with local companies is one of the key strategies that

companies are taking to establish their presence in these markets.

Being a comparatively novel approach, monoclonal antibodies are still to gain confidence of the physicians and patients. The author talks about the variability in acceptance of the MAb products in different countries. In spite of being a novel and expensive approach in therapy,

the author states that it has a bright future and a lot of big players in pharmaceutical sector like Pfizer, Amgen, Merck Serono, Bristol-Myers-Squibb are coming up with their own products.

2.3 Monoclonal Antibodies: A tool in clinical research (Waliza Ansar and Shyamasree

Ghosh, April 2013, Indian Journal of Clinical Medicine)

Monoclonal antibodies are an old immunological tool that is used in a variety of fields which include biotechnology, immunology, biochemistry and applied biology. In this research paper,

authors have covered various aspects related to MAbs i.e. production, application, antibody engineering and its pharmaceutical applications.

The production of MAbs includes fusion of immortal myeloma cells and spleen cells. The hybridomas are produces which are then made to act on specific antigens producing

monoclonal antibodies.

MAbs have a variety of applications in various fields, for example, in gene cloning, protein

purification, as therapeutic tool for treatment of various diseases, for diagnostic purposes. The paper also talks about the limitations of MAbs like antigenicity, anaphylactic reactions.

Moreover, paper also talks about the expensive nature of the products.



2.4 Introduction to Diagnostic and Therapeutic Monoclonal Antibodies: Continuing

education for Nuclear Pharmacists and Nuclear Medicine Professionals (Blaine Templar

Smith, Nov 2012, UNM College of Pharmacy)

The publication provides an integrated knowledge on the basics of monoclonal antibodies.

Monoclonal antibodies being a comparatively new field of therapeutics suffer from lack of knowledge among the patients, companies and physicians.

The publication provides a deeper understanding on different sections. It starts with the basics of immunity, its types and molecules involved in it. Antibody structure is explained in detail and monoclonal antibodies are classified into four types: murine, chimeric, humanized and

human based upon the portion of murine antibody portion in the MAb and their advantages and disadvantages are discussed further.

Another section talks about the methods of radiolabeling of monoclonal antibodies. Radiolabeling offers MAbs ability to be used as diagnostic agents in various diseases. Various

examples of monoclonal antibodies approved as drugs and diagnostic agents include ibritumomab tiuxetan (anticancer agent); Tc-99m arcitumomab (diagnostic imaging of

colorectal cancer); I-131 tositumomab (treatment of Hodgkin’s lymphoma).

2.5 Marketed therapeutic antibodies compendium (Janice M. Reichert, May/June 2012,

Landes Bioscience)

Therapeutic monoclonal antibodies are approved for marketing on a regular basis in countries

like United States, Europe and other regions. The publication talks about the 34 total monoclonal antibodies that were approved for marketing in 2012. It talks about the

classification of these antibodies by type, composition, regions where marketed, etc.

The author talks about the reasons of elimination of 6 out of 34 brands from the market. For

example, first approved MAb orthoclone OKT-3, a murine monoclonal antibody used for kidney graft rejection, its manufacturing was discontinued in 2010 due to availability of better

alternatives with similar efficacy and lesser side effects. Similarly, edrocolomab was approved in Germany in 1995 but was later withdrawn due to lack of efficacy.

2.6 Therapeutic Antibodies: Market considerations, disease targets and bioprocessing (John

G. Elvin, Ruairidh G. Couston, Christopher F. van der Walle, Dec 2011, International

Journal of Pharmaceutics)

The publication provides an overview of the monoclonal antibody market in 2011 and an outlook to 2015. The market has been discussed in the context of molecular targets and the

diseases in which they are to be used. According to the report, the pharmaceutical market in 2010 was $597 billion out of which 75% was of small molecules. 7% of the small molecules market was covered by monoclonal antibodies.



The sale of then marketed 25 monoclonal antibody products was $43 billion. Three-fourth of the revenue came from the top five products: bevacizumab (Avastin®); rituximab

(Rituxan®); adalimumab (Humira®); infliximab (Remicade®) and trastuzumab

(Herceptin®).

The author also talks about next generation formats of monoclonal antibodies which were in developmental phase then. Example includes Brentuximab Vedotin which is an antibody-drug conjugate directed to CD-30, a major marker for Hodgkin’s lymphoma and ALCL. Other

important development includes small antibody constructs such as Nanobodies® (Ablynx) or domain antibodies (Dabs). It possesses fully functional antibody that lack light chains. These

heavy chain antibodies contain a single variable domain and two constant domains.

Research Methodology 2016


Chapter 3

Need for the study, Objectives of the

study and Research Methodology



3.1 Need for the study

The pharmaceutical market is constantly changing leading to its highly dynamic nature. This

change is attributed to new diseases being discovered as well as changing attitude of

prescribers as well as patients i.e. customers and consumers. Nowadays, what they want are

the drugs that have least side effects and quick onset of action with longer duration of effects.

This unmet need led to a new group of drugs i.e. biologics which include the drugs

manufactured in a living system like microorganism, or plant or animal cells. Their market

growth has been ecstatic. According to an IMS report on global spending on medicines, by

2017 biologics will have an estimated sale of approximately 221 billion USD. Moreover, these

will cover 19-20% of the total pharmaceutical sales generated.

Figure 7: The biologics market

Monoclonal Antibodies are the newest players in the field of therapeutics and as we can see,

they have emerged as the topmost gainers. The products have been a blockbuster, for example,

Humira, Avastin, etc. According to a market research report from BCC Research, the

monoclonal antibodies segment should reach around 90 billion USD by 2017. This is more

than one-third of the total biologics sale that is expected in 2017 by IMS. It clearly shows the

importance the monoclonal antibodies hold in the biologics as well as the pharmaceutical

market.

Source: IMS Health, Thought Leadership, September 2013



Thus, an analysis of the global monoclonal antibody market will help us to have a closer look

on the developments that have taken place in this field and also the products that are due for

the future and new indications for which they will be targeted in the coming time.

3.2 Objectives of the Study

3.2.1 Primary Objective

To analyze the monoclonal antibody market in terms of products, both marketed and pipeline

and to analyze its potential in India

3.2.2 Secondary Objective

To find out the current status of monoclonal antibody products in present

pharmaceutical market

To track the growth of monoclonal antibody market since its inception

To analyze the marketed monoclonal antibody products in terms of their indications

and mechanism of action

To analyze the factors responsible for growth of the monoclonal antibody market

To assess the pipeline of companies to look for the monoclonal antibody products

being developed by them

To recommend initiatives to increase the penetration of monoclonal antibodies

3.3 Research Methodology

Type of Research- Exploratory Research

Method Used- Secondary Research

Common Research Objective- Model Building

Source of Data- E-books; Websites; Reports

The first step of the research was to decide the objectives of the research because the objective

was to decide the approach to be taken to fulfil those objectives. Thus, primary and secondary

objectives were lined out that paved the way for further research activities.

The two main objectives outlined are marketed products analysis and pipeline analysis of

monoclonal antibodies.

Marketed Products’ Analysis

A list of marketed products was obtained from a report titled, “The therapeutic

monoclonal antibody market (2015)” by Ecker, Dawn M., Jones, Susan Dana,

Levine, Howard L.



The marketed products were then looked for their indications and mechanism of

actions. This was done using the prescribing information available on United

States- Food and Drugs Administration website for each drug.

The sales revenue of each product for 2014 was collected using websites such

as www.statista.com; www.pmlive.com; etc.

All the collected data was then tabulated and then analyzed using charts and

graphs in excel.

Pipeline Products’ Analysis

The secondary search was done to look for the monoclonal antibody products

that are in pipeline in different companies.

The next step included collecting information about the pipeline products. For

this, websites like www.clinicaltrials.gov and www.adisinsight.com were used.

The data collected included product name, preferred name, phase of clinical

trial in which they are, their proposed indications and the company sponsoring

the trials.

The data was then analyzed using charts and graphs in excel. The data taken for

analysis included the drugs currently in clinical trial phases or that are pre-

registered or registered.

3.4 Limitations of the Study

Since the type of research is exploratory, we cannot use the study for decision making

Most of the companies have not mentioned their sales figure and other information for

financial year 2015-16. Thus, the data used for the research has been taken for the year

2014-15 or earlier

The monoclonal antibody market is still in an early phase in emerging countries. Thus,

the availability of data is limited when we compare emerging nations to that of

developed nations.

http://www.statista.com/

http://www.pmlive.com/

http://www.clinicaltrials.gov/

http://www.adisinsight.com/

Monoclonal Antibody Market 2016


Chapter 4

Monoclonal Antibody Market



4. Monoclonal Antibody Market

After the introduction of the first monoclonal antibody in the market in 1986, i.e. Orthoclone

OKT3 for kidney transplant rejection, the market for MAbs has considerably increased and has

a full potential for growth both in terms of sales and consumers in the coming years. The

products available today are able to cure a variety of diseases, ranging from a hundreds of

thousands of patients suffering from cancers, autoimmune disorders to a relatively orphan

disease such as cryopyrin associated periodic disorders, etc.

4.1 Growth of Monoclonal Antibody Market

The first monoclonal antibody came in the market in 1986. After its arrival, the growth of the

monoclonal antibody market was slow until the late 1990s when the first chimeric antibodies

were produced. The development further took place leading to the arrival of Humanized MAbs

and fully Human MAbs that accelerated the process of approval and enhanced the user base.

The increase in the customer base can be seen from the revenues generated in 2013. Global

sales revenue generated in 2013 was nearly $75 billion, representing approximately half of the

total sales of all biopharmaceutical products. Moreover, new areas of therapy are being

covered by the monoclonal antibodies leading to the expansion in terms of category of

products and the patients treated which will ultimately lead to a further growth in the sales of

monoclonal antibody products in the coming years.

When we look at the number of monoclonal antibody products approved every year, we see a

gradual increase in the number of approvals over the year. The number of products approved

for commercial sale in Europe and US has increased from one or two products in 90s to three

to 5 products approval a year now. A total of fifty-eight products have been approved for use

in US or Europe, but eleven of them were removed from the market for several reasons leaving

a total of forty-seven approved products for sale in the market.

Based on a review of historical success and turnover rates i.e. the time required for a drug to

move from one stage of development to next) of biopharmaceutical products under

development, approximately 26% of the products in phase 2 of clinical trials may achieve

market approval in a time span of approximately seven years. If we take an average number of

approvals to be four per year, then we can look at a number of seventy monoclonal antibody

products in the market by 2020.



0

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11

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20

13

20

14

20

15

No.

of

Produ

cts

appro

ved

Year of Approval

Number of monoclonal antibody product approvals per year

Products approved, but subsequently removed from the market

Mabs and Mab related products

*

Source: Page 10, Volume 7 Issue 1, Ecker, Dawn M., Jones, Susan Dana, Levine, Howard L.

The therapeutic monoclonal antibody market (2015)

Source for 2015 figure (*): www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm279174.html

Figure 8: Annual approval of monoclonal antibody products



6%

94%

Marketed MAb products

E.Coli

Mammalian Cell

4.2 Marketed Monoclonal Antibody Products

According to July 2015 edition of American Pharmaceutical Review, 47 monoclonal antibody

products are available globally for commercial sale globally. The characteristics of the

marketed products include:

Out of the 47 products, 3 products are produced in E.Coli. while other 44 products are

produced in mammalian cell culture

Mammalian cell culture products consist of 8 Fc fusion proteins, 2 antibody drug

conjugates, one radio-labelled conjugate; one Fab protein; one bi-specific antibody and

31 full length naked monoclonal antibody

Out of the three products produced in E.Coli, two are antigen binding fragments while

the third is an Fc fusion protein.

The list also includes the first biosimilar monoclonal antibodies approved in Europe,

Inflectra and Remsima.

Source: Page 9, Volume 7 Issue 1, Ecker, Dawn M., Jones, Susan Dana, Levine, Howard L.

The therapeutic monoclonal antibody market (2015)

Figure 9: Origin of MAb Products



Table 1: List of marketed monoclonal antibody products

S.No. Drug Original

BLA

applicant

Company

reporting US

sales

Class Indication Global

Sales

(2014)

($Mn) 1 Abthrax

(Raxibacumab)

Human

Genome Sciences

GlaxoSmithKline Inhalational anthrax Anthrax 53.25

2 Actemra

(Tocilizumab)

Roche Roche IL-6 receptor

antagonist

Rheumatoid

arthritis

1,224

3 Adcetris

(Brentuximab

vedotin)

Seattle

Genetics

Seattle Genetics CD-30 directed

antibody conjugate

Lymphoma 178.2

4 AlprolIX Biogen Idec Biogen Idec Coagulation Factor

IX (Recombinant),

Fc Fusion Protein

hemophilia B 40

5 Arcalyst

(Rilonacept)

Regeneron

Pharma

Regeneron

Pharma

IL-1 inhibitor Cryopyrin-

associated periodic

syndromes

(CAPS)

(Autoimmune)

17

6 Arzerra

(Ofatumumab)

GlaxoSmith

Kline

GlaxoSmithKline Anti CD-20 B cell lymphoma 85.7

7 Avastin (Bevacizumab)

Genentech Roche Anti VEGF colorectal cancer 7,018

8 Benlysta

(Belimumab)

Human

Genome Sciences

GlaxoSmithKline B-cell activating

factor inhibitor

Systemic lupus

erythematous

209.5

9 Cimzia

(Certolizumab

pegol)

UCB UCB Tumor necrosis

blocker factor

Rheumatic,

psoriatic arthritis

789 (2013)

10 Cyramza

(Ramucirumab)

Eli Lilly &

Co.

Eli Lilly & Co. A human vascular

endothelial growth

factor receptor 2 antagonist

Gastric, Non

small cell lung,

colorectal cancer

76

11 Eloctate Biogen Idec Biogen Idec [Antihemophilic Factor

(Recombinant), Fc

Fusion Protein

Prevent bleeding 58

12 Enbrel

(Etanercept)

Immunex Amgen Tumor necrosis

blocker factor

Psoriatic arthritis 8,915

13 Entyvio (Vedolizumab)

Takeda Pharma

Takeda Pharma Integrin receptor factor

Ulcerative colitis, Crohn's disease

255

14 Erbitux

(Cetuximab)

ImClone

Systems

Bristol-Myers

Squibb

Epidermal growth

factor receptor

antagonist

Head and neck

cancer, colorectal

cancer

2,257



15

Eylea

(Aflibercept)

Regeneron

Pharma

Regeneron

Pharma

Vascular endothelial

growth factor

inhibitor

Neovascular age

related macular

degeneration,

macular edema

following retinal vein occlusion,

diabetic

retinopathy

2,972

16 Gazyva

(Obinutuzumab)

Genentech Roche CD20-directed

cytolytic antibody

chronic

lymphocytic

lymphoma, follicular

lymphoma

49

17 Herceptin (Trastuzumab)

Genentech Roche HER2/neu receptor antagonist

HER2 overexpressing

breast cancer,

HER2-

overexpressing

metastatic gastric or

gastroesophageal

junction

adenocarcinoma

6,863

18 Humira

(Adalimumab)

Abbott

Laboratories

AbbVie Tumor necrosis

blocker factor

Rheumatoid

arthritis, juvenile

idiopathic

arthritis, psoriatic

arthritis, ankylosing

spondylitis,

Crohn's disease,

ulcerative colitis,

plaque psoriasis, Hidradenitis

Suppurativa

12,890

19 Ilaris

(Canakinumab)

Novartis

Pharma

Novartis Pharma interleukin 1-beta

blocker

Cryopyrin-

Associated

Periodic Syndromes

(CAPS), Active

Systemic Juvenile

Idiopathic

Arthritis (SJIA)

199

20 Inflectra

(Infliximab

biosimilar)

Hospira N/A Tumor necrosis alpha

factor inhibitors

Rheumatoid



spondylitis,

Crohn's disease,

ulcerative colitis,

plaque psoriasis

<1mn

(2013)

21 Kadcyla (ado-trastuzumab

emtansine)

Genentech Roche HER2-targeted antibody and

microtubule inhibitor

conjugate

HER-2 positive breast cancer

539.8



22 Keytruda

(Pembrolizumab)

Merck &

Co.

Merck & Co. Programmed death

receptor-1 (PD-1)-

blocking antibody

Metastatic

melanoma

55

23 Lemtrada

(Alemtuzumab)

Genzyme

Therapeutics

N/A CD52-directed

cytolytic antibody

B cell chronic

lymphoytic

lymphoma

3 (2013)

24 Lucentis

(Ranibizumab)

Genentech Roche Vascular endothelial

growth factor

inhibitor

Neovascular

(Wet) Age-

Related Macular

Degeneration

(AMD), Macular Edema Following

Retinal Vein

Occlusion

(RVO), Diabetic

Macular Edema (DME), Diabetic

Retinopathy in

patients with

DME

4,301

25 Nplate

(Romiplostim)

Amgen Amgen Thrombopoietin

receptor agonist

Chronic immune

thrombocytopenia

495

26 Nulojix

(Belatacept)

Bristol-

Myers Squibb

Bristol-Myers

Squibb

Selective T-cell

costimulation blocker

Prophylaxis for

organ rejection in kidney transplant

42

27 Orencia

(Abatacept)

Bristol-

Myers

Squibb

Bristol-Myers

Squibb

Selective T-cell

costimulation blocker

Adult rheumatoid

arthritis, juvenile

idiopathic arhritis

1,650

28 Perjeta

(Pertuzumab)

Genentech Roche HER2/neu receptor

antagonist

HER-2 positive

breast cancer

918

29 Prolia

(Denosumab)

Amgen Amgen RANK ligand

inhibitor

To increase bone

mass

1,482

30 Remicade

(Infliximab)

Centocor Johnson &

Johnson

Tumor necrosis

factor inhibitor

rheumatoid



spondylitis,

Crohn's disease,

ulcerative colitis,

plaque psoriasis

8,807

31 Removab

(Catumaxomab)

Fresenius

Biotech.

N/A Epithelial cell

adhesion molecule (EpCAM) and the

CD3 antigen inhibitor

EpCAM-positive

carcinomas

5 (2013)

32 Remsima

(Infliximab

Biosimilar)

Celltrion N/A Tumor necrosis

factor inhibitor

Rheumatoid


arthritis,

ankylosing

spondylitis, Crohn's disease,

ulcerative colitis,

plaque psoriasis

<1mn

(2013)



33 ReoPro

(Abciximab)

Centocor Lilly Platelet GPIIb/IIIa

receptor inhibitor

Prevention of

cardiac ischaemic

complications

111

34 Rituxan

(Rituximab)

Genentech Roche CD20-directed

cytolytic antibody

Non Hodgkins

lymphoma,

chronic lymphocytic

leukemia,

rheumatoid

arthritis

7,547

35 Simponi Aria

(Golimumab)

Centocor

Ortho

Biotech

Johnson &

Johnson

Tumor necrosis

factor inhibitor

Rheumatoid


arthritis,

ankylosing spondylitis,

Crohn's disease,

ulcerative colitis,

plaque psoriasis

1,876

36 Simulect

(Basiliximab)

Novartis

Pharma

Novartis Pharma Interleukin-2 receptor

alpha chain blocker

Prophylaxis for

organ rejection in

kidney transplant

110

37 Soliris (Eculizumab)

Alexion Pharma

Alexion Pharma Complement C5 inhibitor

Paroxysmal nocturnal

hemoglobinuria,

atypical

hemolytic uremic

syndrome

2,234

38 Stelara

(Ustekinumab)

Janssen-

Cilag

Pharma

Johnson &

Johnson

Human interleukin-

12 and -23 antagonist

Plaque psoriasis,

psoriatic arthritis

1,334

39 Sylvant

(Siltuximab)

Janssen

Biotech

Johnson &

Johnson

Interleukin-6 (IL-6)

antagonist

Multicentric

Castleman’s

disease (MCD)

who are human immunodeficienc

y virus (HIV)

negative and

human

herpesvirus-8 (HHV-8)

negative.

11

40 Synagis (Palivizumab)

Abbott Laboratories

Astra Zeneca Respiraatory Syncitial virus F-

protein inhibitor

Lower respiratory tract disease

caused by RSV

1,334

41 Tysabri (Natalizumab)

Biogen Idec Biogen Idec Integrin receptor factor antagonist

Multiple sclerosis, crohn's

disease

1,960

42 Vectibix

(Panitumumab)

Amgen Amgen Epidermal growth

factor receptor antagonist

Metastatic

colorectal cancer

672

43 Xgeva

(denosumab)

Amgen Amgen RANK ligand

inhibitor

Treatment of

hypercalcemia and bone

metastases in

solid tumors

2,411



13%

15%

11%

15%

4% 4%

6%

32%

Mechanism of Action Interleukin inhibitor

CD directed antibody

Anti-VEGF

TNF Blocker

Fc fusion protein

EGFR antagonist

HER2/neu receptorantagonistOthers

2 2 2 2 3 3 3 4 8

16

0

5

10

15

20

Nu

mber

of

Dru

gs

Company

44 Xolair

(Omalizumab)

Genentech Roche anti IgE antibody Asthma, chronic

idiopathic

urticaria

853

45 Yervoy

(Ipilumumab)

Bristol-

Myers

Squibb

Bristol-Myers

Squibb

Human cytotoxic T-

lymphocyte antigen 4

(CTLA-4)-blocker

Metastatic

melanoma

1,308

46 Zaltrap (ziv-

aflibercept)

Sanofi

Aventis

Sanofi Vascular endothelial

growth factor

inhibitor

Metastatic

colorectal cancer

92

47 Zevalin

(ibritumomab

tiuxetan)

IDEC

pharma

Spectrum Pharma CD20-directed

radiotherapeutic

antibody

Non-Hodgkin's

Lymphoma

22

When we carry out the analysis of the marketed monoclonal antibody products, we have following observations:

36%

43%

4% 17%

Indication

Cancer

Autoimmune

Graft

Rejection

Others

Figure 10: Marketed MAb products by mechanism of

action

Figure 11: Marketed MAb products by therapeutic

indication

Figure 12: Marketed MAb products by company



4.3 Status of monoclonal antibody products in pharmaceutical market

The global pharmaceutical market includes products belonging to different categories viz.

chemically synthesized, biological products and herbal products. The monoclonal antibody

products have made a special place among these products that can be seen from the sales

generated by these products.

When we look at the top 10 pharmaceutical products of 2014 by sales, we can see that six out

of top 10 products are monoclonal antibody products. The top selling product of 2014,

Humira is a monoclonal antibody product.

Table 2: Top 10 pharmaceutical products of 2014 (by sales)

Rank Product Generic Name

Company Pharmacological class

Worldwide

product

sales

(million $) in

2014

1 Humira Adalimumab AbbVie+Eisai Anti-TNF MAb 12,890

2 Sovaldi Sofosbuvir Gilead Sciences

Hepatitis C nucleoside

NS5B polymerase

inhibitor

10,283

3 Enbrel Etanercept Amgen+Pfizer+Tak

eda TNF-alpha inhibitor 8,915

4 Remicade Infliximab J&J+Merck

&Co.+Mitsubishi TNF-alpha inhibitor 8,807

5 Lantus Insulin glargin

recombinant Sanofi Insulin analogue 8,428

6 Rituxan Rituximab Roche Anti-CD20 MAb 7,547

7 Seretide

fluticasone

propionate;

salmeterol

xinafoate

GSK+Almirall+Faes Beta-2 adrenoceptor

agonist+corticosteroids 7,058

8 Avastin Bevacizumab Roche Anti-VEGF MAb 7,018

9 Herceptin Trastuzumab Roche Anti-HER2 MAb 6,863

10 Januvia Sitagliptin

phosphate

Merck & Co + Ono

+ Daewoong +

Sigma-Tau +

Almirall

Dipeptidyl peptidase IV

(DPP-IV) inhibitor 6,358

Source: Pg 63, Evaluate Pharma, World Preview 2015, Outlook to 2020, (2015)



39%

43%

15%

2% 1%

Phase of Development

Phase 1

Phase 2

Phase 3

Pre registration

Registered

52%

18%

5%

25%

Therapeutic Indications

Cancer

Autoimmune

hypersensitivity

Others

4.4 Pipeline product analysis of monoclonal antibody products

As discussed earlier, there are a lot of monoclonal antibody products which are under

development. Some are in discovery stage, some in preclinical, while some are in human

clinical trial stage. The scope of study for the project has been kept limited to clinical trial

stage drugs and those which are in pre-registration phase or are registered.

An analysis of the drugs in pipeline belonging to different companies and prescribed for

different diseases gives us the following results:

phase of development No. of drugs

Phase 1 168

Phase 2 183

Phase 3 63

Pre-registration 9

Registered 3

Total 426

Indications No. of drugs

Cancer 221

Autoimmune 77

hypersensitivity 23

Others 105

Figure 13: Pipeline MAb products by phase of

development

Figure 14: Pipeline MAb products by therapeutic

indications

Table 3: No. of pipeline drugs by phase of

development

Table 4: No. of pipeline drugs by

indications



Table 5: Pipeline monoclonal antibody products for Cancer: Phase 3, pre-registration and

registered

S.No.

Preferred

Name Product Name Phase of Development Company

1 ABP 494 cetuximab Phase 3 Amgen

2 ABP 798 rituximab Phase 3 Amgen

3 APN 311 Apeiron Phase 3 Apeiron; Endo; Gen Ilac; Medison Pharma

4 MPDL 3280A atezolizumab Phase 3 Roche

5 MSB0010718C avelumab Phase 3 Merck KGaA; Pfizer

6 bavituximab bavituximab Phase 3

MD Anderson Cancer Center; Peregrine; University of Texas Southwestern; University of Texas System

7 BCD 021 bevacizumab biosimilar

Phase 3 Biocad

8 BCD 022 trastuzumab Phase 3 Biocad

9 ABP 215 bevacizumab Phase 3 Allergan; Amgen

10 BI 695500 rituximab Phase 3 Boehringer Ingelheim

11 BI 695502 bevacizumab Phase 3 Boehringer Ingelheim

12 MK0646 dalotuzumab; Phase 3 Merck & Co; Pierre Fabre

13 MEDI4736 durvalumab Phase 3 AstraZeneca; Celgene; MedImmune

14 BMS 901608 elotuzumab Registered AbbVie; Bristol-Myers Squibb

15 AMG 412 epratuzumab Phase 3 Immunomedics; UCB

16 MORAb 003 farletuzumab Phase 3 Eisai; Ludwig Institute for Cancer Research; Morphotek

17 WX-G 250 girentuximab Phase 3 Esteve; Janssen Biotech; Johnson & Johnson; Wilex

18 GP 2013 rituximab Phase 3 Novartis

19 PF 5208773 inotuzumab ozogamicin

Phase 3 Pfizer; UCB

20 MABp1 MAb, IL-1 alpha, Xbiotech

Phase 3 XBiotech



21 CAT 8015 moxetumomab pasudotox

Phase 3

AstraZeneca; MedImmune; National Cancer Institute; National Institutes of Health

22 NEOD 001 MAb, amyloid AL/AA

Phase 3 Prothena

23 AMG 888 patritumab Phase 3 Amgen; Daiichi Sankyo

24 PF 05280014 trastuzumab Phase 3 Pfizer

25 PF 06439535 bevacizumab Phase 3 Pfizer

26 PROXINIUM oportuzumab monatox;

Phase 3 Viventia Biotech

27 ABP 980 trastuzumab, Synthon

Phase 3 Allergan; Amgen; Synthon

28 AMG 386 Trebananib Phase 3 Amgen; Takeda

29 CP 675206 Tremelimumab Phase 3 AstraZeneca; MedImmune; Pfizer

30 TGTX 1101 Ublituximab Phase 3 ILDONG; LFB; TG Therapeutics

31 VICINIUM oportuzumab monatox;

Phase 3 Viventia Biotech

32 90Y-hPAM4 yttrium (90Y) clivatuzumab tetraxetan

Phase 3 Immunomedics

33 HuMax-CD38 Daratumumab Registered Genmab; Janssen; Johnson & Johnson

34 LY3012211 Necitumumab Registered Bristol-Myers Squibb; ImClone Systems; Lilly

35 ch14.18-UTC Dinutuximab Registered

National Cancer Institute; National Institutes of Health; United Therapeutics

36 HERZUMA Trastuzumab Registered Celltrion; Nippon Kayaku; VaxGen

37 CNTO 328 Siltuximab Registered Johnson & Johnson



Table 6: Pipeline monoclonal antibody products for Auto-immune diseases: Phase 3, pre-

registration and registered

S.No. Preferred Name Product Name Phase of Development Company

1 ABP 501 Adalimumab Pre-registration Amgen

2 BI 695501 Adalimumab Phase III Boehringer Ingelheim

3 XOMA 052 gevokizumab Phase III Servier; XOMA

4 GP 2017 Adalimumab Phase III Novartis

5 CNTO 1959 Guselkumab Phase III Janssen; Johnson & Johnson; MorphoSys

6 NI 071 Infliximab Phase III Aprogen; Nichi-Iko; Sanofi

7 RG 1594 Ocrelizumab Phase III Biogen; Genentech; Roche

8 PF 06438179 Infliximab Phase III Pfizer

9 SAR 153191 Sarilumab Phase III Regeneron; Sanofi

10 CNTO 136 Sirukumab Phase III GlaxoSmithKline; Janssen Biotech; Johnson & Johnson

11 SCH 900222; MK 3222

tildrakizumab Phase III Merck & Co; Sun Pharma

12 LY 2439821 Ixekizumab Pre-registration Lilly



Table 7: Pipeline monoclonal antibody products for Hypersensitivity disorders: Phase 3,

pre-registration and registered

S.No. Preferred Name Product Name Phase of Development Company

1 MEDI 563 benralizumab Phase III AstraZeneca; BioWa; Kyowa Hakko Kirin; MedImmune

2 REGN 668 Dupilumab Phase III Regeneron; Sanofi

3 RG 3637; MILR 1444A

Lebrikizumab Phase III Chugai; Roche

4 CAT 354 Tralokinumab Phase III AstraZeneca; MedImmune

5 SB 240563 mepolizumab Pre-registration GlaxoSmithKline

6 CEP 38072 Reslizumab Pre-registration Merck & Co; Teva; UCB



4.5 Potential of monoclonal antibodies in India

India, due to its large patient base and growing economy has always been an attractive market

for the drug manufacturers. Among all the countries that fall under the hood of developing

countries, India is one of the biggest and advanced. A number of factors like abundant

manpower, low R&D cost, huge population available for clinical trials make India a good

opportunity for any pharmaceutical firm.

Deloitte in its report titled, “Winning with Biosimilars- Opportunities in Global Market”

evaluated the developed markets of US, EU5 and Japan, and emerging markets like BRICS

(Brazil, Russia, India, China and South Africa) and MIST (Mexico, Indonesia, South Korea

and Turkey) to analyze the potential for growth of biologics in these markets in the near future.

Figure 15: Summary of cross country analysis

Source: Pg-5, Winning with Biosimilars: Opportunities in Global Market (Deloitte)



The analysis focused on six dimensions:

Access to affordable biologics

Regulatory assessment

Payer assessment

Prescriber acceptance

Patient Acceptance

Biosimilars presence

In this report, all the six factors have been discussed in context of India and an analysis of

these factors has been done to look for the potential for biologics, in particular, monoclonal

antibodies, in a country like India.

(A) Access to affordable Biologics

Affordability is a big concern for a developing country like India. In its analysis, Deloitte

has given poor access status to India.

According to statisticstimes.com, the annual per capita income of people in India in

2015 was Rs 87, 748 which is on the lower side compared to the international

standards of per capita income.

Moreover, when we look at the healthcare expenditure in India in 2015, it comes

out to be 120 USD annually. (Source: Budget 2015: In search of an effective

healthcare system; Financial Express: April 9, 2015). If we take the exchange rate

of Dollar and Rupee at that time, then the amount comes out to be approximately

Rs 7500 which is a minimal 8.5% of the income. These figures show that the

purchasing power of people in India is still lower compared to the global standards.

The third and the most important aspect is the price of the biologics, taking

monoclonal antibodies in consideration. The prices are very high and most of the

monoclonal antibody products are out of reach of a common patient. Following are

the prices of some of the MAb products available in India:

o Humira- 1000 USD per vial i.e. approximately Rs 67,520 per vial

o Herceptin- Rs 124000 for 440 mg injection

o Remicade- Rs 41039 for 100 mg injection

o Enbrel- Rs 17170 for 50 mg injection

o Lucentis- Rs 75000 for 0.5 mg injection

o ReoPro- Rs 21552 for 10 mg injection

(Source: www.1mg.com)



People in India who spend around Rs 7500 on an average on healthcare cannot

afford monoclonal antibody products, of which the price of one dose is more than

twice of the annual healthcare expenditure of the people.

(B) Regulatory Environment for Biologics in India

In India, the approval process of biologics is governed by a single body called DCGI i.e.

Drug Controller General of India. There are a number of statutory bodies associated with

the approval process namely:

Genetic Engineering Approval Council (GEAC)

Recombinant DNA Advisory Committee (RDAC)

Review Committee on Genetic Manipulation (RCGM)

Institutional Biosafety Committee (IBSC)

State Biosafety Coordination Committees (SBCC)

District Level Committees (DLC)

The process of approval of biologics involves following steps:

Application processing by RCGM

Examination of Data by DCG(I) advisory committee (Scientific, Biosafety and Ethical Issues)

Clearance for Phase I trial by DCG(I)

Examination of Phase I clinical trial data by DCG(I)

Clearance for Phase II trial by DCG(I)

Examination of Phase II clinical trial data by DCG(I)

Clearance for Phase III trial by DCG(I)

Examination of Phase III clinical trial data by DCG(I)

Clearance for manufacturing activity by DCG(I)

GEAC/DCG(I)/State Drug Controller

Clearance and regular maintenance for manufacturing activity in State



As stated by Deloitte in its analysis, India is one of the few countries that has a well-

developed biologics approval framework. This is a good thing for the monoclonal antibody

companies as the approval process and the authorities are well defined and there is an

established hierarchy for several steps in the approval. It prevents confusion and establishes

confidence in the companies for the country.

(C) Payer Assessment

Unlike the developed countries like United States of America and European Union, the

healthcare expenditure in India is not funded by the Government. Majority of the

healthcare expenditure is borne by the patients.

According to KPMG report on Union Budget Healthcare, in spite of the growing

population and disease burden, gross domestic product (GDP) spending on healthcare

has been slightly over 4%. Low levels of public expenditure on healthcare which

stands at approximately 33% of the total healthcare spending is leading to the burden

of high out of pocket expenditure.

A report of Bain and Company on “India Healthcare Roadmap 2025”, 75% of the total

population in India is without health insurance.

The health insurance sector in India is on a rise. According to CRISIL’s report on

Indian Insurance Industry, the total premium increased from Rs 3,999 crore in 2006-07

to Rs 19,677 crore in 2013-14. This growth is further expected to increase which is a

positive sign when we look at the staggering amount patients are to bear out of their

pockets.

All these points lead to one conclusion that majority of the population which is not

covered by health insurance have to bear the cost of the medicines and treatment all by

themselves. This discourages them to go for expensive products like monoclonal

antibodies and opt for the less expensive conventional products available in the market.

(D) Prescriber Acceptance

In India, sale of biologics could be significant but are usually blocked by high out of

pocket expenses and consumers’ low ability to pay.

In India, a Deloitte survey found out that physicians were willing to prescribe

biologics as first line therapy, if it was offered at a 60-70% discount. This shows an

alignment of physicians towards the biologics. So, if in future the development in

technology could lower the cost of these products, they have a high potential in

Indian market.



On the other hand, the prescriber acceptance for similar biologics is not that good.

According to an article “Safety concerns limit similar biologics uptake in India”,

posted on 26th Feb, 2016 on Gabionline, some physicians remain skeptical with

regards to the safety and efficacy of similar biologics and are slow to adopt these

drugs. Although patients, physicians, insurance providers and the Indian

Government are attracted by the cost savings offered by similar biologics compared

to originator biologicals, there remain concerns regarding the safety, efficacy and

quality of these products.

(E) Patient Acceptance

Treatment rate for flagship biologics is still low as compared to the developed countries

despite the existing demand. Majorly two factors contribute to the limited patient

acceptance for the products:

An average patient in India is not able to afford the products. As stated above, the

average annual spending on healthcare per capita stands at around Rs 7500. An

average biologic product costs more than Rs 10,000 per vial which is out of bounds

for the patients.

Another factor is that unlike the developed countries where the healthcare costs are

borne by third party payers, in India, majority of the cost is borne by patients which

limit them to buy them the expensive biologic products. Only 25% of the

population has health insurance while the rest pay their own bills. This fact along

with the low purchasing power refrains patients from accepting the biologics.

(F) Biosimilars Presence

India has a strong presence of biosimilars. According to an article on

corporatelivewire.com, the Indian market accounts for about 60 approved biologics today,

of which more than half are Biosimilars. The sale was expected to expand at a 14.5%

compounded annual rate through 2020 according to a Livemint report.

By 2016, there are 12 biosimilars of monoclonal antibodies approved for sale in India.

Major companies involved in the manufacturing include Reliance Life Sciences, Torrent

pharmaceuticals, Biocon, Zydus Cadila, Intas Pharmaceuticals, etc.

A list of marketed biosimilars of monoclonal antibodies was obtained from gabionline.net

and the data was tabulated. The price of the products in India was obtained from

www.1mg.com and was added in the table.



S.No. Product

Name

Active

Substance Therapeutic Area

Launch Date

in India Company Price (in Rs)¹*

1 AbcixiRel abciximab Angina, Cardiac ischemia 23-Apr-13 Reliance Life

Sciences 8100 for one vial

2 Adfrar adalimumab

Ankylosing spondylitis,

Plaque psoriasis, Psoriatic

arthritis, Rheumatoid arthritis,

Ulcerative colitis

11-Jan-16 Torrent

Pharmaceuticals

Price Not

Available

3 CanMab trastuzumab Breast cancer 23-Oct-13 Biocon 57500 for 440 mg

1 ml injection

4 Exemptia adalimumab Rheumatoid arthritis 25-Sep-14 Zydus Cadila 25000 for 40 mg

prefilled syringe

5 Infimab infliximab


Crohn’s disease, Psoriasis,

Psoriatic arthritis, Rheumatoid

arthritis, Ulcerative colitis

15-Sep-14 Epirus

Biopharmaceutical

32000 for 100 mg

injection in vial

6 Intacept etanercept


Juvenile idiopathic arthritis

Psoriasis, Psoriatic arthritis,

Rheumatoid arthritis

10-Mar-15 Intas

Pharmaceuticals

10000 for 50

mg/1ml injection

vial

7 Maball rituximab Lymphoma, Non-Hodgkin’s

Lymphoma 03-Feb-15 Hetero Group

42950 for 500 mg

injection

8 MabTas rituximab Lymphoma, Non-Hodgkin’s

Lymphoma 26-Feb-13

Intas

Pharmaceuticals

37500 for 50 ml

injection in vial

9 Razumab ranibizumab

Wet macular degeneration,

Macular edema, Degenerative

myopia, Diabetes

complications

19-Jun-15 Intas

Pharmaceuticals

Price Not

Available

10 Reditux rituximab Leukaemia, Lymphoma,

Rheumatoid arthritis 30-Apr-07

Dr. Reddy’s

Laboratories

39996 for 50 ml

injection in vial

11 Rituximab rituximab Non-Hodgkin’s Lymphoma,

Rheumatoid arthritis 12-Feb-15

Reliance Life

Sciences

Price Not

Available

12 Rituximab rituximab Non-Hodgkin’s Lymphoma 27-Feb-13 Zenotech

Laboratories

Price Not

Available

Source: http://www.gabionline.net/Biosimilars/General/Similar-biologics-approved-and-marketed-in-India

Source *1: www.1mg.com

Table 8: List of monoclonal antibody biosimilar marketed in India

Findings and Recommendations 2016


Chapter 5

Findings and Recommendations



5.1 Key Findings

The global pharmaceutical market is growing with each year and is under a gradual change in

terms of products. The biologics class of drugs are dominating the arena and are gaining a

major share out of the total sale of the products. Based on the analysis of the market, we can

list down the major findings:

Growth in the Sale

The monoclonal antibody market is growing every year. The sales data shows a

considerable increase in the revenue generated by them over the year. The global sale of

monoclonal antibody product in 2006 was 26 billion USD that increased 3 times in 7 years

to approximately 75 million USD in 2013. With time, monoclonal antibody products are

expected to cover new indications other than the conventional ones i.e. Cancer, Auto-

immune and Hypersensitivity which will not only increase its customer base but also

expand its horizon and market share in the existing industry.

Blockbuster Products in the Market

At present, there are 47 products in the market which are for different indications and have

different mechanisms of action. According to the global sales data of 2014, six out of top

ten drugs by revenue belong to monoclonal antibody class of products. Humira, with its

sales of about 13,000 million USD outweighs any other drug by a margin of millions.

Moreover, according to a report of Evaluate Pharma, many of the monoclonal antibody

products will grow at a tremendous rate in terms of revenue by 2020. Opdivo is expected

to grow at a CAGR of 156% that can take its sale from 29 million USD in 2014 to more

than 8,000 million USD in 2020. (Source: Pg 63, Evaluate Pharma, World Preview 2015,

Outlook to 2020, (2015))

Auto-immune and Oncology dominate the segment

Of the total 47 marketed products, 80% products are for different types of cancers and

auto-immune disorders. Different types of cancers for which the monoclonal antibodies are

prescribed today include lymphoma, gastric cancer, colorectal cancer, breast cancer,

melanomas, non-small cell lung cancer, etc. Different auto-immune disorders treated by

these products include rheumatoid arthritis, lupus, ankylosing spondylitis, Wegener’s

Granulomatosis, etc. Majority of the drugs in pipeline are for these two conditions.



Rich Pipeline of Products

There are around 800 monoclonal antibody products in pipeline out of which 426 are in

clinical trials or approved while others are in pre-clinical or discovery phase. These have

different mechanisms of action and some have new indications apart from the conventional

indications.

5.2 Recommendations

Though the monoclonal antibody market is in the growth stage of its life cycle, still there is a scope of improvement in every aspect. Moreover, there are some issues that need to be taken

care of to continue the speed of growth.

Some of the recommendations based on the study include:

(a) Cover new diseases

There are a lot of new diseases which are upcoming these days e.g. Ebola infection, Bird

Flu, etc. Moreover there are other diseases for which the treatment is either not available or if available, is highly dangerous e.g. African sleeping sickness, Polio, AIDS. At the

moment, monoclonal antibody products are mainly targeted towards cancer and auto-immune diseases which is giving them a good growth. But, there is always a scope of expansion across different fields which can provide them a competitive edge.

(b) Coming up with more biosimilars

As seen in the market study, biosimilars are well accepted globally. Their lesser cost

compared to the originator product makes them a good choice for manufacturers as well as

payers. By 2020, a large number of monoclonal antibody products will go off patent.

Development of the biosimilar version of these products will provide the customers with a

less expensive alternative to the patients leading to the growth of the monoclonal antibody

market as a whole.

(c) Reducing the cost of monoclonal antibody products

The major problem with the acceptance of the monoclonal antibody products in the

developing countries has been the high price of the monoclonal antibody products. Patients

are not able to afford the costly drugs. The demand is present in these countries but is

blocked by the price. Thus, the emerging markets may serve as the good opportunities to

the monoclonal antibody products due to their high population, if the price of the products

can be brought to a lower level by the companies.

References 2016


References

References 2016


Bibliography

Bain & Company (2015) India Healthcare Roadmap 2025

Beck, Alain; Wurch, Thierry; Bailly, Christian; Corvaia, Nathalie (2010) Strategies and

challenges for the next generation of therapeutic antibodies. http://eclass.uoa.gr/modules/document/file.php/BIOL177/%CE%A3%CE%95%CE%9C%CE

%99%CE%9D%CE%91%CE%A1%CE%99%CE%91%202011-2012/Gaitanaki%201.pdf

Challener, Cynthia (2014) Monoclonal antibodies key to unlocking the biosimilars market.

Available from http://www.biopharminternational.com/monoclonal-antibodies-key-unlocking-biosimilars-market

Ecker, Dawn M.; Jones, Susan Dana; Levine, Howard L. (2015) The therapeutic monoclonal antibody market.

Available from http://www.tandfonline.com/doi/full/10.4161/19420862.2015.989042

Elvin, John G.; Couston, Ruairidh G.;Van Der Walle, Christopher F. (2013) Therapeutic

antibodies: Market considerations, disease targets and bioprocessing. Available from http://www.ncbi.nlm.nih.gov/pubmed/22227342

Evaluate Pharma (2015) World Preview 2015, Outlook to 2020. Available from http://info.evaluategroup.com/rs/607-YGS-364/images/wp15.pdf

Ghosh, Shyamasree; Ansar, Waliza (2013) Monoclonal Antibodies: A Tool in Clinical Research. Available from

http://www.la-press.com/redirect_file.php?fileId=5099&filename=3781-IJCM-Monoclonal-Antibodies:-A-Tool- in-Clinical-Research.pdf&fileType=pdf

India Brand Equity Foundation Formula of Success: Emerging Trends in Biosimilars in India

IMS Health (2016) A report on Delivering on the Potential of Biosimilar Medicines: The Role

of functioning competitive market Krishnan, Anita; Mody, Rustom; Malhotra, Hemant (2015) Global regulatory landscape of

biosimilars: emerging and established market perspectives. Available from https://www.dovepress.com/global-regulatory-landscape-of-biosimilars-emerging-and-

established-ma-peer-reviewed-fulltext-article-BS

Mc Kinsey & Company (2012) India Healthcare: Inspiring possibilities, challenging journey

Reichert, Janice M. (2012) Marketed therapeutic antibodies compendium.

Available from http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3355480/

References 2016


Rob Jacobey; Erik Smith; Drew Wilkins; Divya Iyer; Sophie Peltre (2015) Winning with Biosimilars: Opportunities in Global Markets. Available from http://www2.deloitte.com/content/dam/Deloitte/us/Documents/life-sciences-health-care/us-

lshc-biosimilars-whitepaper-final.pdf

Srikanth Reddy (Oct 2015) CRISIL’s latest report on Indian Insurance Industry- Details and

Review

Websites Referred:

www.ncbi.nlm.nih.gov

www.gabionline.net

www.statista.com

www.1mg.com

www.medindia.com

www.drugs.com

www.fda.gov

www.accessdata.fda.gov

www.clinicaltrials.gov

www.news.mims.com

www.pmlive.com

www.evaluategroup.com

Websites of Roche, Human Genome Sciences, Seattle Genetics, Biogen Idec, Regeneron

Pharma, GlaxoSmithKline, Genentech, Eli Lily, Bristol Myers Squibb, AbbVie, Novartis,

Amgen, Genzyme, Janssen.

Annexure/s 2016


Annexure/s

Annexure/s 2016


Information on the monoclonal antibody products among top 10 drugs by

sales in 2014:

Rank 1: HUMIRA (Adalimumab) Sales (2014): 12,890 million

USD

Form: Humira (Adalimumab) injection, for subcutaneous use

Mechanism of action: Humira is a Tumor Necrosis Factor blocker

Indications:

Rheumatoid Arthritis: Reducing signs and symptoms; inhibition of progression of structural

damage and improving physical function in adult patients

Juvenile Idiopathic Arthritis: Reducing signs and symptoms in patients 2 years age and older

Psoriatic Arthritis: Reducing signs and symptoms; inhibition of progression of structural


Ankylosing Spondylitis: Reducing signs and symptoms

Adult Crohn’s Disease: Reducing signs and symptoms and maintain clinical remission in

patients having inadequate response to conventional therapy

Pediatric Crohn’s Disease: Reducing signs and symptoms and maintain clinical remission in

patients 6 years of age or younger and not responding to conventional therapy

Ulcerative Colitis: Inducing and sustaining clinical remission in patients showing inadequate

response to conventional therapy

Plaque Psoriasis: Treatment of patients with moderate to serious conditions who are

candidates for systemic therapy or phototherapy

Hidradenitis Suppurativa: Treatment of moderate to severe condition

Dosage and Administration:

Administered by subcutaneous injection

Rheumatoid Arthritis; Psoriatic Arthritis and Ankylosing Spondylitis: 40 mg every other

week

Juvenile Idiopathic Arthritis: 10 kg to <15 kg: 10 mg every other week; 15 kg to <30 kg: 20

mg every other week; >30 kg: 40 mg every other week

Adult Crohn’s Disease and Ulcerative Colitis: Initial dose (Day 1): 160 mg; Second Dose

(Day 15): 80 mg; (Day 29): Maintenance dose of 40 mg

Annexure/s 2016


Pediatric Crohn’s Disease: 17 kg to <40 kg: (Day 1): 80 mg; (Day 15): 40 mg; (Day 29):

Maintenance dose of 20 mg. For children >40 kg give the adult dose

Plaque Psoriasis: 80 mg initial dose followed by 40 mg every other week starting one week

after the initial dose

Hidradenitis Suppurativa: Same as in Adult Crohn’s Disease

Contraindications: None

Adverse Reactions: Infections, injection site reactions, headache and rash

Rank 3: Enbrel (Etanercept) Sales (2014): 8,915 million

USD

Form: Enbrel (Etanercept) is a solution for subcutaneous use

Mechanism of action: Enbrel is a Tumor Necrosis Factor blocker

Indications:



Polyarticular Juvenile Idiopathic Arthritis: Reducing signs and symptoms in patients 2

years age and older









Enbrel is administered by subcutaneous injection.

Adult Rheumatoid Arthritis and Psoriatic Arthritis: 50 mg once weekly with or without

methotrexate

Annexure/s 2016


Ankylosing Spondylitis: 50 mg once weekly

Adult Plaque Psoriasis: 50 mg twice weekly for 3 months, followed by 50 mg once weekly

Juvenile Idiopathic Arthritis: 0.8 mg/kg weekly, with a maximum of 50 mg per week

Contraindications: Sepsis

Adverse Reactions: Infections; Injection site reactions

Rank 4: Remicade (Infliximab) Sales (2014): 8,807 million

USD

Form: Remicade (Infliximab) is a lyophilized concentrate for injection, for intravenous use

Mechanism of Action: Remicade is a Tumor Necrosis Factor blocker.

Indications:



Juvenile Idiopathic Arthritis: Reducing signs and symptoms in patients 2 years age and older






Pediatric Crohn’s Disease: Reducing signs and symptoms and maintain clinical remission in

patients 6 years of age or younger and not responding to conventional therapy

Ulcerative Colitis: Inducing and sustaining clinical remission in patients showing inadequate

response to conventional therapy



Annexure/s 2016



Administered by Intravenous infusion over a period of not less than 2 hours

Crohn’s Disease: 5mg//kg at 0, 2 and 6 weeks, then every 8 weeks

Pediatric Crohn’s Disease: 5 mg/kg at 0, 2 and 6 weeks, then every 8 weeks

Ulcerative Colitis: 5mg//kg at 0, 2 and 6 weeks, then every 8 weeks

Pediatric Ulcerative Colitis: 5mg//kg at 0, 2 and 6 weeks, then every 8 weeks

Psoriatic Arthritis and Plaque Psoriasis: 5mg//kg at 0, 2 and 6 weeks, then every 8 weeks

Ankylosing Spondylitis: 5mg//kg at 0, 2 and 6 weeks, then every 6 weeks

Rheumatoid Arthritis: In conjunction with methotrexate, 3 mg/kg at 0, 2 and 6 weeks, then

every 8 weeks

Contraindications: Doses more than 5 mg/kg should not be given in moderate to severe heart

failure; previous hypersensitivity to Remicade

Adverse Reactions: Infections, Infusion related reactions, headache and abdominal pain

Rank 6: Rituxan (Rituximab) Sales (2014): 7,547 million

USD

Form: Rituxan (Rituximab) injection, for intravenous use

Mechanism of Action: Rituxan is a CD-20 directed cytolytic antibody

Indications:

Non-Hodgkin’s Lymphoma: Treatment of patients with relapsed, refractory, low grade or

follicular, CD-20 directed, NHL in combination with first line therapy or as a single agent

Chronic Lymphocytic Leukemia: For the treatment of previously untreated and previously

treated CD-20 positive CLL in combination with fludarabine and cyclophosphamide

Rheumatoid Arthritis: Treatment of moderately to severely active RA in combination with

methotrexate

Wegener’s Granulomatosis and Microscopic Polyangiitis: Treatment of adult patients in

combination with glucocorticoids

Annexure/s 2016



Rituxan is administered only as an intravenous infusion.

Non-Hodgkin’s Lymphoma: 375 mg/m2

Chronic Lymphocytic Leukemia: 375 mg/m2

in the first cycle and 500mg/m2 in cycles 2-6 in

combination with fludarabine and cyclophosphamide administered every 28 days

Rheumatoid Arthritis: Two 1000 mg intravenous infusions separated by two weeks every 24

weeks with methotrexate

Wegener’s Granulomatosis and Microscopic Polyangiitis: 375 mg/m2

once weekly for 4

weeks


Adverse Reactions:

Non-Hodgkin’s Lymphoma: infusion reactions, fever, chills, lymphopenia, infection

Chronic Lymphocytic Leukemia: Infusion reactions and neutropenia

Rheumatoid Arthritis: Upper respiratory tract infection, nasopharyngitis, urinary tract

infection, bronchitis

Wegener’s Granulomatosis and Microscopic Polyangiitis: infections, nausea, diarrhea,

headache, muscle spasms, anemia, peripheral edema

Rank 8: Avastin (Bevacizumab) Sales (2014): 7,018 million

USD

Form: Avastin (Bevacizumab) is a solution for intravenous infusion

Mechanism of Action: Avastin is a vascular endothelial growth factor-specific angiogenesis

inhibitor

Indications:

Metastatic colorectal cancer: With intravenous 5-flurouracil based chemotheraoy for first or

second line chemotherapy

Metastatic colorectal cancer: With fluropyrimidine-irinotecan or fluoropyrimidine-oxaliplatin

based chemotherapy for second line treatment

Annexure/s 2016


Non squamous non-small cell lung cancer: With carboplatin and paclitaxel for first line

treatment

Glioblastoma: Single agent for adult patients

Metastatic renal cell carcinoma: With interferon alfa


Avastin is for intravenous use but should not be given as an IV push or bolus

Metastatic colorectal cancer: 5 mg/kg IV every two weeks with bolus-IFL; 10 mg/kg IV

every two weeks with FOLFOX-4; 5 mg/kg IV every two weeks or 7.5 mg/kg every three

weeks With fluropyrimidine-irinotecan or fluoropyrimidine-oxaliplatin

Non squamous non-small cell lung cancer: 15 mg/kg IV every three weeks with

carboplatin/paclitaxel

Glioblastoma: 10 mg/kg IV every two weeks

Metastatic renal cell carcinoma: 10 mg/kg IV every two weeks with interferon alfa


Adverse Reactions: Epistaxis, headache, hypertension, rhinitis, proteinuria, taste alteration,

dry skin, rectal hemorrhage, lacrimation disorder, back pain and exfoliative dermatitis

Rank 9: Herceptin (Trastuzumab) Sales (2014): 6,863 million

USD

Form: Herceptin (Trastuzumab) is an intravenous infusion

Mechanism of Action: Herceptin is a HER2/neu receptor antagonist

Indications:

Adjuvant Breast Cancer: Treatment of HER2 overexpressing node positive or node negative

breast cancer either with doxorubicin, cyclophosphamide; or with docetaxel and carboplatin; or

as a single agent

Metastatic Breast Cancer: Treatment of HER2 overexpressing breast cancer either single or

in combination with paclitaxel

Annexure/s 2016


Metastatic Gastric Cancer: Treatment of HER2 overexpressing metastatic gastric or

gastroesophageal junction adenocarcinoma in combination with cisplatin or capecitabine or 5-

fluorouracil


Herceptin is for IV use only and must not be given as an IV push or a bolus.

Adjuvant Treatment of HER2-overexpressing Breast Cancer: Initial dose of 4 mg/kg over

90 minute IV infusion, then 2 mg/kg over 30 minute IV infusion weekly for 52 weeks OR

Initial dose of 8 mg/kg over 90 minutes IV infusion, then 6 mg/kg over 30-90 minutes IV

infusion every 3 weeks for 52 weeks

Metastatic HER2-Overexpressing Breast Cancer: Initial dose of 4 mg/kg over 90 minute IV

infusion, then 2 mg/kg over 30 minute IV infusion

Metastatic HER2-Overexpressing Gastric Cancer: Initial dose of 8 mg/kg over 90 minutes

IV infusion, then 6 mg/kg over 30-90 minutes IV infusion every 3 weeks


Adverse Reactions:

Adjuvant Breast Cancer: Headache, Diarrhea, Nausea and Chills

Metastatic Breast Cancer: Fever, Chills, Headache, Infections, Congestive heart failure,

Insomnia, Cough and Rash

Metastatic Gastric Cancer: Neutropenia, Diarrhea, Fatigue, Anemia, Stomatitis, Weight loss,

Upper respiratory tract infections, Fever, Thrombocytopenia, Mucosal inflammation,

Nasopharyngitis and Dysgeusia