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 EducationandResearch,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 PeripheryIn 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 Polyclonaland MonoclonalAntibodies
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 MonoclonalAntibodies
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 MonoclonalAntibodies 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 monoclonalantibodies
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 Needfor 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.

Monoclonal Antibody Market 2016
Chapter 4
Monoclonal Antibody Market

4. MonoclonalAntibody 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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2010
2011
2012
2013
2014
2015
No.ofProductsapproved
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
arthritis,
ankylosing
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
arthritis,
ankylosing
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 receptor
antagonist
Others
2 2 2 2 3 3 3 4
8
16
0
5
10
15
20
NumberofDrugs
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 ofDevelopment
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 ofdevelopment No. ofdrugs
Phase 1 168
Phase 2 183
Phase 3 63
Pre-registration 9
Registered 3
Total 426
Indications No. ofdrugs
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 ofDevelopment 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 ofDevelopment 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 ofDevelopment 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,
30-Apr-07
Dr. Reddy’s
Laboratories
39996 for 50 ml
injection in vial
11 Rituximab rituximab
Non-Hodgkin’s Lymphoma,
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
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lshc-biosimilars-whitepaper-final.pdf
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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 ofHER2-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

Bishwjit Final Thesis

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