The Future of Monoclonal Antibody

H E A LT H C A R E
The Future of Monoclonal Antibody

Therapeutics
Innovation in antibody engineering, key growth
strategies and forecasts to 2011
By Sarah Riley
TLFeBOOK
Sarah Riley
Sarah Riley is an analyst within the healthcare function of Business Insights. She has a
PhD in physiology from King's College, London and is an expert in autoimmune
diseases and cardiology. She has previously worked on commercial analyses of the
generics market, the future of the diabetes market and pharmaceutical licensing
strategies.
Copyright 2006 Business Insights Ltd

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While information, advice or comment is believed to be correct at the time of

publication, no responsibility can be accepted by Business Insights Ltd for its
completeness or accuracy.
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Table of Contents
The Future of Monoclonal Antibody Therapeutics
Executive Summary 12
Introduction 12
Antibody engineering and innovation in the market 13
The current monoclonal antibody market 14
The antibody pipeline and forecasts to 2011 15
Competitive landscape and future growth strategies 16
Chapter 1 Introduction 18
Summary 18
Introduction 19
History of monoclonal antibodies 20
Monoclonal antibody approval process 21
Current approval process 21
Biogeneric regulations 22
Key trends in the market 23
Advancements in innovation 23
Diversification of therapy areas 24
Big Pharma entering the mAb market 25
Chapter 2 Antibody engineering and

innovation in the market 28
Summary 28
Introduction 29
The move from murine to fully human mAbs 30
Whole IgG monoclonal antibodies 31
Murine 31
Chimeric 31
Humanized 32
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Human 32
Innovations in antibody structures 33
Fab fragments 34
Single chain variable fragments 35
Extended release formulations 36
Innovation in antibody conjugation 37
Types of conjugation 37
Direct arming: antibody conjugation 37
Indirect arming: Bispecific monoclonal antibodies 37
Pre-targeting 38
Marketed conjugated monoclonal antibodies 38
Conjugation technology 39
Seattle Genetics antibody technology 39
ImmunoGen mAb technology 40
Peregrine mAb technology 41
Enhancing monoclonal antibody potency 41
Drug discovery 42
Cambridge Antibody Technology 44
Dyax 45
Morphosys 46
Innovation in drug delivery 47
Drug delivery devices 47
Inhaled monoclonal antibodies 48
Oral monoclonal antibodies 49
Chapter 3 The current monoclonal antibody

market 52
Summary 52
Introduction 53
Strategic analysis 53
Drivers 54
Pipeline drugs 54
Immature market 54
Big Pharma entering the mAb market 55
High level of innovation 55
Approval of new indications 56
Combination therapies 56
Resistors 56
Publicized side effects 56
Drugs suspended from market 57
Competition from small molecule drugs 57
Pricing and reimbursement schemes 57
Analysis of launched drugs 58
Oncology 60
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Rituxan 61
Herceptin 63
Avastin 65
Erbitux 67
Campath 69
Zevalin 70
MyloTarg 72
Bexxar 74
AIID 76
Remicade 76
Humira 79
Raptiva 81
Simulect 83
Zenapax 84
OrthoClone OKT3 84
Hemostasis 86
ReoPro 86
Anti-infectives 87
Synagis 88
Respiratory 89
Xolair 89
Marketed monoclonal antibody forecasts 90
Chapter 4 The antibody pipeline and

forecasts to 2011 94
Summary 94
Introduction 95
Opportunities 97
Clinical trials 97
Erbitux and Avastin 98
Simulect, Zenapax and Campath 98
Campath 98
Others 99
Innovation in antibody engineering 99
New indications 100
Challenges 101
Generic biologics 101
Adverse reactions in clinical trials, side effects and termination of
development 102
High attrition rates 103
Analysis of pipeline drugs 104
AIID 109
Cimzia 109
MRA/Actemra 110
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Eculizumab 112
AMG-162 113
Cardiovascular 115
Pexelizumab 115
Infectious diseases 116
Numax 116
Oncology 117
ABX-EGF 117
MDX-010+MDX-1379 119
Humax 120
Ophthalmology 121
Lucentis 121
Late stage pipeline forecasts 123
The antibody market in 2011 124
Chapter 5 Competitive landscape and

future growth strategies 128
Summary 128
Introduction 129
Key players in the monoclonal antibody market 130
M&A and licensing activity 130
Big Pharma acquiring biotechs and antibody companies 133
AstraZeneca and CAT 134
Novartis and NeuTec 134
Amgen and Abgenix 135
Roche and GlycArt 135
MedImmune and Cellective Therapeutics 136
Pfizer and Bioren 136
Company profiles 137
Big Pharma 137
Roche 137
Company overview 137
Strategic and growth analysis 137
Marketed products 139
Pipeline 140
Novartis 141
Pipeline 143
Pfizer 144
Pipeline 146
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Large biotech 147
Genentech 147
Pipeline 149
MedImmune 150
Company Profile 150
Pipeline products 152
Biogen Idec 153
UCB-Celltech 157
Small biotech/antibody companies 161
Medarex 161
XOMA 165
Technology companies 169
BioWa 169
Crucell 172
Chapter 6 Appendix 178

Sales data 178
Index 179
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List of Figures
Figure 1.1: History of monoclonal antibodies 21
Figure 2.2: Current marketed monoclonal antibodies, 2006 31
Figure 2.3: Therapeutic mAbs entering clinical study, 1980-2004 33
Figure 2.4: Whole antibody and fragment structures 34
Figure 3.5: Drivers and resistors to growth in the monoclonal antibody market 54
Figure 3.6: Market dynamics of current marketed drugs, 2004-5 58
Figure 3.7: Marketed monoclonal antibodies by therapy area, 2006 60
Figure 4.8: Opportunities and challenges in the mAb market 97
Figure 4.9: Antibody structure analysis of forecasted monoclonal antibody sales ($m), 2004-11106
Figure 4.10: Therapy area analysis in monoclonal antibody drug development, 2006 107
Figure 4.11: Therapy area analysis of forecasted monoclonal antibody sales ($m), 2004-11 108
Figure 5.12: Key growth strategies in the monoclonal antibody market, 2005-6 133
Figure 5.13: Roches SWOT analysis in the mAb market 138
Figure 5.14: Novartis SWOT analysis in the mAb market 141
Figure 5.15: Pfizers SWOT analysis in the mAb market 145
Figure 5.16: Genentechs SWOT analysis in the mAb market 148
Figure 5.17: MedImmunes SWOT analysis in the mAb market 150
Figure 5.18: Biogen Idecs SWOT analysis in the mAb market 154
Figure 5.19: UCB Celltechs SWOT analysis in the mAb market 159
Figure 5.20: Medarexs SWOT analysis in the mAb market 162
Figure 5.21: XOMAs SWOT analysis in the mAb market 166
Figure 5.22: BioWas SWOT analysis in the mAb market 170
Figure 5.23: Crucells SWOT analysis in the mAb market 173
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List of Tables
Table 1.1: Current marketed drugs, 2006 24
Table 1.2: Key players in the monoclonal antibody market, 2006 25
Table 2.3: Marketed therapeutic monoclonal antibodies, 1986-2006 30
Table 2.4: Antibody fragment pipeline, 2006 36
Table 2.5: Conjugated antibody engineering technology 39
Table 2.6: Drug development technology 42
Table 2.7: Monoclonal antibody drug discovery technology 43
Table 3.8: Marketed therapeutic monoclonal antibodies, 2004-5 59
Table 3.9: Marketed monoclonal antibody sales forecasts, 2005-11 91
Table 4.10: Other post-marketing clinical trials, 2005-6 99
Table 4.11: Late stage monoclonal antibody pipeline, 2006 105
Table 4.12: Late stage monoclonal antibody pipeline sales forecast to 2011 124
Table 5.13: Key players in the monoclonal antibody market, 2006 130
Table 5.14: Monoclonal antibody collaborations, manufacturing, development and supply
agreements, 2005-6 131
Table 5.15: Key acquisitions in the monoclonal antibody market, 2005-6 134
Table 5.16: Roches marketed monoclonal antibodies, 2006 139
Table 5.17: Roches monoclonal antibody pipeline, 2006 140
Table 5.18: Novartis marketed monoclonal antibodies, 2006 143
Table 5.19: Novartis monoclonal antibody pipeline, 2006 143
Table 5.20: Pfizers monoclonal antibody pipeline, 2006 146
Table 5.21: Genentechs marketed monoclonal antibodies, 2006 149
Table 5.22: Genentechs monoclonal antibody pipeline, 2006 149
Table 5.23: MedImmunes marketed monoclonal antibodies, 2006 152
Table 5.24: MedImmunes monoclonal antibody pipeline, 2006 152
Table 5.25: Biogen Idecs marketed monoclonal antibodies, 2006 156
Table 5.26: Biogen Idecs monoclonal antibody pipeline, 2006 157
Table 5.27: UCB-Celltech monoclonal antibody pipeline, 2006 160
Table 5.28: Medarexs monoclonal antibody pipeline, 2006 163
Table 5.29: XOMAs monoclonal antibody pipeline, 2006 167
Table 5.30: BioWas monoclonal antibody pipeline, 2006 171
Table 5.31: Crucells monoclonal antibody pipeline, 2006 174
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Executive Summary
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Executive Summary
Introduction
The monoclonal antibody (mAb) market has grown rapidly in recent years,
reaching sales of $14bn in 2005, an increase of 36.5% from 2004 sales of $10.3bn.
Khler and Milstein developed the hybridoma method of murine antibody

production in 1975, which allowed the production of the first mAb to market;
Johnson & Johnsons Orthoclone OKT3 (muromonab) in 1986.
The mAb market is highly innovative and a key trend has been the move from
murine to humanized and fully human antibodies. As technology has progressed
these humanized mAbs have prevented immune responses (HAMA), thus having a
larger market potential.
The traditional therapy areas in the mAb market are oncology and autoimmune and
inflammatory disorders (AIID), however this is forecast to change with the
emergence of other therapy areas including infectious disease and ophthalmology.
The clear leader in the mAb market is Genentech with 5 marketed drugs, with sales
totaling $4,116.4m in 2005.
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Antibody engineering and innovation in the market
The last 5 therapeutic mAbs launched in the US were humanized or chimeric,
supporting the trend of a move away from murine mAbs. Currently, there is only
one marketed fully human mAb, Abbott/CATs Humira.
Marketed conjugated mAbs have relatively low sales compared to the leading
unconjugated mAbs, which is attributed to limited efficacy and difficulty in
administration. Conjugated drugs need to be administered in the presence of a
radiologist and oncologist, which is expensive and limits their use.
Current marketed antibody fragments include ReoPro and CEA-scan (diagnosis),

which are both Fab fragments. A key pipeline antibody Fab fragment is
Genentechs Lucentis, filed for FDA approval in December 2005.
Drug discovery firms are using advances in genomics and proteomics, in addition
to proprietary technology to discover new target antigens and antibodies. The 3
leading players in antibody discovery are CAT, Dyax and Morphosys.
mAbs can only be administered via injection or intravenous infusion, due to their
structure and protein composition. Inhaled antibodies present a viable market due to
this delivery method providing an increase in convenience, and being painless
compared to injections. There are no currently marketed inhaled mAbs.
Oral mAb drug delivery is forecast to have a high market potential, as it provides
the most convenient method of drug delivery. A key oral technology is Emisphere
Technologies Eligen, which uses carrier agents to protect the protein from
digestive enzymes and facilitate the transport of the molecules across membranes.
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The current monoclonal antibody market
The leading mAbs are Remicade and Rituxan, with sales of $3.5bn and $3.3bn,
respectively in 2005. However, sales growth of Rituxan is expected to be limited
due to a lack of studies investigating new indications.
The rapid increase in the number of mAb pipeline drugs is a result of innovation in
the market, which has allowed companies to develop fully human drugs with
reduced immunogenicity and mAb fragments that are cheaper to produce and have
a high efficacy.
Despite the high growth in the mAb market, there remain many issues resisting the
market, including mAbs being withdrawn from the market, publicized side-effects,
pricing and reimbursement issues and competition from small molecule drugs.
Oncology is the largest therapy area within the mAb market, with 8 marketed
products. This therapy area is set to increase with numerous early and late stage
products in development. Key oncology pipeline products include Virexxs
OvaRex, Abgenix/Amgens ABX-EGF and Medarex/Bristol-Myers Squibbs
MDX-010 and MDX-1379.
AIID is the second largest therapy area in the mAb market, with 7 marketed drugs.
Many of the marketed AIID drugs are indicated for the same disease, and
consequently there is a high level of competition between drugs. For example the
leading mAb Remicade, with sales of over $3.4bn in 2005, is indicated for
Rheumatoid Arthritis (RA), as is Humira.
Synagis is the only current anti-infective mAb on the market. However, due to a
large number of early and late stage pipeline products, this therapy area is expected
to expand in the next 5 years. Key pipeline products include Numax and Aurograb.
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The antibody pipeline and forecasts to 2011
Key challenges facing the mAb market include the imminent bioequivalent
regulations, which once in place are forecast to heavily impact sales of currently
marketed drugs. The negative publicity from clinical trials or other reported adverse
side effect will also challenge sales due to physicians switching to alternative small
molecule therapies.
There are numerous mAb drugs anticipated to launch in the next 5 years. Lucentis,
Cimzia and ABX-EGF (panitumumab) were all filed for FDA approval in 2005,
and are all antibody fragments which reflects the trend of innovation in antibody
engineering towards alternative antibody structures.
Advancements in antibody engineering and technology act as a huge opportunity

for growth in the mAb market, as fully human antibodies can be developed, for
example Humira. Several pipeline mAbs are fully human, and thus are anticipated
to perform well in the market: ABX-EGF, MDX-010+MDX-1379, ticilimumab and
Humax.
Late stage pipelines show mAbs being developed for cardiovascular, infectious
diseases and ophthalmology, in addition to the traditional indications for mAbs of
oncology and AIID. Widening the indications of mAbs allows companies to gain
access to larger patient potentials and avoids competition from similar drugs.
Lucentis (ranibizumab) is a humanized anti-VEGF mAb fragment, which is based

on Genentechs larger anti-VEGF antibody Avastin. The FDA approved Lucentis
on the 30th June 2006 and sales are forecast to reach 685m in 2011.
High sales are forecast for Numax as it has been shown to be highly efficacious: in
RSV neutralization studies it is 20 times more potent than Synagis. Therefore
Numax, forecast to launch in 2008, has the competitive advantage over Synagis and
has the potential to enable expansion into additional indications further boosting
sales.
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Competitive landscape and future growth strategies
Four types of company have been identified in the mAb market: Big Pharma, large
biotech, small biotech/antibody companies and technology companies. However,
there is a certain degree of overlap between company types and the strategies they
use to grow their share in the market.
The trend of Big Pharma acquiring companies to gain access to mAb pipeline is a
recent trend seen over the past few years. For example, in June 2006 Novartis made
a $569m bid for NeuTec Pharma, a British drug developer with several late-stage
candidates in the pipeline.
Genentech is the market leading mAb developer and currently has 5 marketed
mAbs. Genentechs highest selling mAb is Rituxan, with US sales of $1,574m in
2004, which increased 16.3% in 2005 to $1,831m. However, Genentech pays
royalties to Roche for their marketed mAbs under their long established agreement.
There are many small biotech and specialty antibody players developing antibody
drugs, with one example being XOMA. XOMA does not have any currently
marketed mAb products, although it has mAbs in development and forms
collaborations with other antibody developers who wish to access its proprietary
technology.
Technology players, for example Crucell, are developing proprietary antibody

technologies to produce novel antibodies at a lower cost than conventional
methods, which they can outlicense to larger companies.
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CHAPTER 1
Introduction
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Chapter 1 Introduction
Summary
The monoclonal antibody (mAb) market has grown rapidly in recent years,
reaching sales of $14bn in 2005, an increase of 36.5% from 2004 sales of
$10.3bn.
Khler and Milstein developed the hybridoma method of murine antibody
production in 1975, which allowed the production of the first mAb to market;
Johnson & Johnsons Orthoclone OKT3 (muromonab) in 1986.
The mAb market is highly innovative and a key trend has been the move from
murine to humanized and fully human antibodies. As technology has progressed
these humanized mAbs have prevented immune responses (HAMA), thus having
a larger market potential.
The traditional therapy areas in the mAb market are oncology and autoimmune
and inflammatory disorders (AIID), however this is forecast to change with the
emergence of other therapy areas including infectious disease and
ophthalmology.
The clear leader in the mAb market is Genentech with 5 marketed drugs, with
sales totaling $4,116.4m in 2005.
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Introduction
The monoclonal antibody (mAb) market has grown rapidly since the launch of the first
drug, Johnson & Johnsons Orthoclone OKT3, in 1986. The global mAb market
reached $14bn in 2005, an increase of 36.5% from 2004 sales of $10.3bn. The mAb
market is outperforming the total global pharmaceutical market, which grew 7% in
2005.
This chapter covers the history of mAbs, summarizing technological advances and the
current biologics approval process. The marketed products will also be introduced
along with the major players in the market. Key trends in the mAb market are
described to establish a background to the market.
A key theme of this report is the high level of innovation, as demonstrated by

advancements in antibody engineering with the introduction of chimeric, humanized
and fully human mAbs. Other innovation in antibody technology include advancements
in non-invasive drug delivery technology, which is predicted to lead to a huge boost in
sales in the long-term once drugs that utilize this technology come to market.
Current marketed mAbs are predominantly indicated for oncology or arthritis, immune
and inflammatory disorders (AIID). However, mAbs in all stages of pipelines are being
developed for a broader range of indications. It is expected that mAbs directed at
infectious diseases will increase market share and generate high sales, although the
traditional therapy areas of oncology and AIID will continue to dominate the market in
the short-to-mid term.
Due to the high growth experienced in the mAb market in recent years, an increasing
number of companies are looking to enter the market, as reflected by the large number
of M&A and licensing deals in the last few years. Big Pharma in particular are
establishing themselves in the market, which has been achieved by recent acquisitions
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to gain key pipeline mAbs or antibody technology, for example the acquisition of
Cambridge Antibody Technology (CAT) by AstraZeneca and GlycArt by Roche.
The mAb market as defined in this report consists of global sales of all marketed
monoclonal whole antibodies and fragments, excluding polyclonals.
History of monoclonal antibodies
A time line detailing the history of mAbs is shown in Figure 1.1. Khler and Milstein
developed the hybridoma method of murine antibody production in 1975, which
allowed the production of the first mAb to market: Johnson & Johnsons Orthoclone
OKT3 (muromonab) in 1986. Although there were high expectations for murine mAbs,
due to problems with immunogenicity they have declined from favor. Murine
antibodies are seen as foreign by the immune system, which mounts a response known
as the Human Anti-Mouse Antibodies (HAMA) response, producing unwanted side
effects. In an attempt to overcome the HAMA response antibodies were developed that
were chimeric; consisting of 60% human and 40% mouse immunoglobulin.
The next step in the development of mAbs has been the conjugation of toxins or
radionucleotides to further enhance their cytotoxic action. Other advancements that
have occurred in the market include the development in antibody fragments, such as
Fab and single chain antibodies, which can be produced at lower costs compared to
whole antibodies.
The most recent events in the mAb market are the acquisitions by Big Pharma to gain
products or technology, confirming their desire to enter the mAb market. The most
recent deal has been Novartis acquisition of NeuTec, which has promising pipeline
drugs.
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Figure 1.1: History of monoclonal antibodies
1975 Khler and Milstein developed the hybridoma

method of murine antibody production
Chimeric antibodies (60% human and 40% mouse)

1984
were first reported
The first mAb reached the market: Johnson &

1986
Johnsons Orthoclone OKT3
Humanized antibodies (over 90% human) were first

1986
reported
Medimmunes Synagis was launched for the

1998
indication of anti-infective disease.
The first radionucleotide conjugated mAb was

2003
launched: Corixas Bexxar (tositomomab-I131)
Source: Business Insights Business Insights Ltd
Monoclonal antibody approval process
Current approval process
On June 30, 2003, the Food and Drug Administration (FDA) transferred several
therapeutic biological products that had been reviewed and regulated by the Center for
Biologics Evaluation and Research (CBER) to the Center for Drug Evaluation and
Research (CDER). CDER now has regulatory responsibility, including premarket
review and continuing oversight, over the transferred products, which include mAbs.
The switch from CBER to CDER has allowed an increase in efficiency and consistency
of reviews and resulted in a decreased average review time. A key difference between
the approval process for mAbs compared to small molecule drugs is that mAbs are filed
under a Biologics License Application (BLA) to the FDA, rather than a New Drug
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Application (NDA). The approval process for mAbs involves the manufacturing
facilities being approved in addition to the processes and actual efficacy and safety of
the product; as a result the approval process for mAbs is a longer and more expensive
process than for traditional drugs.
Biogeneric regulations
To date there are no biogeneric regulations in place in the US, EU or Japan. Sandozs
Omnitrope (Somatropin) was the first generic biologic drug approved by the FDA on
the 30th of May 2006 and was filed under an NDA (new drug application). However,
the FDA has stated that this is not a biogeneric, and thus this approval has not paved
the way for future generic versions of biologics. Biogeneric regulations are not
expected to be straight forward, as it is impossible to create an identical generic
biological, due to the nature of protein folding and the specific method of mammalian
cell culture and purification procedures used by the originator. However, a
bioequivalent or biosimilar drug can be produced, which demonstrates the same
efficacy and levels in the blood. Once bioequivalent regulations are established generic
versions of mAbs are expected to impact heavily on branded sales. One factor that
could resist this decline in product price is the difficulty in obtaining biologic generic
approval, as the manufacturing facilities need to be approved along with the product,
and the manufacturing process is more expensive than small compound production,
limiting the number of players and thus reducing competition.
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Key trends in the market
There are several key trends in mAbs, which are forecast to shape the future market.
Changes in the market have been noted in innovation, therapy areas of launched and
pipeline drugs, and companies involved in developing and marketing mAbs.
Advancements in innovation
The mAb market is highly innovative and a key trend has been the move from murine
to humanized and fully human antibodies. Current marketed antibodies are
predominantly humanized, but there is one marketed fully human antibody, Humira.
Technology has progressed in order to develop mAbs with a larger proportion of
human IgG to prevent adverse immune responses (HAMA), and thus have a larger
market potential. Other antibody innovations include methods to improve efficacy that
have focused on different cell-surface target antigens, for example receptors for
cytokines have been found to be highly effective in killing tumor cells.
mAbs conjugated with other drugs or radionucleotides is another technique to improve

mAb function. Conjugated antibodies bind to a specific target to deliver drugs or kill
only specific cell types, and thus improve cytotoxicity. There are currently 4 marketed
conjugated mAbs and this is forecast to increase, as supported by an increase in license
deals involving companies specializing in this technology (Seattle Genetics and
ImmunoGen). Further advancements in antibody engineering include the production of
antibody fragments, which can be produced more economically than whole mAbs and
retain the targeting specificity. The potential for antibody fragments is large, as they
can be conjugated to radionucleotides, toxins or enzymes, engineered to improve
efficacy and have the advantage of greater biodistribution and can be engineered to
have varying clearance properties.
mAbs currently have to be subcutaneously or intravenously injected because their

protein structure means that if taken orally they would be broken down in the stomach
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prior to absorption into the blood. Injections can be painful and inconvenient for
patients and any drug that improves convenience and compliance will have a huge
patient potential. A key trend forecast to result in a large increase in sales is the non-
invasive delivery of antibody drugs. Emisphere is currently investigating oral
technologies to apply to mAbs, but non-invasive mAbs are not expected to reach the
market in the next 5-10 years.
Diversification of therapy areas
There are currently 18 marketed mAb drugs, with the most recent, Biogen Idecs
Tysabri, launched in 2004. Tysabri was voluntarily suspended in 2005, however it was
allowed back on the market by the FDA in June 2006.
Table 1.1: Current marketed drugs, 2006
Brand Generic Originator Therapy area Launch year
Orthoclone OKT3 muromonab-CD3 Johnson & Johnson AIID 1986

ReoPro abciximab Centocor/Lilly hemostasis 1995
Rituxan/MabThera rituximab Biogen Idec oncology 1997
Zenapax daclizumab Hoffman-La Roche AIID 1997
Herceptin trastuzumab Genentech oncology 1998
Remicade infliximab Centocor AIID 1998
Simulect basiliximab Novartis AIID 1998
Synagis palivizumab MedImmune anti-infective 1998
MyloTarg gemtuzumab Celltech Group, Wyeth oncology 2000
ozogamicin
Campath alemtuzumab Genzyme oncology 2001
Zevalin ibritumomab tiuxetan Biogen Idec oncology 2002
Bexxar tositumomab-I131 Corixa oncology 2003
Erbitux cetuximab ImClone oncology 2003
Humira adalimumab Abbott/CAT AIID 2003
Raptiva efalizumab Genentech/Xoma AIID 2003
Xolair omalizumab Genentech/Novartis respiratory 2003
Avastin bevacizumab Genentech oncology 2004
Tysabri* natalizumab Biogen Idec AIID 2004
*Voluntary suspension February 2005, relaunched in June 2006;

AIID = arthritis, immune and inflammatory disorders
Source: Business Insights; Company websites Business Insights Ltd
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The traditional therapy areas covered by mAb drugs are oncology and autoimmune and
inflammatory disorders (AIID), as seen in Table 1.1. However, this is forecast to
change with the emergence of other therapy areas including infectious disease and
ophthalmology. Currently, there is only one infectious disease mAb on the market,
MedImmunes Synagis, but there are many early stage and several key late stage
products in the pipeline. Oncology and AIID are still seen as the major therapy areas in
the mAb market, but the spread of products among the therapy areas is likely to
become more balanced over the next 5 years.
Big Pharma entering the mAb market
The clear leader in the mAb market is Genentech with 5 marketed drugs, with sales
totaling $4,116.4m in 2005. There is a mix of types of companies shown in Table 1.2,
including antibody companies, biotechs and big Pharma.
Table 1.2: Key players in the monoclonal antibody market, 2006
Company Sales ($m) Sales Growth Market Share

2004 2005 2004-05 2005
Genentech 2,838.0 4,116.4 45.2% 29.4%

Hoffman-La Roche 1,862.7 2,704.7 45.0% 19.3%
Centocor 2,145.0 2,535.0 18.2% 18.1%
Abbott 829.1 1,362.4 64.3% 9.7%
MedImmune 942.3 1,060.9 12.6% 7.6%
Schering-Plough 746.0 942.0 26.3% 6.7%
ImClone 244.1 533.7 118.7% 3.8%
Lilly 362.8 296.7 -18.2% 2.1%
Merck KGaA 99.7 218.0 118.7% 1.6%
Genzyme 51.5 60.8 18.1% 0.4%
Novartis 49.7e 54.9e 10.5% 0.4%
CAT* 22.9 37.6 64.3% 0.3%
Biogen Idec 24.0 28.4 18.3% 0.2%
Wyeth 26.0 25.6 -1.5% 0.2%
Biogen Idec/Elan 2.4 21.2 783.3% 0.2%
Johnson & Johnson 17.3e 13.2e -23.7% 0.1%
Corixa 3.8e 8.2e 115.8% 0.1%
Total 10,267.3 14,019.8 36.5% 100.0%
e = estimate based on IMS sales data and authors own research and analysis
CAT = Cambridge Antibody Technology; * acquired by AstraZeneca
Source: Business Insights; Company reports; IMS Business Insights Ltd
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There is a high level of M&A and licensing deals within the mAb market, which
reflects the high interest and opportunity in the market. The mAb market is a high
growth market that many big pharmaceutical companies want to gain access to, and are
generally looking to achieve this via in-licensing or acquisitions. Since 2005, Pfizer,
Novartis and AstraZeneca have all acquired innovative players in the mAb market. Out
of the major pharmaceutical leaders GlaxoSmithKline and Sanofi-Aventis are yet to
make significant moves to enter the mAb market, however should the market continue
to grow at its current rate then it is likely that these companies will look to make
investments in this area sooner rather than later.
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CHAPTER 2
Antibody engineering and

innovation in the market
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Chapter 2 Antibody engineering and
innovation in the market
Summary
The last 5 therapeutic mAbs launched in the US were humanized or chimeric,

supporting the trend of a move away from murine mAbs. Currently, there is only
one marketed fully human mAb, Abbott/CATs Humira.
radiologist and oncologist, which is expensive and limits their use.
Current marketed antibody fragments include ReoPro and CEA-scan (diagnosis),
which are both Fab fragments. A key pipeline antibody Fab fragment is
Genentechs Lucentis, filed for FDA approval in December 2005.
Drug discovery firms are using advances in genomics and proteomics, in addition
to proprietary technology to discover new target antigens and antibodies. The 3
leading players in antibody discovery are CAT, Dyax and Morphosys.
mAbs can only be administered via injection or intravenous infusion, due to their
structure and protein composition. Inhaled antibodies present a viable market due
to this delivery method providing an increase in convenience, and being painless
compared to injections. There are no currently marketed inhaled mAbs.
Oral mAb drug delivery is forecast to have a high market potential, as it provides
the most convenient method of drug delivery. A key oral technology is Emisphere
Technologies Eligen, which uses carrier agents to protect the protein from
digestive enzymes and facilitate the transport of the molecules across membranes.
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Introduction
The mAb market has advanced over the last 20 years due to numerous technological
innovations. This chapter examines the use of antibody engineering to produce
therapeutic mAbs without the risk of immune reactions, such as the HAMA response
seen with murine antibodies. A key trend in the market has been the move from murine
to humanized mAbs, with the future trend forecast to move towards fully human
antibodies.
Antibody engineering can also be used to improve efficacy as well as reduce side
effects, and therefore lead to a larger patient potential. Innovation in drug discovery
technology is another key trend in the market which is detailed in this chapter and
allows the development of a huge range of mAbs through proprietary technology
platforms. Several companies are also looking to improve drug delivery technology, by
applying innovative technology to drug delivery devices or the drug itself. Improved
drug delivery will improve convenience and compliance leading to a larger uptake of
antibody drugs, and thus boosting sales.
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The move from murine to fully human mAbs
The first mAb to market was Orthoclone OKT3, a murine antibody launched in 1986.
Murine antibodies cause problems with immunogenicity, and as a consequence are no
longer pursued in current clinical trials. Part-human part-mouse (humanized and
chimeric) mAbs are increasing evident amongst marketed products, as shown in Figure
2.2 and Table 2.3. The last 5 therapeutic mAbs launched in the US were humanized or
chimeric, supporting the trend of a move away from murine mAbs. Currently, there is
only one marketed fully human mAb, Abbott/CATs Humira; however, developers are
expected to focus much more on fully human antibodies in the future, as suggested by
product pipelines across all phases and data regarding mAbs entering clinical trials, as
shown in Figure 2.3.
Table 2.3: Marketed therapeutic monoclonal antibodies, 1986-2006
Brand Generic Company Description Approval date

US EU
Orthoclone OKT3 muromonab-CD3 Johnson & Johnson murine 06/1986 n/a

ReoPro abciximab Centocor, Lilly chimeric 12/1994 n/a
Rituxan/ MabThera rituximab Genentech, Roche chimeric 11/1997 06/1998
Zenapax daclizumab Hoffman-La Roche humanized 12/1997 02/1999
Simulect basiliximab Novartis chimeric 05/1998 10/1998
Synagis palivizumab MedImmune humanized 06/1998 08/1999
Remicade infliximab Centocor chimeric 08/1998 08/1999
Herceptin Trastuzumab Genentech, Roche humanized 09/1998 08/2000
MyloTarg gemtuzumab Celltech Group, Wyeth humanized 05/2000 n/a
ozogamicin
Campath alemtuzumab Genzyme humanized 05/2001 07/2001
Zevalin ibritumomab Biogen Idec murine 02/2002 01/2004
tiuxetan
Humira adalimumab Abbott, CAT human 12/2002 09/2003
Bexxar tositumomab-I131 Corixa murine 05/2003 n/a
Xolair omalizumab Genentech, Novartis humanized 06/2003 n/a
Raptiva efalizumab Genentech, XOMA humanized 10/2003 09/2004
Avastin bevacizumab Genentech, Roche humanized 02/2004 01/2005
Erbitux cetuximab ImClone chimeric 02/2004 06/2004
Tysabri natalizumab Biogen Idec humanized 11/2004 n/a
Source: Business Insights; Company websites; FDA Business Insights Ltd
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Figure 2.2: Current marketed monoclonal antibodies, 2006
10
9
Number of marketed mAbs 9
7
6
5
5
4
3
3
2
1
1
0
murine humanized chimeric human
Whole IgG monoclonal antibodies
Murine
Murine mAbs are entirely derived from mouse IgG and were the first type of mAbs to
be developed. However, murine mAbs incur problems with immunogenicity, which
mounts a response known as the Human Anti-Mouse Antibodies (HAMA) response,
producing unwanted side effects. Therefore, murine mAbs have not been commercially
successful and as a consequence play a limited role in developers pipelines.
Chimeric
Chimeric mAbs consist of 60% human and 40% mouse IgG and were first reported in
1984. The Fab region of chimeric mAbs is murine, whereas the Fc region is human,
and chimeric mAbs are thus advantageous as an immune response can be induced
comparable to natural antibodies. Chimeric mAbs have an improved immunogenic
profile in comparison to murine mAbs, but have more side effects than humanized and
fully human mAbs. Marketed chimeric mAbs include Centocor/Lillys Reopro, Biogen
Idecs Rituxan/MabThera and Centocors Remicade. The number of chimeric mAbs
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entering clinical trials has started to decline, as shown in Figure 2.3, due to the increase
in humanized and human mAbs, which have little or no murine content, and thus
reduced problems with immunogenicity.
Humanized
Humanized mAbs consist of over 90% human IgG and were first reported in 1986. The
murine region of a humanized mAb is located in the variable region in the Fab portion
of the antibody. Humanized mAbs include Roches Zenapax, Genentechs Herceptin
and MedImmunes Synagis. Humanized mAbs make up the largest group of marketed
therapeutic antibodies, with 9 drugs, as shown in Figure 2.2. Tufts Centre for the Study
of Drug Development (CSDD) data (as shown in Figure 2.3) shows that the number of
humanized drugs entering clinical trials peaked in 1996 and has since started to decline
as a result of the increase of fully human mAbs. Due to the lengthy procedure of drug
development and clinical trials, there is still expected to be numerous humanized mAbs
to reach the market, however fully human antibodies are forecast to be the dominant
type reaching the market in the next 5-10 years.
Human
There is only one fully human mAb on the market to date: Abbott/CATs Humira,
which was launched in the US in 2003. Fully human mAbs are predicted to dominate
future product launches, as suggested by the shear volume of mAbs entering clinical
trials shown in Figure 2.3. Fully human mAbs have the lowest risk of immune related
side effects because there is no murine content and subsequently those mAbs have the
highest sales potential. Promising fully human pipeline mAbs include Amgens
denosumab and Pfizers ticilimumab.
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Figure 2.3: Therapeutic mAbs entering clinical study, 1980-2004
14
Number of mAbs entering clinical study
12
10
Murine
Chimeric
8
Humanized
Human
6
0
1980 1982 1984 1986 1988 1990 1992 1994 1996 1998 2000 2002 2004
Data are presented as two-year moving averages
Source: Tufts CSDD Business Insights Ltd
Innovations in antibody structures
Antibody fragments can be single chain antibodies or antigen binding fragments (Fab),
as shown in Figure 2.4. Other engineered variants include diabodies, triabodies and
minibodies. Fragments are much smaller than whole antibodies, which gives them the
advantage of better infiltration of tissue compared to full length mAbs, in particular
tumors. mAb fragments also cost less to produce as they can be produced by
recombinant technology rather than the more expensive mammalian cell culture. mAb
fragments can also be altered to have a varying half life in the circulation, providing
added benefits over whole mAbs. Current marketed antibody fragments include ReoPro
and CEA-scan (diagnosis), which are both Fab fragments. A key pipeline antibody
fragment is Genentechs Lucentis, which gained FDA approval in June 2006, and like
the marketed fragments is also a Fab.
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Figure 2.4: Whole antibody and fragment structures
Variable region of
heavy chain
Constant region 1 of
heavy chain
Variable region of
light chain
Constant
Constant region of region (Fc)
light chain
Full-size antibody Single-chain

Single- Antigen-binding
antibody (SCA) fragment (Fab)
Fab fragments
A Fab fragment is created by removing the constant (Fc) region, leaving a smaller
molecule (antigen-binding fragment or Fab) that contains the antigen binding site
allowing comparable target specificity to a whole mAb. Eliminating the Fc portion of
an antibody results in decreased non-specific binding and lower immunogenicity. Fabs
are approximately one third of the size of whole antibodies, while single chain
antibodies are around a sixth of the size.
UCB Celltech is an innovator in Fab fragment engineering technology, and use

PEGylation to extend the half life of their fragments. PEGylation is the process of
attaching one or more chains of polyethylene glycol (PEG) to a protein molecule,
which is necessary as removing the Fc region of the antibody means that the fragment
is rapidly cleared from the body. Current preclinical research is using proprietary multi
PEG patented technology, which allows numerous PEG molecules to be attached to
Fab fragments, with the advantage of reduction in manufacturing costs through less
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wastage of PEG and a greater variability in half-life dependant on the size of PEG
fragments attached. UCB Celltechs bioproduction system offers an alternative to
traditional biomanufacturing of mAbs that can significantly lower cost. UCB Celltech
has developed a proprietary system for manufacturing Fab fragments in microbial
systems, rather than by mammalian cell culture (which is one of the main stumbling
blocks of antibody production), and thus allows fragments to be produced on a large
scale at a lower cost.
Fab fragments are forecast to have a greater impact on the mAb market in the next 5
years than currently seen, due to greater publicity from current marketed drugs and
other fragments in late stage clinical trials. Key therapeutic antibody fragments being
investigated are shown in Table 2.4. However, the emergence of newer fragment types
could be a threat to Fab fragments. Although Fc fragments are not currently in clinical
trials and have numerous safety concerns, they have a high market potential as they are
highly potent to tumor cells and strongly induce complement activation.
Single chain variable fragments
Single chain variable fragments (scFvs) consist of the variable heavy (Vh) and variable
light (Vl) regions of a full antibody connected by a synthetic peptide linker. scFvs have
similar binding properties to Fab fragments, but are smaller making them even better at
tissue penetration, increasing specificity and efficacy.
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Table 2.4: Antibody fragment pipeline, 2006
Drug Company Fragment type Stage Indication
ReoPro Centocor/Lilly Fab/chimeric FDA approved Cardiovascular

(abciximab)
Lucentis Genentech/Novartis Fab/humanized Filed Ophthalmology
(ranibizumab)
Pexelizumab Alexion/Procter & Single chain Fv Phase 3 Cardiovascular
Gamble (scFv)/humanized
CDP870 UCB Celltech Fab/PEGylated Phase 3 Crohn's disease
humanized
CDP791 UCB Celltech Fab/PEGylated Phase 2 Cancer
humanized
SGN-17 Seattle Genetics (ScFv) fused to Preclinical Cancer
b-lactamase, human
Source: Business Insights; Company websites; MedTRACK Business Insights Ltd
Extended release formulations
A method of improving a drugs pharmacological profile is to apply technology to

create a controlled or sustained release version, and thus allowing the patient to reduce
the number of doses of drug required, which can therefore lower the cost of treatment.
Another benefit is the improvement in patient compliance because fewer doses are
required. Methods for providing extended release injections include depot injection;
using semi-solid or solid materials impregnated with the drug. The material degrades in
a controlled manner once in the body, releasing the drug over a prolonged period.
Examples of these technologies include Alzas Alzamer and Alkermess Prolease.
Another method of sustained release is to attach polyethylene glycol compound(s) to

the drug molecule to increase the half-life of the protein. PEGylation technology was
used to develop UCBs Cimzia (certolizumab/CDP 870), an antibody fragment in
development for Crohns disease and Rheumatoid Arthritis (RA), to improve the
dosing regimen of the therapy with an anticipated once monthly dosage.
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Innovation in antibody conjugation
Conjugated mAbs can be used as carrier agents of chemotherapy drugs, radioactive

particles, or toxins. Conjugated mAbs allows these molecules to be delivered to a
specific site or target a certain cell type, due to the unique targeting ability of
antibodies, and consequently have a localized and more direct action. Targeted delivery
of drugs or other agents result in reduced side effects on healthy cells, which is not the
case for many traditional systemic oncology drugs.
Types of conjugation
Antibody conjugation can be categorized into 3 types:
Direct arming;
Indirect arming;
Pre-targeting.
Direct arming: antibody conjugation
Conjugated mAbs can be used as carrier agents of chemotherapy drugs, radioactive

particles, or toxins. Conjugated mAbs allows these molecules to be delivered to a
specific site or target a certain cell type, and consequently have a localized and more
direct action. Currently marketed direct arming conjugated drugs include Wyeths
MyloTarg, Biogen Idec/Bayer AGs Zevalin and GlaxoSmithKlines Bexxar.
Indirect arming: Bispecific monoclonal antibodies
Bispecific mAbs bind two different antigens and hold considerable commercial
potential as therapeutic agents. MicroMet, Elusys and TRION Pharma have developed
technology for conjugating two mAbs to generate bispecific therapeutic antibodies.
MicroMets Bispecific T cell Engagers (BiTE) technology conjugates one antibody that
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recognizes killer T-cells with another antibody that recognizes the target cell. The
resultant antibody can capture the antigen, bringing it into close proximity to the T-cell
which can destroy the antigen if it is recognized as foreign. Elusys Therapeutics
bispecific antibody technology, Heteropolymer (HP) Technology, conjugates an
antibody that recognizes a particular antigen to another antibody that recognizes a
complement receptor, CR1, which is found on red blood cells. The bispecific antibody
binds the antigen to red blood cells, and is destroyed by macrophages in the liver.
Elusys also has a modified version of this technology known as antigen-HP, which can
be used to remove antibodies involved in the pathogenicity of autoimmune diseases.
Pre-targeting
Pre-targeting aims to selectively deliver radionucleotides to tumors, or to selectively

activate prodrugs, and thus reduce the systemic toxicities of these cytotoxic agents.
Seattle Genetics have developed antibody directed enzyme prodrug therapy (ADEPT).
ADEPT utilizes mAbs directed to tumors, which are not internalized, but remain on the
cell surface. mAb fragments are fused to enzymes and once administered accumulate in
tumor tissues. A prodrug is subsequently given, which is converted at the target site to
release active drugs to kill cells.
Marketed conjugated monoclonal antibodies
There are currently 4 marketed conjugated antibodies:
Wyeths MyloTarg, calicheamicin conjugate;
Biogen Idec/Bayer AGs Zevalin, radioimmunoconjugate, 90yttrium;
GlaxoSmithKlines Bexxar, radioimmunoconjugate, 131iodine;
131
Peregrines Cotara, radiolabeled tumor necrosis therapy, iodine (approved in
China only).
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radiologist and oncologist, which is expensive and limits their use. Despite the
disadvantages with administration, there is a potential market for conjugated mAb in
complex diseases including cancer where specific targeting, increased tissue
penetration and high efficacy are all important.
Conjugation technology
There is a high level of innovation in conjugated mAbs, with key technologies

developed and licensed to other companies. Table 2.5 shows the major technologies in
the conjugated antibody market, which have been developed by Seattle Genetics,
ImmunoGen and Peregrine Pharmaceuticals.
Table 2.5: Conjugated antibody engineering technology
Company Technology Description
Seattle Genetics Antibody drug ADC technology allows mAbs linked to cytotoxic drugs to
Conjugate (ADC) be internalized, which result in cell type specific cell death.
Antibody directed mAb fragments are fused to enzymes and accumulate in
enzyme prodrug tumor tissues once administered. A relatively inactive form
therapy (ADEPT) of an anti-cancer drug (prodrug) is then given and is
converted by the targeted enzymes to a potent cell-killing
drug.
ImmunoGens Tumor-Activated TAP allows cytotoxic agents to be delivered to specific

Prodrug technology cancer cells. Agents are conjugated to a mAb, which is
(TAP) stable in the circulation, but is rapidly broken down inside
cancer cells.
Peregrine Tumor Necrosis TNT utilizes mAbs directed to dead and dying tumor
Pharmaceuticals Therapy (TNT) cells. Radioisotopes are conjugated to these antibodies,
which are carried into tumors to kill them.
Seattle Genetics antibody technology
Seattle Genetics have developed antibody directed enzyme prodrug therapy (ADEPT)
and antibody drug conjugate technology (ADC). ADC technology allows mAbs linked
to cytotoxic drugs to be internalized, resulting in highly-potent agents. The pipeline
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drugs SGN-35 and SGN-75 employ ADC technology. ADEPT utilizes mAbs directed
to tumors, which are not internalized, but remain on the cell surface. mAb fragments
are fused to enzymes and once administered accumulate in tumor tissues. A prodrug is
then given, which is converted at the target site to release active drug to kill cells. The
ADEPT platform is utilized in the research program SGN-17, composed of a mAb that
binds to a human melanoma-associated antigen and the highly specific enzyme -
lactamase. When the prodrug is activated by the catalytic action of -lactamase, the
fully active agent melphalan is generated.
Numerous licensing deals have been established allowing companies to gain access to
this technology, including Genentech, UCB Celltech, Protein Design Labs, CuraGen,
Bayer and MedImmune. Recent collaborations involving Seattle Genetics and their
proprietary ADEPT or ADC technology include:
PMSA development, collaboration and license utilizing ADEPT, June 2005;
MedImmune collaboration employing ADC technology, April 2005;
Celera collaboration utilizing ADC technology, July 2004.
ImmunoGen mAb technology
ImmunoGens Tumor-Activated Prodrug (TAP) technology can be used to deliver

cytotoxic agents to specific cancer cells. ImmunoGen has designed agents that are
conjugated to an antibody with a link that is stable when in the circulation, but is
rapidly broken once it has entered the cancer cell, which allows more agent to be
delivered compared to a single cytotoxic agent. Advantages of this system include high
specificity, high potency (highly potent small-molecule effector drugs that are at least
100-1000 times more cytotoxic than traditional chemotherapeutics), stable linkage and
release (the cytotoxic agent is only released when inside the cell), reduced toxicity (and
more tolerable side effects) and non-immunogenic (humanized antibodies and non-
protein-based small-molecule effector drugs, reducing the risk of immunogenicity).
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Peregrine mAb technology
Peregrines Tumor Necrosis Therapy (TNT) utilizes mAbs attracted to dead and dying
cells found at the core of tumors. Radioisotopes can be conjugated to these antibodies,
which are carried into the tumors to kill them. Cotara is Peregrines leading TNT
compound. Peregrine has also licensed a TNT therapeutic for the indication of lung
cancer to Medipharm BioTech and is the first radio-labeled mAb approved for cancer
therapy in China.
mAbs can also be conjugated to other antibodies to create a bispecific mAb. These
molecules are still at an early stage of development, but have the potential to greatly
increase efficacy, and thus are forecast to have a high market potential. Due to the
human immune system consisting of polyclonal antibodies to generate an effective
response, bispecific molecules may re-create a natural response, which could be
effective in treating more complex diseases.
Enhancing monoclonal antibody potency
The potency of a mAb is very important as a highly efficacious drug will be more
frequently prescribed and achieve high sales; therefore any method to improve
antibody potency is very attractive. Technology can be applied to marketed drugs to
enhance antibody dependant cellular cytotoxicity (ADCC) (for example as applied to
Rituxan and Herceptin) and fucose-free antibodies can be generated, which have an
increased efficacy. Another method to enhance effector function is Xencors xmAb
engineered Fc domains, which can be inserted into an antibody candidate to improve
ADCC, improve half-life and structural stability. GlycoMAb glycosylation technology
is a method of increasing the potency of therapeutic antibodies targeting undesirable
cells by engineering the carbohydrate component present in all such antibodies. In
particular, GlycoMAb specifically increases ADCC, an immune effector mechanism
crucial for the in vivo target-cell killing activity of antibodies.
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Table 2.6 shows the key drug development technologies for generating enhanced
effector functions.
Table 2.6: Drug development technology
Roche GlycoMAb technology Genetically engineering cells to produce bisected non-

fucosylated oligosaccharides. GlycoMAb antibodies
bind with higher affinity immune effector cells, thus
leading to more efficient killing of the antibody-
targeted cells by ADCC.
BioWa Potelligent technology Proprietary technology used to create fucose-free
monoclonal antibodies, with a marked increase in
antibody dependent cellular cytotoxicity (ADCC).
Xencor xmAb engineered Fc xmAb engineered Fc domains can be inserted into an
domains antibody candidates to improve ADCC, improve half-
life and structural stability.
Drug discovery
There are a large number of specialist drug delivery and technology companies in the
mAb market who partner or license with drug developers to discover new antibody
targets. Some of the leading antibody drug developers, such as CAT and UCB Celltech,
also have their own proprietary technologies, as detailed in Table 2.7. Advances in
genomics and proteomics have really been the catalyst of the growth in this segment of
the market.
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Table 2.7: Monoclonal antibody drug discovery technology
CAT Phage Display and Phage Display and Ribosome Display technologies for
Ribosome Display fully human antibody selection and optimization. CAT
has a vast phage antibody library with over 100bn
distinct antibodies.
Dyax Phage display technology Bacteriophage libraries are used to select and produce
high affinity Fab fragments and antibodies, using an
automated screening system.
Morphosys Human Combinatorial HuCAL generates highly specific antibody fragments
Antibody Library and fully human mAb drug candidates. HuCAL
GOLD
has the added benefit of CysDisplay screening
technology.
Symphogen Symplex Platform for the discovery and identification of
monoclonal and polyclonal drug leads.
Ablynx Nanobody platform Single-domain antibody technology used to discover
and develop high-affinity drug leads.
Vaccinex Library-based antibody Two discovery platforms for antibody discovery: the
discovery technology first based on membrane-bound antibody expression
and the second employing secreted antibodies.
Curagen Genomics Potential drug targets are selected and systematically
prioritized using more detailed expression analysis.
UCB Celltech SLAM (selected SLAM generates a diverse range of high-affinity
lymphocyte antibody antibodies against targets which have proven
method) difficult to raise antibodies against by conventional
hybridoma technology
The 3 leading players in antibody discovery in terms of number of licensing deals made
in the last 2 years are CAT, Dyax and Morphosys, which are discussed in more detail
in the following section. For example, Curagen has extensive knowledge about the
human genome and can use this knowledge to aid the development of therapies. Two
key biotechnology companies, Seattle Genetics and Abgenix, have formed an alliance
with Curagen to develop antibody therapies, combining their own antibody engineering
capabilities with targets that Curagen can supply. This provides a strong platform from
which the two companies can develop antibodies, which would not be possible alone.
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Cambridge Antibody Technology
Cambridge Antibody Technology (CAT) (now part of AstraZeneca) has developed

Phage Display and Ribosome Display technologies for the selection and optimization
of fully human antibodies. CAT has created large libraries of antibody genes collected
from the blood of healthy individuals, and currently has a vast phage antibody library
with over 100bn distinct antibodies. The size of CAT's libraries allows the isolation of
antibodies to potential disease targets rapidly and efficiently. Phage display libraries
form the backbone of CATs strategy to develop a portfolio of antibody-based drugs.
Six fully human therapeutic antibodies developed by CAT are in clinical trials, with
Humira (adalimumab) being the first antibody developed by CAT to reach the market,
launched by Abbott in January 2003.
CAT benefits from using its own proprietary phage display technology as it puts the
company in a strong intellectual property position, in addition to the library being
extremely large and thus having the potential to contain high quality fully human
antibodies that will bind specifically to any given target molecule. Phage display is
advantageous as it speeds up the process of antibody production by avoiding the need
for immunization of animals, which takes several weeks to months before antibodies
can be attained. Further benefits include the wide range of target antigens and
automation of processes. CATs competitors within phage display technologies include
Dyax (with whom CAT has a broad cross-licensing agreement), and Morphosys. Key
deals and collaboration using CATs proprietary technology include:
Gala Biotech, a division of Cardinal Health, announced a cell line engineering

collaboration with CAT, May 2005;
CAT partnered with Chugai to develop novel human mAbs in October 2002.
CAT has the largest antibody library compared to Dyax and Morphosys, and thus has a
competitive advantage. The acquisition of CAT by AstraZeneca also makes CAT an
attractive licensing partner, due to a larger financial backing and enhanced reputation.
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Dyax
Dyaxs phage display technology uses libraries that contain bacteriophages which
display Fab antibody fragments, which are utilized to select and produce high affinity
fully human Fab fragments and antibodies using an automated screening system.
Dyaxs phage display libraries were developed by taking gene fragments from human
donors (encoding the light chain variable region and part of the heavy chain variable
region), modified with synthetic DNA that encodes the key antigen recognition sites in
antibodies. Using this technique Dyax has created phage libraries that contain around
45bn human antibody fragments, with distinct antigen recognition sites. The total size
of Dyaxs libraries is over four times larger than MorphoSyss HuCAL phage display
libraries.
Dyaxs key partnerships include AstraZeneca and Biogen Idec, with the majority of
deals focusing on out-licensing its technology and forming research collaborations.
Key deals and collaboration using Dyaxs proprietary technology in the last 3 years
include:
Dyaxs antibody phage display libraries were licensed to Tanox, Inc. for
therapeutic antibody development in November 2004;
Inhibitex and Dyax announced a collaboration to develop monoclonal antibodies

against enterococci in October 2004;
Dyax and URRMA Biopharma announced a co-development agreement for AIDS

antibodies in October 2003.
Although Dyaxs antibody library is smaller than CATs it is larger than Morphosys
library, and thus is more attractive for licensing partners due to the larger choice of
antibodies.
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Morphosys
MorphoSys has developed a proprietary technology to develop human antigens in

laboratories, called HuCAL (Human Combinatorial Antibody Library). The HuCAL
technology is an in vitro method generating highly specific antibody fragments and
fully human antibody drug candidates. Features of the HuCAL system include rapid,
high-throughput generation of fully human antibodies, with a proven success with
difficult antigens (non-immunogenic or toxic antigens), and binding affinity can be
further increased through targeted optimization. The use of MorphoSys proprietary
trinucleotide mutagenesis technology (TRIM) allows the synthesis of any chosen
amino acid at the variable regions of the antibody, allowing a vast structural diversity.
The HuCAL system also allows easy switching between different antibody formats, for
example monomeric Fab fragments can be converted into a dimeric format. When Fab
fragments are inserted into a standard immunoglobulin expression vector, fully human
IgG antibodies can be produced.
HuCAL GOLD combines the advantages of the Fab format found in the HuCAL Fab
library with the advanced selection properties of the proprietary CysDisplay screening
technology: a novel and efficient display technology for selecting high binding affinity
antibodies from libraries using filamentous phage. The Fab format is particularly well
suited for the development of therapeutic antibodies as it guarantees high stability and
monomeric appearance and is easily convertible into a complete human
immunoglobulin without loss of function.
Morphosys key partnerships are with Bayer, Centocor/Johnson & Johnson, Roche and
Schering, who have all integrated HuCAL into their R&D processes. Other recent key
deals and collaboration using Morphosys proprietary technology include:
MorphoSys' antibodies by design and JPT Peptide Technologies announced a

cooperation agreement in April, 2005;
MorphoSys Antibodies by design and Chimera biotech announced a cooperation

and co-marketing agreement in February, 2006.
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Morphosys has the smallest antibody library of the three companies analyzed here, but
does offer the advantage of increased specificity through antibody optimization,
making it a desirable choice as a licensor.
Innovation in drug delivery
Antibodies can currently only be administered by injection or intravenous infusion,

because of the problem of enzymatic protein degradation in the digestive tract. The
restricted route of administration is a limiting factor to the development of the
antibodies market, as patients prefer painless and convenient methods of drug delivery.
As there is a large market potential for more convenient and/or non-invasive delivery
methods, drug companies are tackling this through innovation in:
Drug delivery devices;
Inhaled monoclonal antibodies;
Oral monoclonal antibodies.
Innovative drug delivery devices for use with mAbs are anticipated to reach the market
in the short-to-mid term. Non-invasive mAbs are forecast to reach the market in the
mid-to-long term, with inhaled mAbs anticipated to launch prior to oral mAbs.
Drug delivery devices
Innovations in drug delivery devices can provide more comfortable administration and
easier self administration, and thus result in improved patient compliance. mAbs are
challenging to deliver non-invasively, and continue to be formulated as injectables.
However, more new mAb drugs are for chronic use, such as RA treatment, in which
frequent injections are inconvenient and uncomfortable. Recent developments in less-
invasive, needle-free injection technology are expected to increase patient compliance
and sales potential for new mAbs and other large proteins in development. High-
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pressure delivery could potentially damage fragile molecules, such as mAbs; successful
delivery of such molecules therefore requires a device with carefully controlled power
levels. Examples of delivery devices include pen-injectors (e.g. Confidoses auto-
injector) and needle-free devices (e.g. Aradigms IntraJect), which can be used with
immediate release and sustained release formulations of proteins.
Prefilled devices could also be used with mAbs, which would be more convenient,
ensure accurate dosing and be more useful for RA patients who can find it painful to
use their hands to manually fill a needle. Several companies are involved in
development of this technology, which include Antares Pharma Inc, Aradigm
Corporation, Bioject Medical Technologies Inc and Biovalve Technologies Inc.
Prefilled delivery devices are anticipated to reach the market in the next 5 years as the
technology is already in place. New injectable delivery devices are forecast to boost
mAb sales due their increase in patient compliance, although sales will decline rapidly
once non-invasive mAbs reach the market.
Inhaled monoclonal antibodies
Inhaled antibodies present a viable market due to this delivery method providing an
increase in convenience, and being painless compared to injections. There are no
currently marketed inhaled mAbs; however several products are in development:
Enzon and Nektar have formed a strategic alliance for the development of Enzons
single-chain antibody products using Nektars Pulmonary Particle technology
(inhalable technology);
In preclinical asthma studies, Alexion has demonstrated efficacy of an inhaled mAb

anti-C5 antibody (eculizumab) to block airway hyper responsiveness;
In June 2000, MedImmune, Inc and Alkermes, Inc announced that they had signed
an agreement to develop an inhalable formulation of a mAb targeting the
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respiratory syncytial virus (RSV) using Alkermes AIR pulmonary drug delivery
technology.
Inhaled mAbs are forecast to reach the market after prefilled injectables, but before oral
mAbs. The impact of inhaled mAbs will have a huge positive impact on the mAb
market; however they will cost more than injectables, which already demand a
premium price and therefore act as a resistor to growth. Another resistor to growth will
be the launch of oral mAbs, as they will further increase patient convenience.
Oral monoclonal antibodies
Oral mAb drug delivery is forecast to have the highest market potential, as it provides
the most convenient method of drug delivery. However, this is still at an early-stage of
development and currently inhalation technology is the most advanced non-invasive
method of mAb drug delivery. A key oral technology is Emisphere Technologies
Eligen, which uses carrier agents to protect the protein from digestive enzymes and
facilitate the transport of the molecules across membranes. Another key technology is
Access Pharmaceuticals proprietary vitamin B12 oral drug delivery technology. In
September 2003, Access entered into a research collaboration with Celltech to develop
oral drug delivery options for Celltech's mAbs and antibody fragments. In preclinical
studies, this technology has already demonstrated its potential to facilitate the
absorption of proteins following oral administration.
Oral mAbs are predicted to have the largest impact on sales growth compared to
prefilled injectables and inhaled mAbs, due to oral administration being simple and
pain free. Oral antibodies are not expected to reach the market in the next 5 years.
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CHAPTER 3
The current monoclonal

antibody market
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Chapter 3 The current monoclonal
antibody market
Summary
The leading mAbs are Remicade and Rituxan, with sales of $3.5bn and $3.3bn,
respectively in 2005. However, sales growth of Rituxan is expected to be limited
due to a lack of studies investigating new indications.
The rapid increase in the number of mAb pipeline drugs is a result of innovation
in the market, which has allowed companies to develop fully human drugs with
reduced immunogenicity and mAb fragments that are cheaper to produce and
have a high efficacy.
Despite the high growth in the mAb market, there remain many issues resisting
the market, including mAbs being withdrawn from the market, publicized side-
effects, pricing and reimbursement issues and competition from small molecule
drugs.
Oncology is the largest therapy area within the mAb market, with 8 marketed
products. This therapy area is set to increase with numerous early and late stage
products in development. Key oncology pipeline products include Virexxs
OvaRex, Abgenix/Amgens ABX-EGF and Medarex/Bristol-Myers Squibbs
MDX-010 and MDX-1379.
AIID is the second largest therapy area in the mAb market, with 7 marketed
drugs. Many of the marketed AIID drugs are indicated for the same disease, and
consequently there is a high level of competition between drugs. For example the
leading mAb Remicade, with sales of over $3.4bn in 2005, is indicated for
Rheumatoid Arthritis (RA), as is Humira.
Synagis is the only current anti-infective mAb on the market. However, due to a
large number of early and late stage pipeline products, this therapy area is
expected to expand in the next 5 years. Key pipeline products include Numax and
Aurograb.
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Introduction
The mAb market is an immature market with only 18 currently marketed mAbs
worldwide, and an additional 3 marketed in China and Japan. The total market has
grown rapidly over the last few years and reached $14bn in 2005, an increase of 36.5%
from 2004 sales of $10.3bn. There are numerous factors which have led to the increase
in sales in the market, which are discussed in this chapter, including drug specific
factors such as approvals in additional indications. Other issues have also shaped the
mAb market in the last 2 years, including clinical trials for currently marketed drugs,
regulations, attrition rates and innovation in antibody engineering.
Strategic analysis
The therapeutic mAb market is an area of high growth with many factors influencing
the market, as shown in Figure 3.5.
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Figure 3.5: Drivers and resistors to growth in the monoclonal antibody
market
Drivers
Pipeline products
Immature market
Entry of Big Pharma
High level of innovation
Additional indications
Combination therapies
Publicised side effects
Drugs pulled from market
Competition from small
molecule drugs
Pricing and reimbursement
Resistors
Drivers
Pipeline drugs
There has been an increase in the number of mAb pipeline drugs over the past few
years, which will act as a huge driver to growth. The rapid increase in the number of
mAb pipeline drugs is a result of innovation in the market, which has allowed
companies to develop fully human drugs with reduced immunogenicity and mAb
fragments that are cheaper to produce and have a high efficacy. Another reason for the
surge in pipeline products is the rapid growth seen in the mAb market over the last 5
years, which has made the market highly attractive.
Immature market
A key driver of growth in the mAb market is the limited number of marketed products,
with 18 drugs marketed globally, in addition to MediPharm Biotech/Peregrines Cotara
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and YM Biosciences nimotuzumab in China and Chugais Actemra in Japan. The
mAb market is an immature market, with a huge potential for future growth in a variety
of disease indications.
Big Pharma entering the mAb market
In the last few years Big Pharma has begun to enter the mAb market, which has been
achieved by M&A and licensing deals with biotech companies that have key mAb
pipeline drugs or proprietary technology. Big Pharma are attracted to the mAb market
as it has demonstrated rapid growth in the last few years and it is immature, with a
huge potential for future growth. Big Pharmas entry to the mAb market will act as a
major driver to growth, due to their large financial power to develop and market
pipeline drugs.
High level of innovation
There is a high level of innovation in the mAb market, which is starting to overcome
some of the issues with currently marketed mAbs. This includes advances in antibody
engineering technology, which has allowed the generation of fully human mAbs.
Humira is currently the only marketed fully human mAbs, however key late stage fully
human mAbs include UCBs Cimzia and Genentech/Novartis Lucentis, which are both
anticipated to launch in 2006. Other innovations are in drug delivery, such as extended
release formulations of existing drugs to improve the pharmacological profile.
Controlled release versions allow the patient to reduce the number of doses of drug
required, leading to improved compliance. Examples of innovative drug delivery
technologies include Alzas Alzamer and Alkermess Prolease. Innovations in drug
delivery devices are another driver to mAb growth as prefilled devices are simpler to
use and increase patient compliance. Drug delivery devices that could potentially be
used with the currently marketed mAbs include pen-injectors (e.g. Confidoses auto-
injector) and needle-free devices (e.g. Aradigms IntraJect), which can be used with
immediate release and sustained release formulations of proteins. However, these will
only act as a driver in the mid-long term.
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Approval of new indications
A major driver to growth in the mAb market is the approval of new indications for
existing drugs. In March 2006 the FDA approved an additional indication of Erbitux
for the treatment of squamous cell carcinoma of the head and neck, in addition to its
primary indication in colon cancer. A key driver to Avastins growth includes its
approval for use across renal cell carcinoma, NSCLC and breast cancer, and for use
with a wider range of cytotoxics and approval for adjuvant therapy. The trend of
additional indications being approved for marketed drugs is set to continue, as it is has
been shown to successfully boost sales and extend product lifecycles.
Combination therapies
Another key driver to growth is in combination therapies, which allow current

marketed products to gain access to a wider range of indications and have a larger
patient potential. Rituxan combined with Valcade is currently in clinical trials, as is
Herceptin in combination with Taxol and Abraxane. In addition, Erbitux is in trials
with carboplatin, paclitaxel, cisplatin, and docetaxel, and will allow the range of
indications to be increased if the results are favorable.
Resistors
Publicized side effects
A resistor to the growth of the mAb market is from negative publicity due to adverse
reaction to mAbs. Warnings on FDA approved drugs are available on the FDA website,
in addition to being publicized on the internet on several sites with the information
compiled. Such information could act to scare the general public into requesting
alternative drugs from their physicians, such as competing small molecule products.
The severe adverse side effects seen in Tegeneros TGN1412 trial in the UK raised
public awareness about mAbs and left the general public with a negative opinion
concerning this type of therapy.
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Drugs suspended from market
In February 2005, Biogen Idec voluntarily suspended Tysabri (natalizumab). Biogen

Idec confirmed that one fatality and one additional case of progressive multifocal
leukoencephalopathy (PML) had occurred in patients receiving Tysabri for multiple
sclerosis (MS). There is no known link between Tysabri and PML, however Biogen
Idec suspended Tysabri as a precautionary measure. In June 2006 the FDA formally
agreed to allow Tysabri back on the market. There is still no known link between
Tysabri and PML, but the benefits of the drug are considered to outweigh the risks.
However, the FDA suggested that patients try another MS drug first and avoid drug
combinations while taking Tysabri. The suspension of Tysabri is expected to have a
negative impact on Tysabri sales, due to risks of the drug being highlighted and its use
being limited. The suspension of Tysabri will not act as a significant resistor to the
mAb market as a whole, but it has provided negative publicity that may discourage
some physicians from prescribing mAbs.
Competition from small molecule drugs
Competition from small molecule drugs is a huge resistor to growth for the current
mAb market. The breast cancer market is predicted to become dominated by small
molecule drugs, for example Abraxane (reformulated paclitaxel) and the pipeline drug
GSKs Lapatinib, which will impact on mAb drugs such as Herceptin. Small molecule
drugs are also set to impact sales of the anti-angiogenesis mAb Avastin, with the
launch of Novartis/Bayer AGs pipeline product PTK787 (vatalanib), while Raptiva
and Remicade are predicted to be impacted by Enbrel (Amgen/Wyeth), a protein
targeting TNF.
Pricing and reimbursement schemes
As a result of high pricing, mAbs are not always covered by government pricing
reimbursement schemes, and this limits the mAb market. Enbrel and Humira had
limited coverage under the US Medicare scheme, but as of 2006 are now fully covered.
In the UK, patients with RA are prescribed 2 different DMARDS prior to mAb therapy
under the NHS, which is largely due to the high price of mAbs.
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Analysis of launched drugs
The market dynamics of the current marketed mAbs are shown in Figure 3.6 and Table
3.8. The leading mAbs are Remicade and Rituxan, will sales of $3,477m and $3,323m,
respectively in 2005. However, sales growth of Rituxan is expected to be limited due to
a lack of studies investigating new indications, while Remicade is predicted to have
limited future growth due to continuing competition from Humira and from UCBs
pipeline mAb Cimzia. The highest sales growth during 2005 has been seen for Avastin,
139.4% ($556.5m), which is mainly due to approval for use a range of indications:
renal cell carcinoma, NSCLC and breast cancer, and for use with a wider range of
cytotoxics and approval for adjuvant therapy. The largest decline in sales growth was
for Orthoclone OKT3 (-23.7% in 2005), which is primarily because of Orthoclones
murine composition leading to adverse reactions such as fever, nausea and vomiting.
Figure 3.6: Market dynamics of current marketed drugs, 2004-5
200%
Avastin
150% Erbitux
Sales growth, 2004-5 (%)
Bexxar Humira
100% Herceptin
Tysabri Xolair Remicade
Raptiva Rituxan/
Zevalin 50%
MabThera
Campath
Mylotarg
Simulect Synagis
0%
-1000 -500 0 500 1000 1500 2000 2500 3000 3500 4000
Zenapax ReoPro
-50%
Orthoclone OKT3
-100%
Sales, 2005 ($m)
AIID Oncology Anti-infective Respiratory Hemostasis
Bubble size represents market share
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Table 3.8: Marketed therapeutic monoclonal antibodies, 2004-5
Brand Generic Company Therapy Sales ($m) Sales Market

area 2004 2005 Growth Share
2004-5 2005
Remicade infliximab Centocor, Schering AIID 2,891.0 3,477.0 20.3% 24.8%

Plough
Rituxan rituximab Genentech, Roche Oncology 2,724.2 3,323.2 22.0% 23.7%
Herceptin trastuzumab Genentech, Roche Oncology 1,148.0 1,730.6 50.8% 12.4%
Humira adalimumab Abbott, CAT AIID 852.0 1,400.0 64.3% 10.0%
Avastin bevacizumab Genentech, Roche Oncology 556.5 1,332.0 139.4% 9.5%
Synagis palivizumab MedImmune Anti-infective 942.3 1,060.9 12.6% 7.6%
Erbitux cetuximab Merck KGaA, Oncology 343.8 751.7 118.6% 5.4%
ImClone
Xolair omalizumab Genentech Respiratory 188.0 326.4 73.6% 2.3%
ReoPro abciximab Lilly Hemostasis 362.8 296.7 -18.2% 2.1%
Raptiva efalizumab Genentech AIID 52.0 79.0 51.9% 0.6%
Campath alemtuzumab Genzyme Oncology 51.5 60.8 18.1% 0.4%
Simulect basiliximab Novartis AIID 49.7 54.9 10.5% 0.4%
Zenapax daclizumab Roche AIID 32.1 29.9 -6.9% 0.2%
Zevalin ibritumomab Biogen Idec Oncology 24.0 28.4 18.3% 0.2%
tiuxetan
MyloTarg gemtuzumab Wyeth Oncology 26.0 25.6 -1.5% 0.2%
ozogamicin
Orthoclone muromonab- Johnson & AIID 17.3 13.2 -23.7% 0.1%
OKT3 CD3 Johnson
Tysabri natalizumab Biogen Idec, Elan AIID 6.4 11.0 71.9% 0.1%
Bexxar tositumomab Corixa Oncology 3.8 8.2 115.8% 0.1%
-I131
Total 10,271.3 14,009.5 36.4% 100.0%
Source: Business Insights; Annual reports; IMS Business Insights Ltd
The mAb market consists of 18 marketed drugs covering oncology, AIID, homeostasis
(cardiovascular), respiratory and infectious disease therapy areas. Oncology and AIID
are the predominant therapy areas with 8 and 7 marketed drugs, respectively, as shown
in Figure 3.7.
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Figure 3.7: Marketed monoclonal antibodies by therapy area, 2006
Respiratory:
Xolair
Anti-infective:
Synagis
Hemostasis:
ReoPro 6%
6%
6% Oncology:
Avastin
Bexxar
Campath
Marketed 43% Erbitux
Herceptin
AIID: mAbs Mylotarg
Humira Rituxan/MabThera
Orthoclone OKT3 Zevalin
Raptiva 39%
Remicade
Simulect
Tysabri
Zenapax
Oncology
Oncology is the largest therapy area within the mAb market, with 8 marketed products.
The oncology therapy area is well suited for mAbs, which can be used to target cancer
cells whilst leaving the surrounding tissue intact. The highest selling oncology drug is
Rituxan, indicated for NHL with sales of $3.3bn in 2005, an increase of 22% from the
previous year. Other oncology mAbs competing in the NHL market include Bexxar and
Zevalin, although Rituxan has the first to market advantage. Another key oncology
drug is Herceptin, which achieved sales of $1.7bn in 2005, an increase of 50.8%.
Herceptin is indicated for HER2 overexpressing metastatic breast cancer and is
currently the only mAb approved for this indication, and thus has a high sales potential
due to a lack of competition. However, Avastin is currently being developed for breast
cancer, which if approved will impact sales of Herceptin. Avastin is already approved
for the indication of colorectal cancer and had sales of $1.3bn in 2005, an indication in
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which it faces competition from Erbitux. Avastin has the competitive advantage over
Erbitux as it is humanized rather than chimeric and provides lower immunogenicity.
Campath is indicated for B cell chronic lymphocytic leukemia, which is a relatively
niche indication, and consequently sales are limited at $60.8m. However, sales of
Campath grew 18.1% in 2005, which is attributed to the drugs monopoly of the market
due to a lack of competition. MyloTarg had the largest decrease in sales growth of the
oncology mAbs during 2005 at -1.5%, which is due to its small patient potential for
older AML patients. Despite this, sales of Mylotarg are not predicted to decline further
as combination therapies are expected to be launched in the next 2 years, which will
sustain sales.
The oncology therapy area is set to grow further in the future with numerous early and
late stage products in development Key oncology pipeline products include Virexxs
OvaRex, Abgenix/Amgens ABX-EGF and Medarex/Bristol-Myers Squibbs MDX-
010 and MDX-1379.
Rituxan
Rituxan (rituximab) was originally developed by Biogen Idec and is marketed by

Genentech, Roche and Chugai, and is indicated for Non-Hodgkins Lymphoma (NHL).
Rituxan is a chimeric mAb targeting CD20, a receptor found on some B cells and
initiates cell death via ADCC and complement activation. Rituxan was launched in the
US in December 1997, and approved in the EU in June 1998 as MabThera for the
additional indication of stage III-IV follicular lymphoma in patients who are chemo-
resistant or in their second or subsequent relapse after chemotherapy. In March 2002,
MabThera was approved in the EU for use in the treatment of aggressive NHL with
standard chemotherapy. More than 370,000 patients have been treated with rituximab
worldwide, and it is marketed in the US, UK, Japan, Australia and Argentina for
transplant rejection and dermatitis. Global sales of Rituxan reached $2,724.2m in 2004,
which increased 22% in 2005 to $3,323.2m.
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Rituxan is widely regarded as the standard treatment of NHL and has a significant first-
to-market advantage. Competitors include GSKs Bexxar (tositumomab), a murine
CD20 monoclonal antibody conjugated to Iodine-131, and Biogen Idecs Zevalin
(ibritumomab tiuxetan), a murine anti-CD20 mAb conjugated to either Indium-111 or
Yttrium-90. In May 2003, Millenniums Velcade (bortezomib) received approval for
the indication of multiple myeloma, and one month later generated positive data in
Phase II studies for NHL. Millennium therefore, intends to expand into the NHL
market, which is a threat to Rituxan sales. However, Phase II NHL trials have since
begun for combined Velcade and Rituxan therapy. Positive results of the
Velcade/Rituxan trial will increase sales of Rituxan. Immunomedicss anti-CD22
humanized mAb, Lymphocide (epratuzumab), was under clinical development with
Amgen for NHL, in both unconjugated and Yttrium-90 conjugated forms. However,
Amgen recently returned the rights to the product to Immunomedics since the
companies were unable to agree on terms and the product is not set to launch over the
forecast period.
Rituxan has been investigated for the indication of RA. In September 2005, Roche filed
for EU approval for MabThera for patients with the most difficult-to-treat RA.
Genentech and Biogen Idec have also submitted a US filing under the Rituxan brand.
Rituxan is currently marketed in Japan by Chugai, which is expected to continue for the
RA indication, and sales are anticipated to increase due to the additional indication.
However, it will be the fifth biologic to be approved for RA, so will suffer from strong
competition from Remicade, and the novel IL-6 inhibitor Actemra.
Clinical trials investigating the use of Rituxan for the indication of RA have had
positive results. In April 2005 Roche, Genentech and Biogen Idec announced that the
Phase III REFLEX (Randomized Evaluation oF Long-term Efficacy rituXimab in RA)
had successfully met its primary endpoint in RA patients who have a poor response to
anti-TNF therapies. Analysis of the Phase IIb trial DANCER (Dose-ranging
Assessment iNternational Clinical Evaluation of Rituxan in RA) showed significant
efficacy of a single course of rituximab in RA (when combined with methotrexate),
which was independent of glucocorticoid treatment.
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Rituxan is also being evaluated in the following immunological studies: Phase II/III
clinical trials for primary progressive MS, ANCA-associated vasculitis, and systemic
lupus erythematosus; a Phase II clinical trial in relapsed remitting MS; and a Phase
II/III clinical trial in lupus nephritis.
Sales of Rituxan are forecast to continue to grow, reaching $4,122.3m in 2011. Sales
are anticipated to be driven by expansion of indications, including RA, MS, Systemic
Lupus Erythematosus and ANCA-associated vasculitis.
Herceptin
Herceptin (trastuzumab) was developed by Genentech, who market the drug in the US,
where it was first launched in 1998. Roche market Herceptin in Europe, following its
launch in Switzerland in August 1999. Herceptin is an anti-human epidermal growth
factor 2 (EGF2/HER2) humanized mAb indicated for the treatment of HER2-
overexpressing metastatic breast cancer. Herceptin inhibits EGF2-mediated cell
proliferation, obstructing breast cancer development and decreasing tumor size in
patients with tumors that over express the HER2 receptor. Herceptin is approved for
use as a first-line therapy in combination with Bristol-Myers Squibbs Taxol
(paclitaxel), and as a second- and third-line therapy as a single agent. Sales of
Herceptin reached $1,730.6m, a 50.8% increase on the previous year sales.
In December 2003, Roche announced the results from a clinical study evaluating
Herceptin in combination with Aventis Taxotere (docetaxel) as a first-line treatment
for HER2-positive metastatic breast cancer patients, demonstrating an increase in
median survival of 51%, or 9.4 months. Data presented in 2004 showed that Phase II
trials investigating Herceptin plus anthracycline demonstrated a significant increase in
pathological complete response. Additionally, there were no recorded cases of
congestive heart failure, which has previously been a concern. Herceptin is under
development in Phase III trials as a potential adjuvant therapy in early breast cancer.
Genentech is also about to complete an additional Phase II trial investigating Herceptin
as a potential therapy for ovarian cancer. In April 2005, preclinical trial data indicated
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that a Herceptin/Taxol combination may be effective in treating Ewing sarcoma.
However, Genentechs attempts to expand the indication range of Herceptin have been
largely unsuccessful.
There are no other mAb therapies approved for the treatment of breast cancer and
Herceptin has a significant first-to-market advantage. In the next 5 years the breast
cancer market is likely to be dominated by reformulated small molecule cytotoxics and
targeted therapies to form complex combinations to tailor therapies to specific patient
subgroups. One example is American BioSciences Abraxane, a reformulated
paclitaxel, which reduces the toxicity and formulation issues associated with Bristol-
Myers Squibbs Taxol. Phase II clinical trials are underway for Abraxane/Herceptin
combined therapy for the indication of locally advanced or metastatic breast cancer. All
patients will receive Abraxane, plus HER2-positive patients will additionally receive
Herceptin. The primary study endpoint is response rate and the secondary study
endpoints are time to tumor progression, overall survival and toxicities. Approval for
the combination should have a small positive impact on Herceptin sales.
Herceptin is currently the strongest product within the breast cancer biologics market,
although pipeline products such as GSKs lapatinib, a dual kinase inhibitor that targets
both EGFR and HER-2, are set to increase competition. Lapatinib is currently in Phase
III trials, and earlier trials indicate that patients unresponsive to Herceptin respond to
lapatinib. Additionally, Medarexs anti-HER2 bispecific humanized antibody will also
compete following its launch, although as this is currently in Phase II clinical trials it is
not forecast to be launched in the next 5 years.
Genentech list a number of factors contributing to the sales growth of Herceptin,

including an extension of the average treatment duration, increased first-line
penetration, growing adoption for unapproved use of the combination of Herceptin,
carboplatin and taxane and price increases of Herceptin. Future growth is likely to be
driven by use of the product in an adjuvant setting, for which it is currently in Phase III
trials. In April 2005, Genentech announced that interim analysis of two large Phase III
trials indicated that Herceptin significantly increases both disease-free survival and
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overall survival for women with early-stage HER2-positive breast cancer. The two
studies evaluated use of Herceptin plus chemotherapy compared to chemotherapy alone
following initial surgical treatment. However, a resistor to sales growth is from safety
concerns over Herceptin being associated with heart damage.
The key factors affecting Herceptins forecast sales are strong Phase III trial data for
the use of Herceptin in the adjuvant setting and the approval of lapatinib that will
increase competition and reduce sales of Herceptin. Additional factors include a greater
uptake of the combination of Herceptin, carboplatin and taxane, continued sales from
prolongation of treatment duration, Herceptins first-to-market position, plus two
approved diagnostic tests for HER2 to boost patient potential in Europe. Sales of
Herceptin are forecast to continue to increase reaching $2,025.4m in 2011.
Avastin
Avastin (bevacizumab) was approved by the FDA in February 2004 and is marketed by
Genentech in the US and Roche in Europe. Avastin is an IgG1 mAb directed to the
vascular endothelial growth factor (VEGF), critical for blood vessel formation
facilitating tumor growth, invasion and metastasis, and thus is an anti-angiogenic
cancer drug. Sales of Avastin reached $1,332m in 2005, an increase of 139.4% on the
previous year sales.
Avastin is approved for first-line treatment of metastatic colorectal cancer in

combination with a 5-FU-based regimen in the US. Genentech is preparing to file
Avastin for first-line non-squamous NSCLC in the US. Chugai, through its alliance
with Roche, is developing Avastin for the Japanese market. Chugai is filing for
approval later this year and the agent may be launched in 2007 for colorectal cancer.
In August 2004, Genentech and the FDA released a warning highlighting the risk of
serious thromboembolic events with Avastin, including cerebrovascular accidents,
myocardial infarctions, transient ischemic attacks, and angina, related to the use of
Avastin. Avastin may increase serious arterial thrombotic events in up to 5% of
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patients, which is double the number than in patients receiving chemotherapy alone.
However, given that the product is meeting a high unmet need in a life-threatening
indication, and demonstrates a strong efficacy, it is unlikely to be a major issue.
Cytotoxic therapies have been the traditional treatment in colorectal cancer, but the
recent introduction of Avastin and BMS/Merck KGaA/ImClones Erbitux (cetuximab)
have transformed the market. Avastin is relatively well tolerated and, because it is a
humanized mAb rather than a chimeric monoclonal antibody like Erbitux, it offers a
lower risk of immune-related side effects.
Recent Phase III trial data indicated that patients with second-line metastatic colorectal
cancer receiving Avastin plus FOLFOX4 (oxaliplatin, 5-fluorouracil and leucovorin)
had a 26% reduction in the risk of death, compared to patients who received FOLFOX4
alone. Median survival for patients receiving Avastin plus FOLFOX4 was 12.5 months,
compared to 10.7 months for those receiving FOLFOX4 alone, a 17% improvement. A
preliminary assessment of the safety profile suggested that Avastin could be combined
safely with FOLFOX4 and adverse events observed in this study were consistent with
other clinical trials in which Avastin was combined with chemotherapy.
Over the short to medium term, the only new competitive threat to Avastin in the anti-
angiogenesis market is likely to come from Novartis/Schering AGs PTK787
(vatalanib). PTK787 is an oral, small-molecule angiogenesis inhibitor that targets
VEGF receptors in addition to platelet-derived growth factor receptor (PDGFr). Early
trial results indicate that PTK787 is comparable, if not slightly more favorable, than
Avastin in terms of response rate and median time to progression. Within the anti-EGFr
product class, the successful development of Amgens fully human anti-EGFr
monoclonal antibody ABX-EGF (panitumumab) will be a competitor to Avastin,
particularly given its reduced immunogenicity profile and its effectiveness as a
monotherapy. ABX-EGF is currently in Phase III trials and set to launch in 2007.
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The key factors affecting Avastins forecasted sales include the launch of PTK787
(vatalanib) and ABX-EGF, and further competition from Erbitux (cetuximab). Key
drivers to growth include Avastins approval for use across renal cell carcinoma,
NSCLC and breast cancer, and for use with a wider range of cytotoxics and approval
for adjuvant therapy. However, warnings that Avastin doubles risk of blood clots will
slightly limit uptake of the drug. Sales of Avastin are forecast to reach $3,741.4m in
2011.
Erbitux
Erbitux (cetuximab), formerly known as IMC-C225, is a chimeric monoclonal IgG1

antibody targeting epithelial growth factor receptor (EGFR). It blocks the signal
transduction of epidermal growth factor (EGF), and other ligands such as transforming
growth factor-alpha, which results in inhibition of cell growth, induction of apoptosis,
and decreased matrix metalloproteinase and vascular endothelial growth factor
production. Over-expression of EGFR is detected in many human cancers including
those of the colon and rectum. Sales of Erbitux reached $751.7m in 2005, an increase
of 118.6% compared to $343.8m in 2004.
Erbitux was developed by ImClone, and in February 2001, received a Fast Track
designation for the treatment of refractory colon cancer. ImClone made a licensing deal
with Bristol-Myers Squibb (BMS) in September 2001 to co-develop and market
Erbitux in the US, Canada and Japan, with a cash payments to ImClone of $1bn,
together with royalty payments on Erbitux sales (around 30% of BMS sales), and
BMS also made a $1bn equity investment in ImClone. In June 2004 Merck KGaA
gained European marketing rights for Erbitux. As Merck KGaA carried out substantial
clinical trials for Erbituxs approval, ImClone receives a much lower royalty of 4-5%
on Merck KGaAs sales.
Erbitux use is restricted to patients who over-express EGFR (EGFR-positive),

estimated at 77% of the colorectal cancer patient population. Patient suitability is
assessed through EGFR testing. While this does not dramatically limit Erbitux usage,
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trials were started in the summer of 2004 in EGFR-negative patients. This trial is due to
end in early 2006, and positive results could ultimately enable an increase in Erbitux
patient potential of 20-25% if no EGFR testing is required.
In March 2006 the FDA approved an additional indication of Erbitux for use in the
treatment of squamous cell carcinoma of the head and neck. Late-stage trials continue
for Erbitux both as a single agent and in combination with radiation (for locally
advanced head and neck cancer), irinotecan (for refractory colorectal carcinoma),
gemcitabine (for metastatic pancreatic carcinoma), carboplatin and paclitaxel (for stage
IV non-small-cell lung cancer; NSCLC), cisplatin (for colon carcinoma), cisplatin and
5-FU or paclitaxel (for metastatic or recurrent head and neck cancer), cisplatin and
radiation (for head and neck cancer), irinotecan, leucovorin and 5-FU (for newly
diagnosed stage IV colorectal cancer), carboplatin and gemcitabine (for chemotherapy-
naive stage IV NSCLC), and docetaxel (for recurrent or progressive NSCLC).
Additional approvals for pancreatic cancer and head and neck cancer could lead to
further strong sales for Erbitux within these niche markets, although the NSCLC
market is forecast to be extremely competitive by the time of Erbituxs approval.
Sales of Erbitux have been strong as a result of its fulfillment of a high unmet need in
advanced colorectal cancer. However, since its US launch, Erbitux has continued to
create controversy, for example over its premium $10,000 per month price-tag, which
has pushed it into the Forbes 2004 overpriced drugs list. To counter this, Erbituxs
intended duration of treatment is short (according to its labeling), at six weeks as a
monotherapy, and at 16 weeks in combination.
ImClone and BMS are looking to expand Erbituxs range of indications to widen
patient potential, and thus boost sales. To enable this, Erbitux is being studied as a
single agent, in combination with first- and second-line FOLFOX (oxaliplatin, 5-FU,
leucovorin) and FOLFIRI (irinotecan, 5-FU, lecovorin) regimens, and a US
government-sponsored study was announced in January 2005 to compare Erbitux and
Avastin treatments for newly diagnosed colon cancer patients. Patients will receive
Avastin, Erbitux or both drugs, all together with chemotherapy. This could provide
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Erbitux with an extremely lucrative first-line opportunity, and in this respect the results
of these clinical trials will be immensely influential for the commercial future of
Erbitux. In the meantime, Erbitux should achieve growing success through its
secondary indications for head and neck cancer (from 2006), and subsequently from
NSCLC and possibly pancreatic cancer.
Sales of Erbitux are forecast to reach $2,177.2m in 2011, which is a steady increase in
sales based on the approval of new indications such as NSCLC and from use in
combination therapy.
Campath
Campath (alemtuzumab) was launched in May 2001 in the US and in August 2001 in
Europe (as MabCampath) for the treatment of B-cell chronic lymphocytic leukemia (B-
CLL) in patients who have been treated with alkylating agents and who have failed
fludarabine therapy. Sales of Campath reached $60.8m in 2005, an increase of 18.1%
from the previous year.
In December 1999, the drugs developers, ILEX and LeukoSite (now Millennium),
filed a BLA with the FDA and received orphan drug designation for Campath. It also
benefited from Fast Track review and on 8 May 2001 received FDA approval. Campath
was approved by the European Agency for the Evaluation of Medicinal Products
(EMEA) in July 2001. In August 1999, Schering AG obtained exclusive worldwide
marketing rights for Campath, excluding Japan and East Asia, from Millennium and
ILEX oncology. In February 2003, Schering AG acquired the rights for Campath in
Japan, China and East Asia, giving the company worldwide marketing rights for the
product. ILEX was subsequently acquired by Genzyme in April 2004 for $1bn, but the
agreement for Campath with Schering AG has remained in place. Genzyme has the
rights for additional indications of Campath (NHL and MS) and should record revenue
for these, though the product is not expected to launch until after 2011 for either of
these indications.
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Genzyme is conducting trials for Campath for additional indications. Campath is in
Phase II trials for multiple sclerosis (MS) and Phase I trials for Non-Hodgkins
Lymphoma (NHL). Schering AG and Genzyme are conducting postmarketing studies
comparing alemtuzumab with chlorambucil to evaluate the safety of Campath in B-
CLL therapy.
In January 2003, ILEX (now Genzyme) started a Phase II trial in the EU to compare
Campath with Seronos Rebif (interferon beta-1a) for treatment of patients with early,
active relapsing-remitting MS. In December 2004, positive clinical data from a trial to
study the efficacy and toxicity of Campath in patients with relapsed or refractory
cutaneous T-cell lymphomas and peripheral T-cell lymphomas (NHL) were presented
at the 46th ASH meeting in San Diego. This trial was conducted for over a year in 10
patients. Complete response (CR) was achieved in two patients, four showed partial
responses and four showed no response.
Sales of Campath are anticipated to grow, as there is a lack of alternative treatments.

However, sales will be limited by the relatively small CLL patient population, so the
drug will be restricted in its future growth. Sales of Campath are forecast to reach
$160.8m in 2011.
Zevalin
Zevalin (ibritumomab tiuxetan) is a conjugated mAb (combined with the radioisotope

yttrium-90 (Y-90)) directed against the CD20 antigen. The drug was the first
radioimmunotherapy approved by the FDA for the treatment of cancer and it is
designed to deliver a therapeutic dose of radiation to malignant B-lymphocytes in
patients with B-cell NHL, as well as on normal mature B-lymphocytes. Zevalin
contains a tiuxetan chelator, which provides a stable linkage between the antibody and
the radioisotope. The beta emission from the isotope induces cellular damage by
forming free radicals in the targeted and neighboring cells.
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Zevalin was developed by Biogen Idec and launched in the US in 2002. In June 1999,
Biogen Idec out-licensed the rest of world rights to Schering AG and in 2004, the
EMEA granted marketing approval in the EU for the treatment of adult patients with
CD20+follicular B-cell NHL who are refractory to or who have relapsed following
Rituxan therapy. Zevalin has been marketed in the EU since 2004 with Biogen Idec
receiving royalties from Schering AGs sales. Sales of Zevalin in 2005 reached
$28.4m, compared to $24.0m in 2004, an increase of 18.3%.
The key competitor for Zevalin is GSKs Bexxar (tositumomab), an anti-CD20 mAb
radiolabeled with iodine-131, which is structurally similar to Zevalin with the
exception of the radioisotope that is used. Bexxar was originally developed and
marketed by Corixa and first demonstrated anti-tumor activity in NHL as early as 1990.
However, Bexxar did not reach the US market until June 2003 giving Zevalin the first
to market advantage.
Bexxar has the distinct disadvantage in that it emits gamma radiation and has a longer
radioactive half-life whereas Zevalin emits radiation and has a relatively short half-
life. Radiation safety measures have to be implemented when using Bexxar, with
treatment requiring a lead shielded hospital room where the patient is kept in partial
isolation. Due to the long half life of the treatment, the patient must be kept from
friends and family until they are no longer deemed a radioactive hazard. The additional
costs and inconvenience associated with patient isolation and safety measures required
to protect staff from Bexxars radiation make Zevalin an easier and cheaper drug to
administer. A Phase III clinical trial is currently recruiting, which will compare Zevalin
versus Bexxar in relapsed or transformed follicular lymphoma. The study is expected to
show favor for Zevalin, further broadening the gap between the two drugs within the
marketplace.
Another competitor to Zevalin is Millennium Pharmaceuticals Velcade, which is the

first in a new class of medicines called proteasome inhibitors and is now fully approved
for use in relapsed mantle cell lymphoma (MCL), a very specific form of lymphoma
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with a very small patient population. This drug, although not a direct competitive threat
to Zevalin, may slightly reduce its patient population through off-label usage.
Zevalins sales potential (like Bexxar) is restricted in that its use is limited to patients
who have become refractory to Rituxan. Although Zevalin has shown some positive
clinical data, concerns have been raised over the possibility of secondary tumors
developing over time due to the use of internal radiation therapy. Toxicity in the form
of myelosuppression, secondary leukemia and myelodysplastic syndrome is also
associated with both Bexxar and Zevalin treatment. Zevalins market potential may be
restricted due to its high cost.
Despite a drop in sales for Zevalin in 2004, revenues are expected to increase over the
next 5 years. There are a number of factors which are expected to contribute to
Zevalins growth including increasing market investment to support US sales with 800
prescribing centers. Biogen Idec is also investing in their US marketing strategies to
ensure greater future market penetration. More noticeably however, are the number of
factors which are expected to limit the up-take and subsequent growth of Zevalin over
the next 5 years. These include increasing competition from Bexxar, high pricing and
inconvenient administration of Zevalin, pricing pressure and difficulty penetrating the
European market. Sales of Zevalin are forecast to reach $84.8m in 2011.
MyloTarg
MyloTarg (gemtuzumab ozogamicin) consists of a cytotoxic drug (calicheamicin)

linked to a humanized mAb specific for the CD33 antigen, a glycoprotein commonly
expressed by myeloid leukemic cells. Calicheamicin was originally isolated by Wyeth-
Ayerst from a bacterium in caliche clay. MyloTarg is delivered via a two-hour infusion
once every 14 days for up to three courses of treatment. The antibody portion of
MyloTarg was developed by Fred Hutchinson Cancer Research Center in Seattle,
subsequently licensed to Wyeth, and was then humanized by Celltech. MyloTarg
gained fast track FDA approval in the US on May 18 2000 for the treatment of acute
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myeloid leukemia (AML), and was launched in the US by Wyeth in June 2000. Sales
of MyloTarg were $25.6m in 2005, a 1.5% decline in sales from the previous year.
Sales of MyloTarg have been limited, due to the restrictive approval of MyloTarg for
only a small subset of AML patients (60 years and older), as second-line therapy.
MyloTarg was an innovative product when launched, but sales have not reflected this.
Nevertheless, Wyeth considers MyloTarg as an important treatment option for older
patients with relapsed CD33-positive AML who are often unable to tolerate
conventional combination chemotherapy. In addition, the fact that MyloTarg can be
administered in out-patient settings is desirable to many patients. In order to make
MyloTarg a commercial success, Wyeth clearly needs to expand its indications. Wyeth
plans to broaden MyloTargs list of indications to include other categories of AML,
including pediatric relapsed AML, and has begun trials to test the drug in combination
with other chemotherapies to increase the response rate in first-line therapy.
In July 2004, a study by the Catholic University of the Sacred Heart in Rome reported
that recombinant human granulocyte colony-stimulating factor (rhG-CSF) can enhance
the efficacy of gemtuzumab ozogamicin (MyloTarg) treatment in AML patients.
Another study by the Erasmus Medical Center published in June 2004 stated that
gemtuzumab ozogamicin (MyloTarg) induces remission in approximately 30% of
relapsed AML patients. MyloTarg has shown promise in combination trials, and this
should boost sales growth for new approved indications and for off-label combination
therapy usage. Several randomized Phase III trials are examining MyloTarg as a first-
line therapy for patients with newly diagnosed AML. The approval of MyloTarg as a
first-line drug would be financially beneficial for Wyeth. However, MyloTarg is an
expensive therapy, which is likely to act as a resistor to sales. Further, the risk of veno-
occlusive disease following therapy may make some physicians reluctant to prescribe
this drug if the patient is likely to need transplant imminently.
Sales of MyloTarg are forecast to reach $66.3m in 2011. Major factors affecting this
forecast include the expanded use of MyloTarg within combination therapies currently
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under evaluation and the launch in the EU and Japan for AML by late 2005 to early
2006.
Bexxar
Bexxar (Tositumomab-I131) is a mAb that targets the b-cell marker CD20 and is
attached to a radioactive iodine isotope. The compound is indicated for the treatment of
non-Hodgkins lymphoma (NHL). Bexxar received FDA approval in June 2003, having
experienced a number of regulatory delays despite its orphan drug status. Sales of
Bexxar reached $8.2m in 2005, an increase of 115.8% from 2004 sales.
Bexxar was developed by Corixa and initially co-licensed to GSK in the US market,
with Amersham Health acquiring marketing rights in Europe. In December 2004, GSK
announced that it had reached an agreement with Corixa to acquire worldwide rights
relating to the manufacture, development and commercialization of the Bexxar
franchise. Corixa initially filed its BLA for Bexxar in September 2000, and the FDA
requested additional clinical and manufacturing data on two occasions, but gained
approval in June 2003 and GSK and Corixa announced that Bexxar was available on
the market at the end of July 2003.
Clinical trials have shown positive results for Bexxar, including a pivotal study
involving a combined patient population of 432 patients who had failed previous
treatment with traditional chemotherapy or with unconjugated mAb therapy, 58% of
patients treated with Bexxar entered remission and remained free of disease
progression at interim analysis. Analysis of data concerning 582 patients with relapsed,
refractory low-grade or transformed low-grade NHL who received Bexxar in clinical
trials, showed that Bexxar produced an overall response in 57% of patients, half of
whom remained in remission for 14.3 months or more. Around 28% of patients showed
total elimination of disease, confirmed by clinical or radiological evaluation, after
Bexxar therapy. Half of these patients remained in remission for five years or longer. In
another study reported at the American Society of Hematology meeting, Bexxar in
combination with chemotherapy (fludarabine) was administered as part of a first-line
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regimen in 35 patients. All patients responded to the treatment, with 77% achieving a
complete response. After a median of 23 months of follow-up, more than half of the
patients showed no signs of disease progression.
Bexxar plus traditional chemotherapy (cyclophosphamide, doxorubicin, vincristine and

prednisone) is being investigated for the treatment of other types of NHL. Grade IV
toxicities were reported in over a third of the evaluable patients and 13% experienced
additional Grade IV toxicity who had received the standard chemotherapy. In 17
patients (24%), the addition of Bexxar to standard chemotherapy improved the overall
best response, either from a partial to a complete response or from an unconfirmed to a
confirmed complete response.
The uptake of Bexxar will be impacted by Biogen Idecs Zevalin (a CD20 targeted
mAb connected to Yttrium-90), Bexxars direct competitor, which was approved by the
FDA in February 2002 thus gaining a first to market advantage. In clinical trials,
Bexxar was reportedly associated with stronger immune targeting of the antibodies
compared to Zevalin. However, Bexxar potentially offers clinical advantages in terms
of its conjugate, as I-131 is associated with a much longer half-life, and therefore a
greater period of efficacy, than Zevalins Yttrium-90. I-131s half-life has been
measured at eight days, versus around three days for Yttrium-90. Bexxar also offers
advantages gleaned from its long approval process, which has resulted in the drug
being tested in a higher than average number of clinical trials, with more diverse
patient populations and complementary therapies, before launch. Sales of Bexxar are
forecast to reach $41.1m in 2011.
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AIID
AIID is the second largest therapy area in the mAb market, with 7 marketed drugs.
Many of the marketed AIID drugs are indicated for the same disease, and consequently
there is a high level of competition between drugs. For example the leading mAb
Remicade, with sales of over $3.4bn in 2005, is indicated for RA as is Humira. Humira
is the first fully human mAb to market, which has the advantage of having lower
immunogenicity compared to chimeric or human antibodies. However, Remicade has
the first to market advantage in the mAb RA market and is being developed for
additional indications, such as Ulcerative Colitis, that will increase its patient potential.
Both Orthoclone OKT3 and Zenapax are approved for organ transplant rejection.
Zenapax has the competitive advantage over Orthoclone OKT3 as it is a humanized
mAb rather than murine, and thus Zenapax has a more favorable side effect profile.
Zenapax is also in development for MS and asthma in order to increase its indications
and boost sales.
Like the oncology therapy area, there are many AIID drugs in development, suggesting
that this will continue to be a major area of the mAb market. Key pipeline drugs
include UCB Celltechs Cimzia and Alexions Soliris.
Remicade
Remicade (infliximab) was developed by Centocor, which became a wholly owned

subsidiary of Johnson & Johnson in October 1999. Remicade was launched in the US
in 1998 for the treatment of Crohns disease, and was approved by the FDA in 1999 for
RA. Schering-Plough has international marketing rights to Remicade outside the US,
except in Japan and parts of East Asia. Tanabe holds distribution rights to Remicade in
Japan (launched in 2002), and co-exclusive rights in parts of East Asia. Remicade is the
market leading mAb, with sales of $3,477m in 2005, an increase of 20.3% from 2004.
Remicade is a chimeric IgG antibody which targets a key mediator of inflammation,

tumor necrosis factor alpha (TNF-a), and neutralizes its activity. Remicade has
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benefited from its first-to-market status as the first mAb for Crohns disease and RA.
Remicade is also indicated for psoriatic arthritis, ankylosing spondylitis, ulcerative
colitis and pediatric Crohns disease. However, RA is the key indication for Remicade
generating the majority of sales, with the additional indications contributing to growth
by widening the potential patient population.
Remicade faces strong competition from Amgen/Wyeths Enbrel (etanercept), a

dimeric fusion protein targeting TNF, which was the first biologic launched for
rheumatoid arthritis. It was approved in November 1998 in the US for moderate to
severe rheumatoid arthritis for use in combination with methotrexate in patients who
have not previously responded to methotrexate therapy. However, Remicade was able
to overtake Enbrels market leader position because of Enbrels limited manufacturing
capacity when it was first launched, which has since been resolved. While the key
disadvantage of Remicade is that it is administered intravenously and thus has to be
administered by healthcare professionals, Enbrels dosing regimen also has its
disadvantages. While Enbrel is administered by subcutaneous injections allowing the
self-administration by the patients themselves, it requires a far higher frequency of
dosing (twice-weekly) than Remicade (once every eight weeks). Remicade now has an
advantage over Enbrel, as a result of the FDA approving Remicade in combination
with methotrexate as a first-line therapy for moderate to severe RA in September 2004.
Although Enbrel has not been developed for Crohns disease, Amgen is developing the
product in similar areas as Remicade, which includes psoriatic arthritis, ankylosing
spondylitis and psoriasis.
Sales of Remicade face further competition from Abbotts fully human anti-TNF-a
mAb therapy, Humira (adalimumab), which was launched in January 2003 in the US
and has demonstrated rapid uptake. Humiras strong uptake is driven by its improved
efficacy and its favorable dosing regimen (once every two weeks by subcutaneous
injection) over Remicade and Enbrel. In addition, Humira has the advantage of being a
fully human antibody compared to Remicade, which is chimeric, providing Humira
with a lower risk of immunogenic reactions. Although Humira has only been approved
for use in the treatment of RA, Abbott is also developing the product for Crohns
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disease, psoriasis and ankylosing spondylitis. Humira is set to expand into the psoriatic
arthritis market, with approval for this indication expected in 2006. Humira has
demonstrated strong efficacy and dosing data for psoriatic arthritis, indicating that it
would be a strong competitor to Remicade following approval.
Remicades position is also under threat for a number of products in development,

which include UCBs Cimzia (certolizumab pegol) and Biogen Idec/Genentech
/Roches Rituxan (rituximab). Cimzia is forecast as the greatest pipeline threat to
Remicade, as it has shown efficacy as a therapy for Crohns disease and RA. It is
expected that Cimzia will have a once-monthly dosing regime by subcutaneous
injection. Once Cimzia is approved, it will have the most convenient dosing regime of
any marketed biological therapy for RA and Crohns disease. Cimzia is expected to be
launched in 2006 in the US for Crohns disease, followed by RA the following year.
Cimzias favorable dosing regimen over Remicade is expected to heavily impact sales.
J&J has attempted to drive sales of Remicade by widening its approved indications, for
example for the treatment of ulcerative colitis. According to J&J there are
approximately 500,000 patients affected by ulcerative colitis in the US, with no
approved therapy available to treat moderate to severe active ulcerative colitis.
Therefore, Remicade is expected to be the first biologic approved for this segment of
the population. Remicade is also being developed for psoriasis, and is predicted to be
approved in this indication over the next few years. Early clinical data suggest that
Remicade is highly efficacious in psoriasis and although dermatologists will be
concerned about Remicades adverse side effects, these concerns are likely to be
outweighed by its benefits. Remicade will face tough competition in the psoriasis
market from Genentech/XOMAs Raptiva (efalizumab) and Biogen-IDECs Amevive
(alefacept). Enbrel is also in development for this indication, and has shown to be more
efficacious than Raptiva or Amevive.
The recent changes in the US Medicare system are expected to impact Remicades
sales. Until recently, Remicade had the advantage that it was covered by the Medicare
scheme because it was administered intravenously by healthcare professionals, while
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self-administered drugs, such as Enbrel and Humira, were not. However, in December
2003, it was decided that Medicare would offer federal assistance with drug costs. As a
result, from 2004 onwards, Enbrel and Humira were covered by Medicare for a limited
basis. From 2006, Enbrel and Humira were covered for all Medicare beneficiaries.
Remicades sales are forecast to slow over the next 5 years, as a result of the launch of
Cimzia, the impact of Medicare changes and continued competition from Humira and
Enbrel. Sales of Remicade are forecast to reach $4,120.9m in 2011.
Humira
Humira (adalimumab) was developed by CAT and Abbott and is marketed by Abbott
in the US and Europe. Humira was launched in the US in January 2003 for moderately
to severely active RA patients who have had insufficient response to one or more
traditional disease modifying antirheumatic drugs (DMARDs). Humira was approved
for use in combination with methotrexate or as a monotherapy, similar to Enbrels
approved regime. Humira is the first human mAb approved for RA, but the third
treatment to target TNF. Humira is the first fully human mAb, and thus faces less
adverse side effects compared to murine, chimeric and humanized antibodies. Humiras
sales in 2005 were $1,400m, an increase of 64.3% from 2004.
The approval and marketing launch of Humira was a rapid process. The FDA approved
Humira on December 31, 2002, only nine months after simultaneous regulatory
submissions from Abbott in the US and Europe. Humira was made available at
pharmacies in Germany and the UK within five days of EMEA approval in September
2003, and it was rapidly launched across other EU countries over the following months.
Humira was launched earlier than expected in the US in January 2003, indicated for
RA, and went on to beat Abbotts internal forecasts for its first year on the market.
Humira was approved for psoriatic arthritis in the EU in August 2005 and in the US in
October 2005. In October 2005, Abbott also filed for approval in the US and Europe
for ankylosing spondylitis. In February 2004 Humira was reported to be in Phase II
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trials with Eisai in Japan. In April 2005 Eisai and Abbott signed a joint development
agreement for Humira to be developed for psoriasis, which supplements the basic
agreement signed in June 1999 for the joint development and marketing of Humira for
the RA indication in Japan.
The strong uptake of Humira has been driven by its improved efficacy and favorable
dosing regimen compared to its competitors; Amgens Enbrel (etanercept) and J&Js
Remicade (infliximab). Humira requires a twice-monthly dosing by subcutaneous
injection, compared with Enbrel, which requires a twice-weekly dosing via
subcutaneous injection, while Remicade has to be administered by intravenous infusion
once every eight weeks. The subcutaneous administration of drugs by injection is
usually preferred over intravenous infusions by patients and physicians as they can be
self-administered.
Despite Humiras rapid uptake, growth in the US is restricted due to limited coverage
under the Medicare federal insurance program for the elderly and disabled, whereas
Remicade has greater coverage. However, from 2006, Humira will be able to compete
more effectively against Remicade, as it will be covered for all Medicare beneficiaries
under the new prescription drug benefit approved in the US in December 2003.
The future growth potential of Humira is expected to be limited by the launch of new
DMARDs over the next few years. In particular, the anticipated launch of UCB
Celltechs Cimzia for RA in 2007 is expected to affect Humira, as Cimzia has an
improved dosing regimen to Humira, requiring an expected once-monthly dosing via
subcutaneous injection. Should Cimzia also prove to have similar or superior efficacy
to Humira, it is expected that it will pose a key threat to Humiras position in the
market and adversely effect sales.
Humira sales are forecast to be driven by its favorable dosing regime, as further
indications are approved and as Humira begins to be covered for all Medicare
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beneficiaries in the US. Despite the launch of new treatments for RA, Humiras sales
will not be adversely impacted and are forecast to reach $4,009.3m in 2011.
Raptiva
Raptiva (efalizumab) is a humanized anti-CD11a mAb indicated for the treatment of

chronic moderate-to-severe plaque psoriasis in adults. It is a non-lymphocyte depleting
antibody that has a triple mechanism of action: prevention of the activation of T-cells,
prevention of their migration to sites of inflammation, and prevention of T-cell
adhesion to skin cells.
Raptiva was co-developed by Genentech and XOMA as part of a research collaboration

agreement formed in April 1996. Raptiva was approved in October 2003 by the FDA
and was launched in November 2003. Sales of Raptiva reached $79m in 2005, an
increase of 51.9% from the previous year sales.
In August 2002, Genentech formed a marketing agreement for Raptiva with Serono.
Serono have marketing rights in specific areas of the world outside the US and have the
opportunity to co-develop Raptiva for additional indications. Serono received
marketing approval in Switzerland, its first European market, in March 2004, and in
October 2004 gained approval from the EMEA.
In February 2005, data from a 3-year clinical trial was released, which indicated that
Raptiva demonstrated sustained improvement in psoriasis symptoms through three
years of continuous treatment. The 3-year time-course of the study represents the
longest study of psoriasis patients receiving continuous treatment with a biologic. The
data indicated that Raptiva showed long term and sustained clearing in moderate-to-
severe psoriasis. At 33 months 75% of patients showed at least 75% improvement on
the Psoriasis Area Severity Index and 41% of patients showed at least 90%
improvement.
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The psoriasis market contains strong biologic and non-biologic products that are aimed
at the estimated five million psoriasis patients in the US. Standard non-biologic
treatments include oral systemic methotrexate and cyclosporine therapies, and
phototherapy with UV. Raptiva is expected to face significant competition from other
biologics in the psoriasis market, for example Biogen Idecs Amevive (alefacept),
Amgen/Wyeths Enbrel (etanercept), which was FDA approved for psoriasis in April
2004, and Johnson & Johnsons Remicade (infliximab), which is set to be approved in
this indication by the end of 2006. Amevive was the first biologic drug approved for
the treatment of psoriasis in 2003.
Raptiva can be self-administered by patients as a single, once-weekly, subcutaneous

injection. However, Genentech recognizes that Amgens Enbrel is likely to make a
significant impact on Raptiva sales. Enbrel is set to be the gold standard biologic
psoriasis product, due to its faster onset of action compared to current therapies. Sales
of Raptiva are also expected to be threatened by UCBs pipeline drugs Cimzia, which
is a pegylated, anti-TNF-alpha mAb fragment currently in Phase III development for
RA and Crohns disease. Cimzia has an efficacy that is slightly greater than that of
Enbrel and Remicade and its cheaper method of manufacture will allow it to be sold at
a lower cost than full length mAbs, such as Raptiva. UCB has plans to develop the
product for psoriasis, although the product is unlikely to launch for psoriasis in the next
5 years. BMS Orencia was approved by the FDA in December 2004 and is a CTLA4-
Ig co-stimulation fusion protein and has also been studied in psoriasis. Its method of
manufacture should also allow it to be cheaper than Enbrel and Remicade.
Factors influencing sales of Raptiva include a sales price increase implemented in

September 2004, positively impacting sales. Sales are forecast to increase as
Genentechs marketing strategy will sufficiently differentiate the product from Humira
and Remicade, including phase II trials for immunosuppression of islet transplantation
in type I diabetes, and phase II trials for discoid lupus erythematosus of the scalp. Sales
of Raptiva are forecast to reach $447.9m in 2011.
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Simulect
Novartis launched Simulect (basiliximab) in 1998. Simulect is a chimeric mAb (IgG1k)

that functions as an immunosuppressive agent, specifically binding to and blocking the
interleukin-2 receptor a-chain (IL-2Ra, also known as CD25 antigen) on the surface of
activated T-lymphocytes. Simulect is a glycoprotein obtained from fermentation of an
established mouse myeloma cell line genetically engineered to express plasmids
containing the human heavy and light chain constant region genes and mouse heavy
and light chain variable region genes encoding the RFT5 antibody that binds
selectively to the IL-2Ra. Sales of Simulect reached $54.9m in 2005, an increase of
10.5% from 2004 sales. Sales of Simulect are forecast to reach $77.9m in 2011.
Simulect is indicated for the prophylaxis of acute organ rejection in patients receiving
renal transplantation. Simulect is a two-dose, high-affinity mAb that binds and blocks
the interleukin-2 (IL-2) receptor on the surface of T lymphocytes, and thus inhibits the
cellular immune response involved in allograft rejection. The clinical benefit of
Simulect is not limited to specific subpopulations based on age, gender, race, donor
type (cadaveric or living donor graft) or history of diabetes mellitus.
In clinical trials, Simulect does not increase the risk of adverse events seen in organ
transplantation patients as a consequence of their underlying disease and the concurrent
administration of immunosuppressants and other medications.
Competitors of Simulect include other mAbs indicated for use in transplant rejection,
however due to its chimeric composition it has an advantage over the murine OKT3.
Zenapax is also a key competitor to Simulect, but has lower sales of $29.9m and thus is
a minimal threat.
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Zenapax
Zenapax (daclizumab) is a humanized mAb that binds to the IL-2 receptor on activated
T cells, inhibiting inflammation leading to organ transplant rejection and autoimmune
and related diseases. Zenapax reached sales of $29.9m in 2005, a decline in sales of
6.9% from the previous year. Sales of Zenapax are forecast to remain stagnant
throughout the forecast period, accruing $27m in 2011.
Zenapax was developed by Protein Design Labs (PDL) and is marketed by Roche for
the indication of transplant rejection, launched in 1997. In August 2005 Biogen
acquired Zenapax from PDL as part of a strategic collaboration to co-develop,
manufacture and market three Phase II antibody products, including Zenapax for the
indication of multiple sclerosis. The drug is currently undergoing Phase II trials for MS
and is not expected to reach the market until after 2011.
In September 2004 Roche and PDL announced a worldwide agreement to co-develop

and commercialize Zenapax for asthma and related respiratory diseases, based on
recent positive phase II data in patients with moderate to severe asthma.
Zenapaxs key competitors include Orthoclone OKT3, which is also indicated for use
in transplant rejection, in addition to competition from drugs in future approved
indications (for example for MS and asthma).
OrthoClone OKT3
In 1986 Johnson & Johnson launched the first mAb, OrthoClone OKT3 (OKT3),
generic name muromonab-CD3. Although there were high expectations for this drug, it
failed to capture significant market share because of immunogenicity problems
(HAMA response) due to its murine composition. Sales of OrthoClone OKT3 reached
$13.2m in 2005, a decrease of 23.7% from the previous year. Sales of OKT3 are
forecast to fall to $7.7m in 2011.
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OKT3 is indicated for organ transplant rejection, including the heart, kidneys and liver.
OKT3 sterile solution is a murine mAb to the CD3 antigen of human T cells which
functions as an immunosuppressant. OKT3 reverses graft rejection, and acts by
blocking the function of all T cells which play a major role in acute allograft rejection.
OKT3 reacts with and blocks the function of a 20kDa molecule (CD3) in the membrane
of human T cells that has been associated in vitro with the antigen recognition structure
of T cells and is essential for signal transduction.
In a controlled randomized clinical trial, OKT3 was significantly more effective than
conventional high dose steroid therapy in reversing acute renal allograft rejection. In
this trial, 122 evaluable patients undergoing acute rejection of cadaveric renal
transplants were treated either with OKT3 daily for a mean of 14 days, with
concomitant lowering of the dosage of azathioprine and maintenance steroids (62
patients), or with conventional high dose steroids (60 patients). OKT3 reversed 94% of
the rejections compared to a 75% reversal rate obtained with conventional high dose
steroid treatment. In open clinical trials, acute renal allograft rejection was reversed in
92% (n=126) of the patients treated with OKT3. OKT3 also was effective in reversing
acute renal, hepatic, and cardiac allograft rejections in patients where steroids and
lymphocyte immune globulin preparations were contraindicated or were not successful.
Commonly reported adverse events in clinical trials of OKT3 included weakness

(10%), chills (43%), fever (77%), high (19%) or low (25%) blood pressure, fast heart
rate (26%), headache (28%), tremor (14%), diarrhea (37%), nausea (32%), vomiting
(25%), edema (12%), difficulty breathing (16%) and rash (14%).
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Hemostasis
Currently, there is only one marketed drug for hemostasis: Johnson & Johnsons
Reopro. There are currently no late stage hemostasis drugs in development and this
therapy area is not forecast to expand in the next 5 years.
ReoPro
ReoPro, the first GPIIb/IIIa antagonist available, was launched in 1995 by Centocor
(now Johnson & Johnson) and Lilly in the US, and is marketed by Lilly outside of the
US. ReoPro was initially indicated for the prevention of acute cardiac ischemic
complications in percutaneous transluminal coronary angioplasty (PTCA) patients
considered to be at high risk of abrupt closure of vessel being treated. However, in
1997, the FDA and regulatory bodies in five European countries approved the product
for use as adjunctive therapy to prevent cardiac ischemic complications in a broad
range of angioplasty patients. The drug was also approved for the treatment of unstable
angina patients scheduled to undergo an angioplasty procedure within 12 hours, not
responding to conventional medical therapy. More recently, the compound was
approved for use in stenting, following the results of the ADMIRAL study. Sales of
ReoPro in 2005 reached $296.7m, a decrease of 18.2% from the previous year.
The GPIIb/IIIa class is continuing to experience high growth driven by new drugs on
the market; Mercks Aggrastat and Schering-Plough/Millenniums Integrilin
(eptifibatide). These drugs represent ReoPros main competitors and are quickly
eroding its market share, at least in part because of their higher levels of cost
effectiveness.
Following the results of the GUSTO (Global Use of Strategies to Open Occluded
Coronary Arteries) IV trial, which showed that ReoPro was no more effective than
placebo in reducing adverse events in patients not undergoing reperfusion and actually
increased the risk of bleeding, the 2002 American College of Cardiology/American
Heart Association UA/STEMI (ST segment elevation myocardial infarction) guidelines
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no longer recommended the use of ReoPro in this setting. It is now recommended that
ReoPro only be used in patients undergoing balloon angioplasty or stenting. The other
two marketed GPIIb/IIIa products have also been downgraded, although they retain
their positive rating, which is likely to impact on prescriptions of ReoPro because this
additional lack of flexibility provides an important advantage for Integrilin.
Eptifibatide is expected to become the market leader due to its cheaper price and the
strong sales and marketing strength of Schering-Plough in the US.
ReoPro is in Phase III trials in the US for the indication of stroke. Results from the
Phase II AbESTT (Abciximab in Emergent Stroke Treatment Trial) study suggested
that treating ischemic stroke patients with ReoPro may increase recovery of normal or
near-normal function and reduce mortality, even when administered up to six hours
after the onset of stroke. Lilly is also investigating safety and the potential benefits of
administering ReoPro in combination with Activase and Centocor/Roches Retavase
(reteplase). ReoPro in combination therapy is anticipated to boost sales.
Sales of ReoPro are forecast to grow at a very slow rate due to the negative impact of
GUSTO IV results. A major driver to growth is the additional indication for acute
ischemic stroke anticipated in the US in late 2007, and Europe mid-2008. ReoPro will
also face competition from Integrilin (eptifibatide) and Aggrastat (tirofiban) which
offer price advantages and declining US sales. Sales of ReoPro are forecast to reach
$442.8m in 2011.
Anti-infectives
Synagis is the only current anti-infective mAb on the market. However, due to a large
number of early and late stage pipeline products, this therapy area is expected to
expand in the next 5 years.
Key pipeline products include Numax and Aurograb. There are also a larger number of
early pipeline infectious disease products in comparison to late stage products, for
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example Medarexs ipilimumab (MDX-010) indicated for HIV-infected patients and
valortim (MDX-1303), both currently in Phase I trials.
Synagis
Synagis (palivizumab) is a humanized mAb directed against the F protein of respiratory

syncytial virus (RSV), which is necessary for the virus to infect cells. Palivizumab
received FDA approval in June 1998, and EMEA approval in September 1999 for the
prevention of serious lower respiratory tract disease requiring hospitalization caused by
RSV in high-risk infants.
Synagis was developed by MedImmune as a follow-up product to its first-generation

RSV product, RespiGam, a polyclonal IgG antibody. Abbott entered an exclusive
marketing alliance with MedImmune to co-promote palivizumab in the US and has
exclusive rights to market and distribute the drug outside the US. Under the terms of
the agreement, MedImmune consolidates all US sales of the drug and pays Abbott a
royalty based on its contribution to sales. Outside the US, Abbott records sales and
pays MedImmune a flat royalty rate. Sales of Synagis reached $1,060.9m in 2005, an
increase of 12.6% from 2004.
Synagis is currently the leading prophylactic treatment available for RSV, although the
sales potential of Synagis has been limited by low diagnosis rates and the poor
availability of diagnostic tests. However, the major impact to Synagis over the forecast
period will be the launch of MedImmune/Abbotts next-generation RSV treatment,
Numax, in 2009. Sales are expected to grow until 2009 due to the low competition, but
will be heavily impacted after the launch of Numax. Sales of Synagis are forecast to
fall to $282.3m in 2011.
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Respiratory
Xolair is the only marketed mAb in the respiratory therapy area. There are no
respiratory mAbs in late stage clinical trials, however promising early stage drugs
include GSKs Mepolizumab/SB240563, an anti-IL5 mAb in phase II trials for the
treatment of asthma and nasal polyposis.
Xolair
Xolair (omalizumab) is a humanized anti-Ig-E mAb that gained FDA approval in 2003
for the indication of severe allergy-related asthma inadequately controlled with inhaled
corticosteroids alone. Xolair is administered as a subcutaneous injection every two to
four weeks. Xolair binds to circulating IgE antibodies in the blood, reducing the IgE
binding to mast cells, and thus lowering the release of inflammatory mediators such as
histamine, prostaglandins and leukotrienes. Sales of Xolair reached $326.4m in 2005,
an increase of 73.6% from the previous year sales.
Xolair is co-marketed in the US by Genentech and Novartis. Xolair is a joint

collaboration between Genentech, Novartis and Tanox, however its development has
generated years of litigation. The issue was settled in February 2004, when Genentech
and Novartis paid Tanox $6.6m to cover TNX-901 development costs in exchange for
Tanox giving up the right to produce Xolair. Genentech now pays Tanox a royalty of
approximately 12% and Novartis manufactures Xolair.
Novartis filed for approval of Xolair in the US and Europe in June 2000, however the
FDA requested more analysis for animal and human efficacy as well as human
pharmacokinetic profiles, following safety concerns. The launch of Xolair was delayed
by 3 years and made penetration of the asthma market more difficult. In addition to
strong competition from the highly genericized inhaled corticosteroid market, Xolair
faces competition from novel asthma product classes such as selective PDE-4
antagonists, such as Altana/Pfizers Daxas (roflumilast).
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The lifecycle management of Xolair is focused on widening its range of indications in
order to increase its patient potential. Xolair is currently in Phase III trials in pediatric
patients suffering from moderate to severe persistent asthma, which started in May
2004. Xolair is also under clinical development for the treatment of allergic rhinitis. In
January 2003, Novartis signed an agreement with Sankyo to codevelop omalizumab in
Japan, where it is currently in Phase III trials.
Xolair is expected to find it difficult to further penetrate the highly competitive asthma
market, with pricing and patient compliance issues being the main barriers. The
product will be competing against a wide range of inhalable products, including many
low-cost generic products. Xolair is in competition with non-invasive products, and
therefore as an injectable future sales of Xolair are restricted, as patients prefer painless
and convenient products.
Sales of Xolair in the EU are limited, due to restrictive labeling. In the US Xolair is
indicated for severe asthma rather than moderate to severe asthma. Another resistor to
growth is high treatment costs compared to other asthma therapies, which will lead to
slow uptake rates in the EU. Xolair is forecast to reach $755.4m in 2011.
Marketed monoclonal antibody forecasts
The current mAb market is forecast to grow to over $23bn in 2011, as shown in Table
3.9, which does not include pipeline products that will further boost sales. Humira and
Avastin are set to drive sales with CAGRs (2005-11) of 19.2% and 18.8%,
respectively. Key drivers of Humiras sales growth are its favorable dosing regimen
(twice monthly), its coverage by the Medicare scheme and its fully human
composition, which minimizes immunogenicity. Avastin is an anti-VEGF (anti-
angiogenesis) mAb and its high forecasted sales are attributed to its expanding range of
indications including colorectal cancer, renal cell carcinoma, NSCLC and breast
cancer, which maximize the patient potential. Remicade and Rituxan are the current
market leading mAbs with sales of $3,477m and $3,323m, respectively in 2005. Sales
of Remicade and Rituxan are forecast to have limited sales growth to 2011, with
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CAGRs (2005-11) of 2.9% and 3.7% respectively. Current sales of Remicade are high
due to its status as the first mAb to market for the indication of Crohns disease and
RA, however sales will be impacted by Humira and the launch of UCBs Cimzia. Sales
of Rituxan are already high, and thus further increases will be limited. Rituxan is
planned to be approved for the indication of RA, although this area is highly
competitive and will provide restricted sales growth.
Table 3.9: Marketed monoclonal antibody sales forecasts, 2005-11
Product Company Therapy Sales ($m) CAGR

area 2005 2008 2011 2005-11
Remicade Centocor, Johnson AIID 3,477.0 4,023.6 4,120.9 2.9%

& Johnson
Rituxan/MabThera Genentech, Roche Oncology 3,323.2 3,828.3 4,122.3 3.7%
Herceptin Genentech, Roche Oncology 1,730.6 1,946.6 2,025.4 2.7%
Humira Abbott, CAT AIID 1,400.0 2,709.5 4,009.3 19.2%
Avastin Genentech, Roche Oncology 1,332.0 3,032.4 3,741.4 18.8%
Synagis MedImmune, Abbott Anti-infective1,060.9 547.3 282.3 -19.8%
Erbitux ImClone, BMS Oncology 751.7 1,728.9 2,177.2 19.4%
Xolair Genentech, Novartis Respiratory 326.4 523.5 755.4 15.0%
ReoPro Centocor, Lilly Hemostasis 296.7 362.5 442.8 6.9%
Raptiva Genentech, XOMA AIID 79.0 259.2 447.9 33.5%
Campath Genzyme, Bayer AG Oncology 60.8 98.9 160.8 17.6%
Simulect Novartis AIID 54.9 65.4 77.9 6.0%
Zenapax Roche AIID 29.9 28.4 27.0 -1.7%
Zevalin Biogen Idec, Bayer AG Oncology 28.4 49.1 84.8 20.0%
MyloTarg Celltech group, Wyeth Oncology 25.6 41.2 66.3 17.2%
Tysabri Biogen Idec, Elan AIID 21.2 219.1 440.0 65.8%
Orthoclone OKT3 Johnson & Johnson AIID 13.2 10.1 7.7 -8.5%
Bexxar Corixa, GSK Oncology 8.2 18.4 41.1 30.8%
Total 14,019.8 19,492.2 23,030.6 8.6%
Source: Business Insights; Annual reports; IMS Business Insights Ltd
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CHAPTER 4
The antibody pipeline and

forecasts to 2011
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Chapter 4 The antibody pipeline and
forecasts to 2011
Summary
Key challenges facing the mAb market include the imminent bioequivalent
regulations, which once in place are forecast to heavily impact sales of currently
marketed drugs. The negative publicity from clinical trials or other reported
adverse side effect will also challenge sales due to physicians switching to
alternative small molecule therapies.
There are numerous mAb drugs anticipated to launch in the next 5 years.
Lucentis, Cimzia and ABX-EGF (panitumumab) were all filed for FDA approval
in 2005, and are all antibody fragments which reflects the trend of innovation in
antibody engineering towards alternative antibody structures.
Advancements in antibody engineering and technology act as a huge opportunity
for growth in the mAb market, as fully human antibodies can be developed, for
example Humira. Several pipeline mAbs are fully human, and thus are anticipated
to perform well in the market: ABX-EGF, MDX-010+MDX-1379, ticilimumab
and Humax.
access to larger patient potentials and avoids competition from similar drugs.
Lucentis (ranibizumab) is a humanized anti-VEGF mAb fragment, which is based

on Genentechs larger anti-VEGF antibody Avastin. The FDA approved Lucentis
on the 30th June 2006 and sales are forecast to reach 685m in 2011.
High sales are forecast for Numax as it has been shown to be highly efficacious:
in RSV neutralization studies it is 20 times more potent than Synagis. Therefore
Numax, forecast to launch in 2008, has the competitive advantage over Synagis
and has the potential to enable expansion into additional indications further
boosting sales.
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Introduction
The future of the mAb market is predicted to continue to have a high level of growth,
as there are strong late stage and promising early pipeline drugs being developed. A
large proportion of late stage pipeline drugs are fully human antibodies, which have a
better side effect profile compared to chimeric or humanized antibodies. Pipeline drugs
have also been produced utilizing antibody fragment technology, such as UCB
Celltechs Cimzia, which offers superior tissue penetration and can be manufactured at
lower costs. Another driver of growth for the future mAb market is Big Pharmas
recent financial investment in this area through M&A and licensing deals, which will
provide more effective sales and marketing for mAbs once they are launched, and thus
maximize sales. There are several key issues in the mAb market that are expected to
impact on future sales, such as the impending biogeneric or bioequivalent regulations
and clinical trials. This chapter discusses key pipeline drugs and their potential in the
market.
Strategic analysis
The mAb market is currently experiencing rapid growth which is anticipated to

continue over the next few years. There are several key issues that will have positive or
negative effects on the mAb market, as shown in Figure 4.8.
Opportunities that are set to boost the mAb market include positive outcomes of
postmarketing clinical trials, which will increase physician prescribing of these drugs if
they are found to be more effective compared to other drugs, and consequently increase
mAb sales. Recent advances in antibody innovation will also have a positive impact on
the mAb market, for example non-invasive drug delivery is a huge growth opportunity
as pain-free and convenient dosing are very attractive to patients and would increase
compliance, and thus boost sales. Innovation in antibody structure such as the move
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towards fully human mAbs and the development of mAb fragments are also predicted
to increase growth in the market, as they are seen as attractive by patients and
physicians due to decreased side effects, enhanced efficacy and antibody penetration.
Another opportunity is expanding the therapy areas that mAb are approved in, for
example several mAbs are forecast to launch for infectious diseases over the next 5
years. Launching mAb in different therapy areas increases the patient potential for
mAbs, and avoids competition in areas where several antibodies have the same
indication, such as RA.
Key challenges facing the mAb market include the imminent bioequivalent regulations,
which once in place are forecast to heavily impact sales of currently marketed drugs.
The negative publicity from clinical trials or other reported adverse side effect will also
challenge sales due to physicians switching to alternative small molecule therapies.
Late stage attrition of pipeline drugs is another challenge to the market, as although the
current late stage pipelines contain many promising drugs they are not guaranteed to
reach the market. Late stage attrition is very costly to developers as vast amounts of
money have been invested in these drugs without any return.
The opportunities in the mAb market are considered to outweigh the challenges. It is
anticipated that the mAb market will continue to experience high growth over the next
few years due to innovation and new product launches in different therapy areas.
However in the mid-to-long term the market is expected to stabilize once
biosimilar/follow-on biologics regulations are established.
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Figure 4.8: Opportunities and challenges in the mAb market
Opportunities
Positive outcome of post marketing clinical trials
Innovation in antibody engineering
Approvals in a wider range of therapy areas
Promising late stage pipeline drugs
Challenges
Establishment of bioequivalent regulations
Negative outcome of clinical trials and adverse
side effects
Competition from pipeline small molecule
compounds
High attrition rates
Opportunities
Clinical trials
Post marketing clinical trials are conducted on launched drugs and can provide an
increase in sales growth if the outcome is positive. For example marketed drugs can be
compared to one another and if one is found to be safer or have a higher efficacy this
will result in higher physician prescribing, and thus boost sales. However, a negative
outcome such as poor response rates or adverse side effects will decrease sales. There
are 3 key Phase IV trials that will affect currently marketed drugs:
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Erbitux and Avastin
In May 2006 a trial was initiated for the elaboration of a model for predicting efficacy
of mAb in patients with colorectal cancer and liver metastases. The primary objective
was to create an advanced model for rapidly predicting (day 21) the response to
monoclonal antibodies anti-EGFR and anti-VEGF (Erbitux and Avastin: both indicated
for colorectal cancer) based on biological markers and/or functional imaging. The
response to treatment was evaluated by conventional methods after 2 months (RECIST
criteria). Secondary objectives included analyzing the correlation between the
magnitude of response to treatment at 2 months and to develop a metastases colorectal
cancer tumor bank. A positive outcome from this trial could boost sales of Erbitux
and/or Avastin dependant on which mAb is found to be more efficacious and result in
patient switching to the more favorable mAb.
Simulect, Zenapax and Campath
Key therapies used in immunosuppressive regimens are the calcineurin inhibitor

tacrolimus, the anti-proliferative agent mycophenolate and induction agents which are
used to provide effective early suppression of the rejection process; these include mAbs
such as IL-2 receptor blocking antibodies (Simulect and Zenapax) and the anti-CD52
antibody Campath-1H (alemtuzumab). A trial began in October 2005 to compare
alemtuzumab/tacrolimus versus Interleukin-2 receptor mAb/tacrolimus/mycophenolate
in kidney transplantation. The primary hypothesis is that the alemtuzumab/tacrolimus
regimen is as effective and safe as the IL-2R mAb/tacrolimus/mycophenolate regimen.
This trial is due to complete in November 2007. The outcome of this study will affect
sales of Simulect, Zenapax and Campath depending on how effective each therapy is,
with the most effective drug gaining an increase in sales from patient switching and
increased physician prescribing.
Campath
A randomized phase IV pilot study of steroid and calcineurin inhibitor avoidance in

renal transplant recipients is currently recruiting patients. All patients will receive two
doses of alemtuzumab (Campath-1H, 30mg); one at the time of renal transplant, and
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one on post-operative day two to achieve peripheral T-cell depletion. Intravenous
glucocorticoids will be administered prior to Campath administration to limit cytokine
release syndrome in association with this mAb, and continued for the first two days
post-transplant. Thereafter, steroids will not be used for immunosuppression. If this
treatment is found to be effective then this regimen will be increasingly used for
transplant patients, and thus boost sales of Campath.
Others
Other clinical trials that are notable are summarized in Table 4.10, which gives an
update of current clinical trials for approved mAbs. The outcome of these trials will
impact on the future sales of these drugs depending on how efficacious they are and if
they produce any adverse side effect.
Table 4.10: Other post-marketing clinical trials, 2005-6
Date Drug Company Trial details
10/2005 ReoPro Lilly AbESTT-II. Abciximab in Emergent Stroke Treatment Trial-II.

(abciximab) Phase III trial of ReoPro acute ischemic stroke, has been
temporarily suspended, due to safety concerns. An independent
Safety and Efficacy Monitoring Committee observed is
currently evaluating the benefit-risk profile of REOPRO.
04/2006 Tysabri Biogen AFFIRM and SENTINEL. Phase III Multiple Sclerosis studies
(natalizumab) Idec showed significant effects on pre-specified health- related
quality of life measures, in addition to those previously
reported on disability progression, relapse rate and MRI.
Source: Business Insights; Clinicaltrials.org Business Insights Ltd
Innovation in antibody engineering
Advancements in antibody engineering and technology offer a huge opportunity for

growth in the mAb market. Antibody engineering has progressed to the development of
fully human antibodies, for example Humira, which reduces the risk of adverse side
effects as seen with murine or part murine mAbs. Several pipeline mAbs are fully
human, and thus are anticipated to perform well in the market: ABX-EGF, MDX-
010+MDX-1379, ticilimumab and Humax. Antibody fragments offer an opportunity
for growth in the mAb market to produce efficacious mAbs with high tissue
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penetration, which are attractive to patients and physicians. Drug developers can also
maximize revenues as antibody fragments are cheaper to produce than whole mAbs as
they can be produced by recombinant technology rather than by expensive mammalian
cell culture. Antibody fragment technology is utilized in late stage mAb pipeline drugs,
such as Lucentis (FDA approved in June 2006) and Cimzia. Lucentis is a high-affinity
Fab variant, whereas Cimzia is a PEGylated Fab fragment.
New indications
access to larger patient potentials and avoids competition from similar drugs. Several
drugs have also filed or are in clinical development for a range of indications in order
to gain a wider patient potential for their products. mAbs can be effective for more than
one indication depending on their mechanism of action, for example Remicade inhibits
TNF-a, which has been implicated in a range of AIIDs such as RA, Crohns disease,
ankylosing spondylitis and ulcerative colitis. Examples of pipeline drugs in
development for more than one indication include:
Cimzia, which been filed for FDA approval for the indication of Crohns disease in
March 2006 and is also in development for RA;
MRA/Actemra has been approved in Japan for Crohns disease and is in

development for the indication of multiple myeloma, Crohns disease and RA;
Eculizumab is currently in phase III trials for PNH, phase II trials for RA and
hormone ablation therapy and phase I trials for dermatomyositis;
Denosumab/AMG-162 is in development for osteoporosis, in addition to RA,

hormone ablation therapy induced bone loss and metastatic bone disease.
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Challenges
Generic biologics
Novel small molecule drugs face a high level of generic competition once they lose
patent protection. Generics producers are particularly keen to gain FDA approval for
the active pharmaceutical ingredient of blockbuster drugs, as these are the generics that
have the highest sales potential. The price of an original branded drug rapidly decreases
once its patent expires due to generic competition, as a result of cheap generic versions
selling as low as an estimated 20% of the price of the brand name drug. However,
regulations concerning the approval process of generic biologics or biosimilars are not
yet established in the US or EU.
mAbs are approved using a different process compared to small molecules drugs, as
mAb FDA approval is filed under a BLA (Biologics License Application) rather than
an NDA (New Drug Application). Companies wishing to produce a generic version of
a small molecule drug can then submit an ANDA (Abbreviated New Drug Application)
once the branded drugs patent has expired. However, a biologic such as a mAb cannot
be produced as an exact replica of the original product due to their complex protein
structure and their production from mammalian culture, which produces a
heterogeneous mixture of proteins. It is thought that instead of the term biogeneric, the
term biosimilar or bioequivalent should be used. A bioequivalent is a biologic than has
the same efficacy, availability in the blood and safety compared to the original.
Several mAb producers (Genentech/Pfizer/Pharmacia) are concerned by the threat of

bioequivalent drugs and have submitted citizen petitions to the FDA. For example
Genentech, who would be greatly affected by generic biologicals, submitted a petition
to the FDA in April 2004 against the FDA draft guide for standards for similar
biologics products. Genentech states that such guidelines would infringe on their legal
rights regarding their trade secrets and confidential commercial data and information.
In addition, Genentech state that biotechnology derived products would not actually be
able to be reproduced through a different manufacturing process.
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Biogeneric drugs present a large sales opportunity for generic manufacturers such as
Sandoz, once regulations are in place Sandoz already has the biogeneric drug
Omnitrope (human growth hormone), launched in Australia in November 2005 and
approved in the EU in April 2006 and the US in May 2006. The FDA approved
Omnitrope under an NDA and have stated that it is not a follow on or biogeneric, and
thus there is no established approval process for generic mAbs. The FDA stated that:
There is no abbreviated approval pathway analogous to 505(b) (2) or 505(j)

of the Act for protein products licensed under section 351 of the Public
Health Service Act. Such a pathway for the approval or licensure of follow-on
protein products under the Public Health Service Act would require new
legislation.
Sandoz now has the experience to develop bioequivalent drugs and a strong legal
department to gain FDA approval, despite the FDA having stated that Omnitrope is not
a biogeneric.
The threat of biosimilars will have a negative effect on future sales of currently
marketed mAbs. However, due to the biosimilar approval process not yet being
established and the high production costs of mAbs, it is predicted that a limited number
of competitors will emerge, and thus the impact over the next few years will be
minimal. Bioequivalent regulations are however expected to be in place in the short-to-
mid term.
Adverse reactions in clinical trials, side effects and termination of

development
In May 2006 Tegeneros phase I mAb TGN1412, designed to treat RA, leukemia and
multiple sclerosis caused a severe adverse effect in clinical trials. Six men were left
with multiple organ failure after receiving TGN1412 in a trial run by contract research
organization, Parexel. The Medicines and Healthcare products Regulatory Agency
(MHRA) reported that the most probable cause of the severe side effects were an
unexpected biological action of the drug in humans. The MHRA concluded that there
were no errors in manufacture, formulation, dilution or administration. The impact of
this trial will challenge the mAb market as it highlights the potential side effects that
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antibody therapies can cause. However, this reaction is particularly extreme and
currently marketed drugs are considered to be relatively safe with minimal side effects.
In addition, mAbs are administered by physicians who are making decision regarding
the choice of therapies rather than the general public who would be anxious about mAb
therapies.
In another example of an adverse reaction caused through administration of a mAb,

Mallinckrodt Imagings NeutroSpec (technetium [99m Tc] fanolesomab) was
suspended from the market in December 2005. The FDA notified healthcare providers
of the immediate suspension, which is pending further investigation of
cardiopulmonary reactions. The FDA received reports of 2 deaths and 15 life-
threatening adverse effects following administration of NeutroSpec. Although
NeutroSpec is a diagnostic mAb, the widely publicized suspension will have an impact
on the therapeutic mAb market, by challenging future sales and potentially influencing
physicians to opt for alternative drugs.
Another challenge to the future mAb market includes publicized side effects of mAb on
websites and the link between Humira and Remicade and the increased risk of certain
types of cancer and infection. Negative press for currently marketed drugs is forecast to
impact future sales, however the extent of this is predicted to be minimal.
High attrition rates
High attrition rates pose a huge challenge to the mAb market as developers invest vast
sums of money into products, with the anticipation to regain their investment on
products launch. Although mAbs generally have a higher approval success compared to
small molecule compounds, late stage attrition is financially detrimental to developers.
Approval success rates for mAbs, as stated by TUFTS Center for the Study of Drug
Development, are reported to be 69% from phase I to II, decreasing to 33% from II to
III, with 100% success rates for phase III to approval. The criteria used by TUFTS
mAb data set contained 355 therapeutic products in clinical study sponsored by more
than 100 commercial firms located worldwide. The low phase II to III success rates for
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mAbs is a threat to the mAb market, as drugs in these phases have a high cost of
development.
An example of late stage product termination was CATs discontinued development of

Trabio (lerdelimumab) in March 2005. CAT announced that in its second pivotal
clinical trial (phase III), Trabio failed to meet its primary endpoint of improving the
outcome of surgery for glaucoma, which was consistent with the EU clinical trial
results announced in November 2004. This late stage attrition was a dramatic blow to
CAT, as they invested huge amounts of money in Trabio throughout all phases of
clinical trials, which they have no way of recouping.
Analysis of pipeline drugs
The mAb market is an attractive market due to its immaturity and rapid growth. The
growth seen in the mAb market has been driven by advancements in antibody
engineering, such as the production of fully human antibodies with a low risk of
adverse side effects. In addition, the market has been driven by mAbs being developed
in a wider range of indications where there is limited competition, and thus developers
can maximize sales for these mAbs.
The late stage pipeline drugs, shown in Table 4.11, indicate that there are many mAb
drugs anticipated to launch in the next 5 years. The late stage mAb pipeline reflects the
innovation in the market, as it consists of 9 fully human antibodies. Another example
of innovation driving the market is antibody fragment technology. Lucentis, Cimzia
and ABX-EGF (panitumumab) were all filed for FDA approval in 2005, and are all
antibody fragments which reflect the trend of innovation in antibody engineering
towards alternative antibody structures. Lucentis gained FDA approval in June 2006.
The therapy areas that mAbs are indicated for are set to widen, with drugs forecast to
launch in ophthalmology (Lucentis) and infectious disease (Numax, TNX-355, and
Aurograb). However, AIID and oncology are still predicted to dominate the market in 5
years time.
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Table 4.11: Late stage monoclonal antibody pipeline, 2006
Brand Company Type Stage Launch

date
AIID
Cimzia (certolizumab) Nektar/UCB Humanized Filed 2006
MRA/Actemra (tocilizumab) Roche Humanized Phase III 2007
Soliris (eculizumab) Alexion Humanized Phase III 2007
Ticilimumab Pfizer Human Phase III 2008
Nuvion (visilizumab) PDL Humanized Phase III 2008
Denosumab (AMG 162) Amgen Human Phase III 2010
CNTO 1275 Medarex/Centocor Human Phase III 2010
CNTO 148 (golimumab) Centocor/Shering-Plough Human Phase III 2010
Cardiovascular
Pexelizumab Alexion/Procter & Gamble Humanized Phase III 2007
Infectious disease
Numax MedImmune/Abbott Humanized Phase III 2008
TNX-355 Biogen Idec/Tanox Humanized Phase III 2009
Aurograb Novartis/ NeuTec Human Phase III >2011
Oncology
ABX-EGF (panitumumab) Abgenix/Amgen Human Filed 2007
OvaRex United Therapeutics/ViRexx Murine Phase III 2007
MDX-010 + MDX-1379 Medarex/BMS Human Phase III 2007
IGN-101 Igeneon Murine Phase III 2007
Humax (Zanolimumab) Genmab/Medarex Human Phase III 2008
MLN-2704 Millennium Humanized Phase III 2008
Rencarex (WX-G250) Esteve/Wilex Chimeric Phase III 2009
LymphoCide (epratuzumab) Immunomedics/Amgen Humanized Phase III >2011
MT201 CAT/Micromet/Serono Human Phase III >2011
Ophthalmology
Lucentis (ranibizumab) Genentech/Novartis Humanized Approved 2006
Source: Business Insights; Company reports; FDA Business Insights Ltd
The future antibody market is anticipated to move towards humanized and fully human
mAbs, as indicated in Figure 4.9. Humanized mAb pipeline drugs are expected to
drives sales to 2011, as products such as Cimzia and Lucentis are launched, whereas
pipeline fully human mAbs with high forecast sales include ticilimumab and ABX-
EGF. Chimeric mAbs are expected to continue to grow, however this will be driven by
currently marketed chimeric mAbs rather than pipeline products.
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Figure 4.9: Antibody structure analysis of forecasted monoclonal antibody
sales ($m), 2004-11
14,000
12,000
10,000
chimeric
Sales ($m)
8,000
6,000
humanized
4,000
2,000 human
murine
0
2004 2005 2006 2007 2008 2009 2010 2011
Source: Business Insights; company reports; IMS Business Insights Ltd
Figure 4.10 shows that in the mAb late stage pipeline oncology and AIID therapy areas
are dominant, which is currently the trend seen in marketed mAbs. However, numerous
other pipeline mAbs are being developed in other therapy areas, in particular for
infectious diseases. There is currently only one marketed drug indicated for infectious
diseases, Synagis, but this is set to change in the long term as shown by the large
number of early-stage drugs in development. The respiratory area also has a small
number of drugs at all stages of development, suggesting an increase in sales of mAbs
in this therapy area in the future. Therefore, in the long term the mAb market is
predicted to cover a wider range of therapy areas than is currently seen and be less
dominated by oncology and AIID drugs, although these therapy areas will continue to
feature heavily in the market.
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Figure 4.10: Therapy area analysis in monoclonal antibody drug development,
2006
Pre-clinical Phase I Phase II Phase III
Oncology
AIID
Infectious disease
Respiratory
Unknown
CNS
Cardiovascular
Diabetes & endocrinology
Ophthalmology
Women's Health
Renal
Hematology
0 20 40 60 80 100 120 140 160 180

Number of drugs in development
Source: Business Insights; company reports; Med TRACK Business Insights Ltd
The sales forecast for each therapy area in the mAb market is shown in Figure 4.11,
and shows that oncology and AIID are expected to continue to be the major therapy
areas in the mAb market throughout the next 5 years. AIID mAbs are forecast to reach
high sales of $11bn in 2011, due to anticipated product launches of ticilimumab and
Nuvion in 2008. The infectious disease therapy area is also predicted to perform well
over the next 6 years, reaching sales of $1,952m in 2011. Although infectious disease
mAbs will not reach the same scale of sales as oncology and AIID, the increase in sales
shows that infectious disease mAbs are an attractive area that is forecast to have an
extremely high sales growth, which is attributed to key product launches (Numax and
TNX-355) boosting sales and a low level of competition in the market. Other therapy
areas, which include hemostasis, respiratory, cardiovascular and ophthalmology are
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forecast to remain fairly constant, although as the products in early phase pipelines
progress to market these areas will grow correspondingly.
Figure 4.11: Therapy area analysis of forecasted monoclonal antibody sales

($m), 2004-11
16000
14000
12000
10000
8000 Oncology
6000
4000
Sales ($m)
AIID
2500
2000
1500
Infectious disease
1000 Ophthalmology
Hemostasis
500
Respiratory Cardiovascular
0
2004 2005 2006 2007 2008 2009 2010 2011
AIID Oncology Infectious disease Respiratory

Cardiovascular Hemostasis Ophthalmology
Source: Business Insights; company reports; IMS Business Insights Ltd
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AIID
Cimzia
Cimzia (certolizumab), previously known as CDP 870, is a fully human mAb fragment
in development as an anti-TNF therapy for the treatment of RA and Crohn's disease.
UCB Pharma has partnered with Nektar to develop Cimzia using advanced PEGylation
technology. The majority of current treatments require daily or weekly administration;
however Nektar Advanced PEGylation reduces the dosing frequency to once every four
weeks, and thus improves convenience and compliance. UCB Celltech filed for FDA
approval of Cimzia for Crohns disease in March 2006, and expects to launch Cimzia
later in 2006. A filing for the indication of RA is anticipated in late 2006, with a launch
in 2007.
The high price of biologics is a major barrier to their uptake, but the advantage of
Cimzia is its lower production costs. The advantage of producing PEGylated Fab is that
the antibody fragment is smaller compared to a full length antibody, and can therefore
be produced using prokaryotic expression fermentation systems rather than more
expensive mammalian cell culture.
In July 2005, UCB announced positive results from two pivotal Phase III trials
(PRECiSE 1 & 2) evaluating the use of Cimzia in moderate to severe Crohns disease.
UCB announced that primary efficacy endpoints were met in both PRECiSE 1 and 2
trials. Additional Phase III trials have been conducted: the RAPID trial, which assessed
efficacy and safety of Cimzia over a year (results expected in Q4 2006/Q1 2007), and a
second RAPID trial began in July 2005 to test a pivotal liquid formulation.
Cimzia will compete with the only marketed therapeutic for moderate-to-severe
Crohns disease, J&Js TNF inhibitor Remicade (infliximab), a second-line treatment
launched in 1998. In addition, Abbotts Humira (adalimumab) which is marketed for
RA is currently in Phase III trials for Crohns disease. As Cimzia is also being
developed for the indication of RA it will compete with Enbrel and Remicade (which
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are already established in the market) and more recently Humira (which has seen a
rapid uptake) in this indication. Prior to the launch of Amgens Enbrel (etanercept) in
1998, the historical gold standard DMARD for RA was Methotrexate. Cimzia is
expected to be prescribed as a second or third line therapy in RA, as there is a large
amount of competition from high efficacy established mAbs. However, the low cost of
production of Cimzia, is expected to provide UCB with a significant pricing advantage
over its competitors, and Cimzia also offers advantages in terms of administration,
being a monthly subcutaneous injection. UCB is considering exploring the efficacy of
the drug for further indications, such as psoriasis and psoriatic arthritis. These
indications will provide further opportunities to maximize revenues from Cimzia.
Whilst UCBs potential pricing of Cimzia is not known, UCB could gain a large market
share by selling Cimzia at a lower price than its rivals, or maximize profit by pricing in
the same range as whole antibody mAbs thus gaining the advantage from lower
manufacturing costs. Both strategies are predicted to provide UCB with large sales for
Cimzia. The major factors positively impacting sales of Cimzia are the launch of
Cimzia for RA in late 2007, the low cost of Cimzia against Enbrel and Remicade and a
convenient dosing regimen. However, Cimzia will face competition from the more
established RA biologic therapies and is the second biologic treatment to reach the
market for Crohn's disease. Cimzia is predicted to reach sales of $1,266m in 2011.
MRA/Actemra
MRA/Actemra (tocilizumab) is a humanized mAb targeted against the human IL-6

receptor. Chugai and Roche are co-developing Actemra for the treatment of multiple
myeloma, Castlemans disease, Crohns disease and RA.
In September 2005 results from a phase III trial of MRA/Actemra in patients with RA
showed positive results. Decreased C-reactive protein levels and erythrocyte
sedimentation rates were noted, as was a slight increase in total serum cholesterol and
decreased serum VEGF levels. The Phase II CHARISMA study showed efficacy in the
short-term in combination with MTX. Patients received four infusions of
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MRA/Actemra or placebo at four-weekly intervals either alone or together with 10mg
to 25mg of methotrexate weekly or placebo. The results included a dose-related
response and definite synergy in combination with methotrexate.
MRA/Actemra was approved for the treatment of Castleman's disease

(lymphoproliferative disease based on the over production of IL-6) on April 11, 2005
in Japan and was launched on June 13, 2005. MRA/Actemra is predicted to be
launched in the US in 2007. Actemra is the first drug available for Castleman's disease.
Chugai and Roche are also developing the drug for the potential treatment of multiple
myeloma, Crohn's disease and other IL-6 related disorders. MRA/Actemra binds to
both surface and soluble IL-6 receptors, similar to the etanercept mechanism of binding
to both surface and soluble forms of TNF. Although there is little evidence of increased
efficacy in this model, it may prove an advantage in successfully treating a wider
number of patients.
Chugai is Roches exclusive Pharma representative in Japan. As MRA/Actemra has

already been launched in Japan for Castlemans disease it is anticipated to be marketed
for RA in Japan before other countries, with Chugai expected to file for approval in
2006. Approval is expected to be sought in the US and the EU in the next two years, as
the relevant data is assessed by the FDA and EMEA. In June 2005, Chugai announced
plans to follow in the footsteps of Roche by creating Strategic Marketing Units (SMUs)
to oversee drug development, with the aim boosting their marketing of MRA/Actemra
in Japan and ultimately strengthening sales. For example, the management of a
staggered launch in various indications will be managed, with the initial approval for
Castlemans disease, prior to RA and other indications, which will allow further safety
data to be obtained.
A disadvantage of MRA/Actemra is its humanized structure, which creates a risk of

immunogenicity. MRA/Actemra will be competing with fully human antibody
treatments such as Humira, and fully human fusion protein etanercept, which have
minimal risks of adverse side effects. MRA/Actemra is forecast to reach sales of
$413.5m in 2011, based on the indications of Castlemans disease and Crohns disease.
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Eculizumab
Eculizumab is a long-acting, humanized mAb which, like pexelizumab, inhibits the

activation of C5 complement protein. Eculizumab was developed at the preclinical
stage under collaboration with GTC Biotherapeutics. There is currently no specific
treatment available for PNH (eculizumabs primary indication), and thus eculizumab
has the potential to gain a large share of prescriptions for this indication. Eculizumab
has been granted orphan drug status in the US and Europe, and Alexion is believed to
be independently developing the product now for four key indications:
Paroxysmal nocturnal hemoglobinuria (PNH) (Phase III);
Rheumatoid arthritis (Phase II);
Membranous nephritis (Phase II);
Dermatomyositis (Phase I).
Eculizumab is also being investigated in the treatment of other complement-related

disorders, but its first approval is expected to be for the indication of PNH in 2007.
TRIUMPH, a pivotal Phase III trial for PNH began in November 2004, and the
companion safety trial, SHEPHERD, began in January 2005. In clinical trials to date,
eculizumab has been shown to reduce hemolysis of red blood cells and transfusion
requirements in transfusion-dependent PNH patients. The drug has also shown to be
well tolerated in trials. It is thought that the dosing regimen will require PNH patients
to have a weekly or a twice-monthly infusion of the drug.
Eculizumab is currently in Phase II development for the lucrative indication of RA.

Results from trials to date have shown that monthly doses of eculizumab have
moderate improvements on ACR20 score, a standard measure for assessing RA, versus
placebo. However, a twice weekly dose made no significant improvement of the
ACR20 score. Further clinical trial results are required to fully assess the potential of
the drug. Eculizumab is expected to be limited to the moderate to severe spectrum of
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the disease, as it is administered by infusion. If it does successfully reach the market, it
will face considerable competition from other biologic products, including UCBs
Cimzia (certolizumab pegol) and Abbotts Humira (adalimumab), which have the
advantage of being administered by subcutaneous injection and have strong marketing
support. As such, Alexion will need to consider forming a marketing alliance with a
company, such as Boehringer Ingelheim, that can provide strong marketing support for
eculizumab to maximize sales.
Eculizumab also appears to have potential as a treatment for idiopathic membranous

nephritis, where the glomeruli in the kidney are damaged by deposits of immune
complexes. Further clinical data is required to assess eculizumabs full potential in this
indication, however, based on eculizumabs mechanism of action, it could become a
key therapy for idiopathic membranous nephritis.
The uptake of eculizumab is expected to be rapid, due to a high unmet need in PNH.
The fast uptake of the drug, in addition to high pricing means that sales are forecast to
reach $426m in 2011, with sales boosted by the approval for use in the treatment of RA
and membranous nephritis.
AMG-162
AMG-162 (denosumab) is a fully-human mAb to RANKL (NF Kappa B ligand) being

developed by Amgen for the treatment of a number of disorders including osteoporosis,
RA, hormone ablation therapy-induced bone loss (i.e. for breast and prostate cancer)
and metastatic bone diseases. Currently in Phase III, the osteoporosis program is one of
the most advanced indications in development, but is not expected to reach completion
until Q1 2008. Therefore, FDA filing for AMG-162 is predicted to occur in 2009 with
approval/launch forecast in 2010.
Data from Phase II studies in postmenopausal osteoporosis were presented at the 26th
American Society for Bone and Mineral Research (ASBMR) meeting in October 2002.
AMG-162 increases bone mineral density within 1 month in postmenopausal women
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with low bone mineral density (BMD). In this 12-month study, postmenopausal women
were randomized to receive a placebo, AMG-162 or the current gold-standard therapy,
Fosamax (alendronate). Endpoints were BMD, bone turnover markers and safety
measurements. Treatment with AMG-162 resulted in a rapid dose-dependent decrease
in turnover markers serum C-telopeptide, urinary NTX/creatine. The drug was also
well tolerated, with the most common adverse event being dyspepsia. AMG-162
increased BMD in postmenopausal women within one month of dosing and appeared to
be more effective than alendronate at cortical bone sites.
AMG-162 is currently being investigated in late-stage trials for the treatment of

postmenopausal osteoporosis and as such will be targeting the largest patient group. In
order to compete with bisphosphonates, the main competitors to AMG-162, Amgen
could also investigate AMG-162 in glucocorticoid-induced osteoporosis (as well as the
cancer treatment-induced bone loss already under investigation) and male osteoporosis.
Early Phase I studies suggest that the drug could demonstrate a beneficial effect in
reducing male osteoporotic bone loss.
As an antiresorptive, AMG-162 will be entering a competitive market. By 2010 it is

expected that at least two novel SERMs and two novel bisphosphonates will be
available for osteoporosis treatment, not to mention other products such as strontium
ranelate and the parathyroid hormone therapies. Although AMG-162 will have to show
comparable efficacy to Fosamax, other bisphosphonates, such as Aclasta and Boniva,
could also be threats due to their longer-interval dosing regimen. One advantage that
semi-annual AMG-162 has compared to the other two drugs IV formulations is its
subcutaneous delivery method and therefore it may be more acceptable to patients and
improve compliance. A further resistor to sales is that AMG-162 is forecast to be more
expensive than Fosamax. AMG-162 will benefit from Amgens experience in
marketing, especially due to Amgen already marketing leading RA products, such as
Enbrel. Amgen will have a sales force experienced in targeting rheumatologists, which
will allow Amgen to exploit this advantage and to encourage early use among
physicians familiar with prescribing biologic compounds. In addition, the anticipated
high cost of AMG-162 could be less of a barrier among such specialist prescribers.
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AMG-162 is forecast to reach sales of $70m in 2011, due to its launch occurring only a
year before in 2010.
Cardiovascular
Pexelizumab
Pexelizumab is a short-acting fragment of Alexions humanized antibody, eculizumab,

which inhibits the C5 protein in the complement cascade. Pexelizumab was developed
using Enzons single chain antibody technology and is in Phase III development for the
prevention of reperfusion injury in patients who have undergone coronary artery
bypass graft (CABG) surgery, along with cardiopulmonary bypass (CPB). Pexelizumab
is also in Phase III development for the prevention of reperfusion injury in acute
myocardial infarction patients treated with primary percutaneous coronary intervention
(PCI). Pexelizumabs mechanism of action is to prevent the activation of the
complement cascade, thereby reducing inflammation that contributes to complications,
including myocardial infarction and stroke. Pexelizumab is anticipated to launch in
2007.
In 1999 Alexion formed a collaboration agreement with Procter & Gamble to jointly
develop and commercialize pexelizumab in the US. Outside the US, Procter & Gamble
have licensed the exclusive rights to pexelizumab.
In 2003, pexelizumab completed its first Phase III trial, PRIMO-CABG (Pexelizumab
for Reduction in Infarction and Mortality in Coronary Artery Bypass Graft Surgery), in
patients undergoing CABG surgery along with CPB. However, the drug failed to meet
the trials primary endpoint. Regardless of this, Procter & Gamble and Alexion
initiated a second Phase III PRIMO-CABG trial, as pexelizumab reached important
secondary endpoints in the first Phase III trial and previous clinical trials.
The results from pexelizumabs Phase II COMMA (Complement Inhibition in

Myocardial Infarction Treated with PTCA) trial for acute myocardial infarction
patients treated with PCI, has shown positive results, indicating that it reduces the
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mortality rate compared to placebo. Phase III trials began in 2004, and it is thought that
Alexion and Procter & Gamble will file for approval for this indication in mid-2007,
gaining approval late in 2008, as it has been granted fast track approval status by the
FDA. If approved pexelizumab is expected to benefit from first to market status for
these life-threatening indications. However, due to the failure of pexelizumab to reach
its primary endpoint in the first PRIMO-CABG trial, there is uncertainty regarding
pexelizumabs efficacy, which will act as a resistor to sales growth.
Although Alexion has no marketing experience, sales of pexelizumab are predicted to

be high due to marketing support from Procter & Gamble. Approval is expected to be
gained initially for use in a limited patient population that are at high risk of
complement activation, undergoing CABG surgery along with CPB, in Europe and US
in 2007. In 2008 pexelizumab is forecast to gain approval for the additional indication
of acute myocardial infarction treated with PCI, which will boost sales. Sales of
pexelizumab are forecast to reach $426m in 2011.
Infectious diseases
Numax
MedImmune has formed a number of product development alliances with Applied

Molecular Evolution (AME), one of which was for the directed molecular evolution
(DME) optimization of the anti-RSV mAb Synagis, and resulted in the development of
anti-RSV mAb Numax. Numax is a next-generation mAb that has created an
opportunity for MedImmune to gain a greater share of Numax revenues flow to
MedImmune than was the case for Synagis, as Abbott has the marketing rights for
Synagis outside of the US. Numax has been found in RSV neutralization studies to be
20 times more potent than Synagis, and approximately 50 times more effective in
reducing RSV in the lungs of cotton rats. Therefore Numax, forecast to launch in 2008,
has a competitive advantage over Synagis.
Phase III trials for Numax were initiated in December 2004, and were designed to
evaluate the safety and efficacy of Numax in reducing RSV infection in healthy full-
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term Native American (Navajo and White Mountain Apache) infants. Results from the
Phase III trial are expected to be released in 2006. MedImmune is planning to expand
late stage clinical trials of Numax development with more trials in the next two years.
In December 2005 MedImmune completed the enrollment of 6,600 high risk infant
patients in a pivotal Phase III study comparing the efficacy and safety of Numax to
Synagis. In addition, MedImmune has recently completed enrolling 620 patients in a
separate, late-stage clinical study with Numax in children with hemodynamically
significant congenital heart disease (CHD). Again, this randomized, double-blind,
palivizumab-controlled study will evaluate the safety, tolerability, immunogenicity and
pharmacokinetics of Numax in children with CHD.
MedImmune agreed that Abbott would have exclusive marketing rights to Numax
outside of the US, however MedImmune later ended the agreement in August 2005 as a
strategic move to maximize its revenues. Numax is expected to perform well in Phase
III trials and reach the market in 2008 with first year sales forecast at $594m. From
2008 to 2010 the company will heavily invest in switching patients from Synagis to
Numax, with Numax becoming MedImmunes leading brand. This will have a
significant impact, with Numax sales forecast to reach $1,512m in 2011 and Synagis
sales declining to $282.3m in 2011.
Oncology
ABX-EGF
Abgenix/Amgens ABX-EGF (panitumumab) is a fully human mAb directed towards

the epidermal growth factor receptor (EGFR). ABX-EGF is in development as both a
monotherapy and combination therapy in a range of tumor types including colorectal,
RCC and NSCLC. ABX-EGF shows promise as monotherapy or in combination
therapy for colorectal cancer. In December 2003, development of ABX-EGF for use in
prostate cancer was terminated following unsatisfactory phase II clinical trials.
However, in August 2005, the FDA granted Fast Track status for ABX-EGF in the
treatment of metastatic colorectal cancer in patients who are non-responsive to standard
chemotherapy. ABX-EGF is predicted to launch in this indication in 2007.
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Interim results from a Phase II clinical trial investigating a combination of ABX-EGF,
paclitaxel and carboplatin in Stage IIIb and IV NSCLC patients have been promising.
ABX-EGF did not result in increased toxicities over those associated with paclitaxel
and carboplatin. In January 2004, Amgen initiated a pivotal Phase III study of ABX-
EGF as third-line monotherapy every other week versus best supportive care in
advanced colorectal cancer in the US. A second pivotal Phase III trial outside the US
was also initiated in January 2004, for which 460 patients were enrolled under the same
trial design. In April 2005, the PACCE (Panitumumab Advanced Colorectal Cancer
Evaluation) study was initiated, a Phase III trial aiming to administer first-line ABX-
EGF alongside either Genentech/Roches Avastin (bevacizumab) or a standard
oxaliplatin-based (Sanofi-Aventis Eloxatin) or irinotecan-based (Pfizers Camptosar)
chemotherapy regimen to 1,000 metastatic colorectal cancer patients.
ABX-EGF is generally well tolerated among the majority of patients, with Grade 3 skin
rash the most common adverse event reported. This is to be expected, as rash is a
common toxicity associated with EGFR blockade, and could constitute a biomarker for
ABX-EGF activity.
A significant advantage of ABX-EGF over competitor products is that, as a fully

humanized mAb rather than a chimeric version such as Erbitux, it should have a more
favorable toxicity profile. ABX-EGF also offers a superior dosing regimen over
Erbitux, as it may be administered once every two to three weeks compared to once
weekly dosing for Erbitux. However, a disadvantage of ABX-EGF is its intravenous
administration, which is viewed less favorably in comparison to oral drug delivery used
in small molecule molecular targeted therapies.
A key opportunity for Amgen lies in ABX-EGF combination regimens. If Phase III
clinical trials do confirm a survival advantage associated with combined ABX-EGF,
Amgen has an experienced sales and marketing team to use these results to their
advantage, however there is expected to be a high level of competition in the mAb
oncology market which will resist sales. Sales of ABX-EGF are forecast to reach
$179.8m in 2011.
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MDX-010+MDX-1379
In November 2004, Medarex entered an agreement with BMS to co-develop MDX-010

with MDX-1379 in the US and Europe, equally sharing costs. MDX-010 is a fully
human mAb in development as a monotherapy and in combination with other therapies
for the treatment of several cancers and HIV. MDX-010 is an immunostimulatory
antibody that binds to CTLA-4 on T-cells, inhibiting the down regulation of an immune
response. MDX-010 was developed using Medarexs fully human antibody engineering
technology platform, UltiMab.
MDX-010s most advanced trials are for use in the treatment of advanced metastatic
melanoma, in combination with MDX-1379; a peptide vaccine based on gp100
melanoma-associated antigens. In addition, Phase III trials are underway for the use of
MDX-010 as a monotherapy in melanomas, as well as breast and prostate cancer. In
June 2004, MDX-010 received orphan drug status from the US FDA for the treatment
of high risk stage II, stage III and stage IV melanoma, due to high unmet need in this
indication.
Phase III trials are currently underway evaluating the use of MDX-010 in combination
with MDX-1379, MDX-010 alone or MDX-1379 alone in Stage III or Stage IV
metastatic melanoma patients who failed to respond to other standard therapies. The
combination therapy of MDX-010 with MDX-1379 is thought to hold greater potential
than the monotherapies. The combination therapy is forecast to launch mid-2007 in
Europe and the US, with a premium price in the region of $30,000 per treatment cycle,
which is approximately $10,000 more expensive than the current oncology mAbs per
treatment cycle.
The launch of MDX-010+MDX-1379 in 2007 is forecast to be highly successful, with

sales predicted to reach $1,155.8m in 2011. Under the terms of the agreement with
BMS, neither party has disclosed the level of royalties Medarex will be paid. Should
the combination therapy of MDX-010 with MDX-1379 reach the market and show
adequate efficacy over the monotherapy, it is believed that Medarex and BMS will
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terminate the development of the monotherapy and focus on the combinational therapy.
Sales of MDX-010 as a monotherapy are forecast to be lower than the combination
therapy, with sales of the monotherapy expected to be boosted by its approval as a
salvage therapy for breast cancer and prostate cancer in 2009.
Humax
Humax (AMG-714) is a fully human mAb against interleukin 15 (IL-15) and is being
co-developed by Genmab and Amgen. IL-15 is a cytokine that appears early in the
sequence of events that leads to inflammatory disease. Preclinical studies have shown
that IL-15 induces both the production of TNF-alpha, another cytokine that has been
shown to play a pivotal role in inflammation, as well as the recruitment of
inflammatory T-cells. Humax has the potential to treat a wide range of patients as it is
designed to block the activity of IL-15, and thus may interfere broadly with the
inflammatory processes involved in diseases such as RA, psoriasis and Crohns
disease. Humax is predicted to gain approval in 2008.
Phase II trials of Humax for the indication of RA began in March 2003. Interim data
from the Phase II trial, presented in March 2004, were suggestive of a clinical effect in
RA. Phase III trials are underway for the indication of T cell lymphoma in patients who
are refractory or intolerant to Targretin (bexarotene) and one other standard therapy.
The most recent results from a Phase II trial were announced in October 2004. The
objective was to assess the efficacy and safety of twice-monthly administration of
Humax in patients with active RA who have failed one or more DMARDs. The groups
receiving AMG-714 demonstrated a trend with a higher proportion of patients with
ACR-20 scores than placebo. The observed incidence of adverse events was similar in
Humax (60.9%) and placebo (56.5%). AMG-714 also shows promise in many other
indications, including an increase in BMD for osteoporosis.
In July 2003, Amgen exercised its commercialization options for both the Humax
antibody program and the IL-15 receptor program from Genmab. Amgen has also
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expanded the agreement to include another antibody program. This was originally
scheduled to occur after Phase II was completed and this advance in the agreement
indicates Amgens confidence in this product. In September 2003, Genmab received a
$500,000 milestone payment. If successful commercialization occurs for all three
products Genmab will be entitled to receive up to $135.5m.
Cytokine inhibitors, such as Humax, are typically not expected to be used in the
treatment of active RA unless the patient has been unresponsive to a traditional
DMARD such as methotrexate. In addition, patients are more likely to be tried on at
least two of the already available TNF-inhibitors before this product is used. However,
Humax is also in clinical trials to treat a wide variety of inflammatory diseases such as
psoriasis, inflammatory bowel disease, lupus and multiple sclerosis, and thus aims to
gain a wider patient potential through multiple indications.
Humax is forecast to launch in the US in 2009, when it will experience a relatively

small uptake despite being a first in class IL-15 inhibitor. Physicians will have
numerous biologic targets to use, including TNF, B cell, T cell co-stimulatory and IL-6
inhibitors before IL-15 inhibition is likely to be considered. The inhibition of
interleukin molecules has not proven commercially successful for Amgen as yet, and
the declining sales of IL-1 inhibitor Kineret are an example of this rejection by
rheumatologists. Humax must be differentiated from Kineret, and good clinical results
and clever marketing may allow this product to become a useful alternative. Sales of
Humax are forecast to reach $69.8m in 2011.
Ophthalmology
Lucentis
Lucentis (ranibizumab) is a humanized anti-VEGF mAb fragment indicated for

ophthalmology, which is based on Genentechs larger anti-VEGF antibody Avastin.
Lucentis is a high-affinity Fab variant, and therefore enables better penetration of the
eye, but has a shorter half-life. It is under development for the treatment of the wet
form of age-related macular degeneration (AMD), a leading cause of blindness in the
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elderly, and once launched will be available in both an injectable and an ophthalmic
formulation.
Data from the Phase III MARINA study showed there was a 17 letter difference in
mean change in visual acuity from study entry between patients treated with Lucentis
and those in the control group, as measured by the Early Treatment of Diabetic
Retinopathy (ETDRS) eye chart. Data from the Phase I/II FOCUS study of Lucentis in
combination with verteporfin photodynamic therapy (PDT) showed there was a 13
letter difference in mean change in visual acuity from study entry between the two
treatment groups. Both studies met the primary endpoint of maintaining vision among
patients with wet AMD. However, adverse effects were noted in the study, including
endophthalmitis, recurrent uvveitis and central retinal vein occlusion.
In January 2005, Genentech initiated a Phase IIIb PIER trial to evaluate the safety and
efficacy of Lucentis for wet classic or occult AMD. The trial was designed to study a
less frequent dosing regiment (6 doses per year) than Pfizer/Eyetech's Macugen
(pegaptanib; 9 doses a year). Enrollment for the trial had completed by April 2005.
Lucentis is being co-developed with Novartis Ophthalmics, who acquired the rights to
develop and market Lucentis outside the US. Under the terms of the agreement,
Genentech and Novartis will share specific global development costs, with Genentech
additionally receiving an upfront fee, milestone payments and royalties. Genentech
submitted a BLA with the FDA in December 2005 for Lucentis for the indication of
neovascular wet AMD. The FDA accepted the BLA in Q1 2006 and granted Genentech
a Priority Review designation, which gives the FDA six months from the Agency's
receipt of the submission to make a decision on the application. The FDA approved
Lucentis on the 30th June 2006. Lucentis is forecast to reach sales of $238m in 2007,
increasing to $685m in 2011.
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Late stage pipeline forecasts
Key late stage mAb pipeline drug sales are forecast to 2011 as shown in Table 4.12.
The late stage pipeline shows the trend of innovation in antibody engineering, as
demonstrated by 9 of the late stage mAbs being fully human.The leading pipeline
products are anticipated to be Numax, Cimzia and MDX-010+MDX-1379, with sales
in 2011 of $2,190m, $1,266m and $1,155m, respectively.
High sales are forecast for Numax as it has been shown to be highly efficacious: in
RSV neutralization studies it is 20 times more potent than Synagis, and
approximately 50 times more effective in reducing RSV in the lungs of cotton rats.
Therefore Numax, forecast to launch in 2008, has the competitive advantage over
Synagis and has the potential to enable expansion into additional indications further
boosting sales;
Cimzia is expected to gain high sales due to its advantageous dosing regimen (once
every 4 weeks), in addition to its low manufacturing costs compared to fully human
mAbs. However, Cimzia will be threatened by competition from established drugs
Remicade and Humira in its RA and Crohns disease indications;
MDX-010+MDX-1379 is indicated for oncology and has high forecasted sales in

2011, as a result of its fully human structure and superior dosing regimen compared
to its competitor Erbitux.
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Table 4.12: Late stage monoclonal antibody pipeline sales forecast to 2011
Drug Company Therapy area Sales ($m)

2008 2011
Numax (MedImmune) MedImmune, Abbott Infectious disease 594.0 1,512.0

Cimzia (CDP 870) UCB AIID 710.0 1,266.0
MDX-010 + MDX-1379 Medarex, BMS Oncology 436.0 1,155.8
Lucentis Genentech, Novartis Ophthalmology 320.0 685.0
MRA/Actemra (tocilizumab) Chugai, Roche AIID 86.4 413.5
Eculizumab Alexion AIID 103.4 415.7
ABX-EGF Abgenix, Amgen Oncology 82.0 179.8
TNX-355 Biogen Idec, Tanox Infectious disease - 158.4
CNTO 148 (golimumab) Centocor, Shering -Plough AIID - 94.6
Denosumab (AMG 162) Amgen AIID - 70.0
Humax-CD4 (Zanolimumab) Genmab, Medarex Oncology 22.6 69.8
CNTO 1275 Medarex, Centocor AIID - 53.9
OvaRex United Therapeutics, ViRexx Oncology 22.0 38.9
Nuvion PDL AIID 13.0 32.0
IGN-101 Igeneon Oncology 13.0 32.9
Rencarex (WX-G250) Esteve, Wilex Oncology - 26.7
MLN-2704 Millennium Oncology 7.5 19.7
Aurograb (anti-MRSA mAb) Novartis, NeuTec Infectious disease - -
Lymphocide (Epratuzumab) Immunomedics, Amgen AIID - -
MT201 Micromet, Serono, CAT Oncology - -
Total 2,601.9 6,650.7
Source: Business Insights; company reports Business Insights Ltd
The antibody market in 2011
The mAb market is predicted continue to rapidly grow with sales of the current
marketed drugs forecast to reach $23.0bn in 2011 and the total market (including new
product launches) achieving sales of $29.7bn.
The antibody market in 2011 is expected to consist of a wider range of therapy areas
than currently seen. In particular more mAbs will be indicated for infectious disease,
for example MedImmunes Numax and Biogen Idec/Tanoxs TNX-355. However, the
AIID and oncology therapy areas will continue to dominate the antibody market with
forecasted sales of $11.5bn and $13.9bn, respectively.
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The future mAb market is anticipated to move towards fully human antibodies, due to
several fully human mAbs launched in the next few years, for example ticilimumab and
ABX-EGF. Humanized mAbs are forecast to be the leading type of antibody structure
in terms of sales, reaching $12.9bn in 2011, with high forecasted sales of Herceptin and
Avastin and for the pipeline drugs Cimzia and Lucentis.
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CHAPTER 5
Competitive landscape and

future growth strategies
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Chapter 5 Competitive landscape and
future growth strategies
Summary
Four types of company have been identified in the mAb market: Big Pharma,
large biotech, small biotech/antibody companies and technology companies.
However, there is a certain degree of overlap between company types and the
strategies they use to grow their share in the market.
The trend of Big Pharma acquiring companies to gain access to mAb pipeline is a
recent trend seen over the past few years. For example, in June 2006 Novartis
made a $569m bid for NeuTec Pharma, a British drug developer with several
late-stage candidates in the pipeline.
Genentech is the market leading mAb developer and currently has 5 marketed
mAbs. Genentechs highest selling mAb is Rituxan, with US sales of $1,574m in
2004, which increased 16.3% in 2005 to $1,831m. However, Genentech pays
royalties to Roche for their marketed mAbs under their long established
agreement.
There are many small biotech and specialty antibody players developing antibody
drugs, with one example being XOMA. XOMA does not have any currently
marketed mAb products, although it has mAbs in development and forms
collaborations with other antibody developers who wish to access its proprietary
technology.
Technology players, for example Crucell, are developing proprietary antibody

technologies to produce novel antibodies at a lower cost than conventional
methods, which they can outlicense to larger companies.
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Introduction
Four types of company have been identified in the mAb market: Big Pharma, large
biotech, small biotech/antibody companies and technology companies. However, there
is a certain degree of overlap between company types and the strategies they use to
grow their share in the market.
This chapter looks at the drug developers and marketing partners behind the current
marketed mAb products and key pipeline mAbs, and the key growth strategies of these
companies for the future. A huge number of M&A and licensing deals have occurred in
the mAb market over the last few years, which are indicative of the high growth and
interest in this market, and key deals are summarized in this chapter.
A key trend seen in the last few years is the entry of Big Pharma into the mAb market
via acquisitions, for example AstraZenecas acquisition of CAT. Big Pharma want to
gain a larger share in the mAb market due to the recent high growth seen in the market.
Smaller biotech and antibody companies also want to increase their market share and
become more fully integrated players, as indicated by a large number of M&A and
licensing deals.
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Key players in the monoclonal antibody market
mAb sales of the key players in the market are shown in Table 5.13.
Table 5.13: Key players in the monoclonal antibody market, 2006
Company Sales ($m) Sales Growth Market Share

2004 2005 2004-5 2005
Genentech 2,838.0 4,116.4 45.2% 29.4%

Hoffman-La Roche 1,862.7 2,704.7 45.2% 19.3%
Centocor 2,145.0 2,535.0 18.2% 18.1%
Abbott 829.1 1,362.4 64.3% 9.7%
MedImmune 942.3 1,060.9 12.6% 7.6%
Schering-Plough 746.0 942.0 26.3% 6.7%
ImClone 244.1 533.7 118.7% 3.8%
Lilly 362.8 296.7 -18.2% 2.1%
Merck KGaA 99.7 218.0 118.7% 1.6%
Genzyme 51.5 60.8 18.1% 0.4%
Novartis 49.7e 54.9e 10.5% 0.4%
Biogen Idec 26.4 49.6 87.9% 0.4%
CAT 22.9 37.6 64.3% 0.3%
Wyeth 26.0 25.6 -1.5% 0.2%
Johnson & Johnson 17.3e 13.2e -23.7% 0.1%
Corixa 3.8e 8.2e 115.8% 0.1%
Total 10,267.3 14,019.8 36.5% 100.0%
e = estimate based on IMS sales data
M&A and licensing activity
The mAb market is very attractive due to the large growth seen in the last few years, as
a result of continued advancements in antibody engineering and drug discovery
platforms. The high level of innovation in antibody technology has led to numerous
M&A and licensing deals in the mAb market, as this technology can be utilized to
develop highly efficacious and safe drugs, as shown in Table 5.14.
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Table 5.14: Monoclonal antibody collaborations, manufacturing, development
and supply agreements, 2005-6
Companies Deal Date
Xoma, Schering Plough Collaboration for therapeutic antibody discovery and 05/23/2006
development
Seattle Genetics, Manufacturing agreement for Seattle Genetics' SGN-33 and 04/25/2006
Laureate Pharma SGN-70 humanized monoclonal antibody product candidates.
Crucell, Millennium Crucell Announces STAR Research License Agreement 04/06/2006
Argos Therapeutics, Agreement to develop treatment for systemic autoimmune 03/14/2006
Novo Nordisk disorders
Cerimon Pharmaceuticals, License for worldwide rights to Simulect for the treatment 02/21/2006
Novartis Pharma of inflammatory bowel disease
BioWa, Aphton Licensing agreement for BioWas Potelligent technology 02/14/2006
Cardinal Health, Centocor Collaboration on cell line development for expression of 01/05/2006
Centocor mAbs
Crucell, Genzyme STAR research licensing agreement for mAb production 12/19/2006
MedImmune, Xencor License for Xencors XmAb Technology to create antibody 12/07/2005
therapeutics against select tumour targets
BioWa, OncoTherapy Collaboration to develop anticancer mAbs with enhanced 10/24/2005
Science ADCC, and target newly discovered membrane antigens
Crucell, DSM, IQ PER.C6 (cell line) licensing agreement with IQ corporation 10/19/2005
corporation for production of mAbs against anthrax
Agensys, Merck & Co. Co development and marketing deal for the Agensys novel 10/17/2005
AGS-PSCA cancer therapy antibody
Takeda, Merck KGaA Co-development and co-promotion of investigational 09/29/2005
compound for the treatment of cancer
MedImmune, GlaxoSmith- License of rights for anti-Staphylococcal antibody 08/29/2005
Kline programme from GlaxoSmithKline
Peregrine Pharmaceuticals, Licensing agreement to develop vascular targeting antigens 08/25/2005
Medarex
Serono, Genmab Global development and commercialization agreement for 08/18/2005
Human-CD4
Schering-Plough, Centocor Commercialization and development agreement for 08/16/2005
Centocors Rheumatoid Arthritis mAb, CNTO 128.
Xencor, Centocor Research collaboration deal to improve antibodies. Xencor 07/18/2005
licenses engineered Fc domains to Centocor to enhance
therapeutic efficacy
Seattle Genetics, PSMA Seattle Genetics has licensed its proprietary antibody-drug 06/20/2005
Development, PDC conjugate technology to PDC.
ImClone Systems, ImClone signed licensing agreements with Genentech and 01/26/2005
Genentech and Centocor Centocor for technology rights covering anti-EGFr
Xencor, Roche Collaboration for optimized antibodies; Roche licenses 01/12/2005
Xencors XmAb technology to enhance antibody efficacy.
Source: Business Insights; MedTRACK Business Insights Ltd
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There are several key trends that have been noted from the high level of M&A and
licensing activity:
Big Pharma is acquiring large antibody/biotechs with currently marketed mAbs, for
example AstraZenecas acquisition of CAT;
Big Pharma is collaborating with large antibody/biotechs to become the marketing

partner for mAbs, for example Roches established collaboration with Genentech;
Big Pharma and large biotechs are acquiring smaller biotechs/antibody companies
to gain antibody technology, for example Amgens acquisition of Abgenix;
Small biotechs/antibody companies are licensing technology to big Pharma and

large biotechs, for example Roche licensing Xencors XmAb technology.
Examples of major growth strategies used in the mAb market are shown in Figure 5.12.
This model shows that numerous relationships can be formed between companies and
that deals can be established in order to gain either technology (Roche acquiring
GlycArt or Medarex licensing BioWas technology) or directly boosting mAb
portfolios by product licensing (Schering-Plough licensing Centocors CNTO 148) or
acquisition (AstraZeneca acquiring CAT). The complex relationships formed between
companies demonstrates that few players are fully integrated. The shear number of
deals made indicates that the high level of innovation is driving the market, which has
resulted in high sales growth and has made the mAb market even more attractive.
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Figure 5.12: Key growth strategies in the monoclonal antibody market, 2005-6
Product license
e.g. Schering-
Plough to develop
Centocors CNTO Technology
148. (08/16/2005 Big Pharma
companies
Acquisition
e.g. AZ acquisition
of CAT.
*
Technology license
05/12/2006 e.g. Crucell license
STAR technology to
# Millennium. 04/06/2006
Small biotech/ Development

In-house Large biotech Antibody company collaborations
development e.g. Abmaxis,
e.g. Genentech Maimonidex
collaboration on RA
Technology license treatment. 09/21/2005
e.g. BioWa and Medarex, second
license for BioWa's Potelligent
Technology for the enhancement of
ADCC. 05/24/2005
* Acquisition
e.g. Roche acquire GlyArt Biotech (gain technology).
07/19/2005
Technology licence
e.g. Roche licenses Xencors XmAb technology. 01/12/2005
# Technology license
e.g. Crucell license STAR technology to Genzyme. 12/19/2005
Big Pharma acquiring biotechs and antibody companies
Big Pharma companies have made several deals in the mAb market in the last few
years, as highlighted in Figure 5.12. In an attempt to enter the mAb market, many large
pharmaceutical companies have acquired biotechs and antibody companies to attain
marketed mAbs, pipeline products and antibody technology. Table 5.15 shows key
acquisitions made by Big Pharma that have occurred in the mAb market since 2005.
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Table 5.15: Key acquisitions in the monoclonal antibody market, 2005-6
Date Acquirer Target Therapeutic/strategic focus

announced
June 2006 Novartis NeuTec Development of recombinant antibodies

May 2006 AstraZeneca CAT mAb: Humira and pipeline drugs CAT
3888 and CAT 354
Dec 2005 Amgen Abgenix Monoclonal antibodies
Oct 2005 Novartis Chiron Vaccines
Sept 2005 MedImmune Cellective Therapeutics mAb drug discovery and developer
Aug 2005 Pfizer Bioren Optimizing antibody technology
Jul 2005 Roche GlycArt Biotechnology Swiss biotech, focused on antibodies
AstraZeneca and CAT
AstraZeneca (AZ) announced its acquisition of CAT on May 12th 2006 for the value of
706m. AZ already owns 19.2% of CAT as a result of a previous research deal in 2004
and on completion of the acquisition will own 67% of CAT. The key reason for this
acquisition was to alleviate concerns over AZs pipeline. Upcoming patent expiries of
their major brands Nexium, Seroquel and Toprol XR (combined 40% of AZs revenue)
are set to substantially threaten sales, in addition to key pipeline drugs (Exanta and
Galida) being pulled. The deal will allow AZ to gain access to successful marketed
mAb Humira and CATs promising pipeline drugs, including CAT 3888 and CAT 354.
The deal is considered to be a good long term strategy for AZ for delivering biologics.
Novartis and NeuTec
In June 2006 Novartis made a $569m bid for NeuTec Pharma, a British drug developer
with several late-stage candidates in the pipeline. NeuTecs Mycograb has been
submitted to the EMEA as a therapy for invasive candidiasis and Aurograb is in Phase
III trials as a therapy for MRSA. This acquisition is an example of Novartis, like other
Big Pharmas, becoming more involved in the mAb market, due to the rapid growth of
mAbs seen over the last few years. This deal also fills a gap in Novartis pipeline,
which now that Lucentis has been approved by the FDA, lacks late-phase pipeline
mAbs.
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Amgen and Abgenix
Amgen announced its acquisition of Abgenix for approximately $2.2bn in December

2005. Abgenix specializes in the discovery, development and manufacture of human
therapeutic antibodies. Under the terms of the agreement, shareholders of Abgenix will
receive $22.50 in cash per common share and it is expected that Abgenix to be kept as
a networked company.
The acquisition of Abgenix provides Amgen with full ownership of one of Abgenixs
most important advanced pipeline products, panitumumab. Working closely with
Abgenix under a co-development agreement that Amgen assumed as a result of its
acquisition of Immunex Corporation in 2002, Amgen has led the development and
commercialization strategy for panitumumab. The acquisition also provides additional
value to Amgen by eliminating a tiered royalty that Amgen would have paid to
Abgenix on future sales of denosumab (formerly AMG 162), which was created using
Abgenix's XenoMouse technology. Amgen will additionally gain Abgenixs scientific
expertise and assets, such as the ownership and capabilities of the proprietary fully
human mAb technology, XenoMouse.
Roche and GlycArt
In July 2005, Roche announced its agreement to acquire 100% of GlycArt

Biotechnology AG, a privately owned Swiss biotech company, and to fully integrate
GlycArt into the parent company. Roche will pay approximately 235m Swiss francs in
cash in exchange for all of GlycArts outstanding capital stock.
GlycArt owns the proprietary GlycoMAb glycosylation technology, a method of

increasing the potency of therapeutic antibodies, which specifically increases ADCC.
GlycoMAb thus has the potential to generate best-in-class antibody therapeutics in
disease areas such as oncology, that will further strengthen Roches expertise in
therapeutic antibody research and development, where Roche is the global market
leader. In addition, Roche will acquire GlycArts development pipeline which includes
three mAbs in preclinical development for cancer.
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MedImmune and Cellective Therapeutics
In September 2005, MedImmune announced an agreement to acquire Cellective

Therapeutics, in a deal that furthers its strategy of increasing new drug candidates in
cancer and autoimmune diseases such as lupus and RA. Under the terms of the
agreement, MedImmune acquired all outstanding equity interests of Cellective in a
cash transaction. Financial details of the transaction were not disclosed. MedImmune
will also provide Cellective shareholders with future payments for the company's three
preclinical antibody programs should certain product development and sales milestones
be achieved.
MedImmune gains three preclinical stage programs from Cellective Therapeutics

developing mAb that target the B-cell antigens CD19, CD20 and CD22. The
acquisition also benefits Cellective, as MedImmunes financial power and experienced
sales and marketing team will be provide a more successful launch for Cellectives
products.
Pfizer and Bioren
In August 2005 Pfizer announced its completion of its acquisition of Bioren Inc. Pfizer
purchased all outstanding stock of Bioren for an undisclosed amount. Bioren is a
California-based, privately held company specializing in technology for optimizing
antibodies. Bioren has developed Walk-Through Mutagenesis (WTMTM) and Look-
Through Mutagenesis (LTMTM) technologies to improve the drug development of
antibodies.
Over the last five years Pfizer has made significant internal and external investments,
including the acquisition of Bioren, which have resulted in a substantial portfolio of
therapeutic proteins and other macromolecules currently in various stages of
development.
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Company profiles
Key players in the mAb market can be broadly categorized into Big Pharma, large
biotechs, small biotech or antibody companies and technology companies. Each type
utilizes different strategies in order to gain revenue and to grow their market share in
the mAb market. Profiles of companies in each category are given in the following
section, with key trends discussed regarding innovation and therapy areas among their
marketed and pipeline drugs.
Big Pharma
Roche
Company overview
Roches pharmaceutical division develops mAbs, and in addition Roche generates

revenue from Genentechs sales of mAbs, due to Roches 58% stake of Genentech. As
part of its relationship with Genentech, Roche has the right to market Genentechs
products outside the US.
Strategic and growth analysis
Roche has a strong collaboration strategy that has enabled the development of a diverse
pipeline. Roches performance is strongly linked with Genentech, as it has a majority
equity holding in the company and secures European sales of key oncology products
such as Avastin and MabThera. An opportunity for Roche is to capitalize on its links
with Genentech and its strong position in oncology to increase penetration of the US
market, which will help to reduce reliance on the increasingly regulated European
market. Another strategy of Roches is to expand the indications for currently marketed
drugs in order to boost sales, as seen by the approval of Rituxan for AIID indications in
February 2006.
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Roches continuing evolution as the leading mAb company is set to strengthen the
companys position over the next few years. Roches strong product development
strategy, driven by its portfolio management and extensive licensing and collaboration
will help drive long-term growth. Roches strategic position is analyzed in Figure 5.13.
Figure 5.13: Roches SWOT analysis in the mAb market
Roche
Strengths Weaknesses
Majority equity holding of Lack of product diversity in terms

Genentech of therapy area
Strong licensing and collaboration Lack of in-house antibody
strategy technology
Opportunities Threats
Capitalise on links with Competition from companies

Genentech launching drugs in similar areas to
Expansion into other therapy Roche/Genentechs marketed
areas e.g. infectious disease products
Roche has made several M&A and licensing deals over the past few years in the mAb
field, in addition to its close long-term collaborations with Genentech and Chugai.
These deals have allowed Roche to gain access to advanced technology in the mAb
market to develop high efficacy antibodies:
In October 2005, Roche and Epitomics announced a research agreement granting

Roche a license to Epitomics' rabbit monoclonal antibody technology (RabMab
technology) for the discovery and development of mAbs to treat cancer and other
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TLFeBOOK
diseases. Epitomics' proprietary technology approach utilizes mAbs from rabbits,
potentially improving the quality and efficiency of drug discovery;
Dutch biotechnology company Crucell N.V. and allied contract manufacturer DSM
Biologics signed a PER.C6 research license agreement with Roche in February
2006. This license agreement allows Roche to use the PER.C6 cell line for
production of mAb products;
In January 2005, Xencor announced a collaboration with Roche to create mAbs

with greatly enhanced potency. Roche will use Xencor's XmAb technology on its
proprietary cancer target. Xencor will receive technology access and license fees,
and is eligible to receive additional license fees, milestones and royalties in the
event that Roche advances candidates into development.
Marketed products
Roches marketed products are shown in Table 5.16. The oncology drugs Avastin,
Herceptin and Rituxan were all developed by collaboration partner Genentech, and are
sold by Roche outside of the US. Roches highest selling mAb is Rituxan, with Roche
generating sales of $1,150.2m in 2004, which increased 29.7% in 2005 to $1,492.2m.
Roches total mAb sales were $2,704.7m in 2005, an increase of 45.2% from the
previous year.
Table 5.16: Roches marketed monoclonal antibodies, 2006
Name Therapy area Indication Launch date
Avastin Oncology Colorectal cancer 2005

Herceptin Oncology Breast cancer 1999
Rituxan/MabThera Oncology NHL 1997
Zenapax AIID Kidney transplant 1997
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Pipeline
Roches mAb pipeline (excluding products under development by Genentech) is shown

in Table 5.17.
Table 5.17: Roches monoclonal antibody pipeline, 2006
Name Therapy area Indication Phase Launch date
Atlizumab (MRA) AIID Rheumatoid arthritis Phase II 2009

Omnitarg Oncology Solid tumors Phase II >2011
R1594 (PRO70769) AIID Rheumatoid arthritis Phase I >2011
R1594 (PRO70769) Oncology Hematologic malignancies Pre-clinical >2011
Actemra, MRA
Atlizumab (Actemra, MRA) is a humanized anti-interleukin-6 receptor mAb. It was

originated by the Japanese company Chugai Pharmaceutical and is being developed for
the treatment of RA, Crohn's disease, multiple myeloma and the lymphoproliferative
disorder giant lymph node hyperplasia (Castleman's disease). Atlizumab is forecast to
launch in 2009.
Omnitarg
Omnitarg is a humanized mAb and the first in a new class of agents known as HER
dimerization inhibitors (HDIs). HDIs block the ability of the HER2 receptor to
associate with other HER receptor family members and ultimately lead to cancer cell
growth inhibition and death of the cancer cell. HDIs, because of their unique mode of
action, have the potential to work in a wide variety of tumors, including those that do
not over express HER2. Genentech, in collaboration with Roche, is in a Phase II
clinical trial with Omnitarg in combination with chemotherapy for the treatment of
platinum-resistant ovarian cancer. Omnitarg is forecast to launch in the next 5-10 years.
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Novartis
Company overview
In 2005, Novartis generated revenues of over $32bn, an increase of 14% over the
previous year. Sales from mAbs reached $54.9m in 2005, an increase of 10.5% from
the previous year.
Novartis has made several deals in a bid to enter the attractive mAb market, such as its
acquisition of NeuTec Pharma in June 2006. NeuTec Pharma has several late-stage
candidates in the pipeline, which fills a gap in Novartis pipeline, which now that
Lucentis has been approved by the FDA, contained no mAbs. Novartis strategic
position is assessed in Figure 5.14.
Figure 5.14: Novartis SWOT analysis in the mAb market
Novartis
Strong sales and marketing Lack of early stage mAb pipeline

abilities. products
Acquisition of Neutec in June
2006 to gain a late stage mAb
pipeline.
Experience in the mAb market
from currently martketed products,
Xolair and Simulect
Large R&D spend, which will Competition from companies

facilitate in licensing of antibody experienced in antibody
technology development.
Further acquisitions to broaden
its mAb pipeline.
Key late stage pipeline products
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TLFeBOOK
Novartis has been very active in M&A activity over the last few years, with several key
deals made:
In June 2006 Novartis made a $569m bid for NeuTec Pharma, which has developer
with several late-stage candidates in the pipeline. NeuTecs Mycograb has been
submitted to EMEA as a therapy for invasive candidiasis and Aurograb is in Phase
III trials as a therapy for MRSA;
Cerimon Pharmaceuticals announced in February 2006 that it has licensed the

exclusive worldwide rights to develop and commercialize Simulect (basiliximab)
from Novartis Pharma. Under the terms of the agreement, Cerimon will be
responsible for the development and marketing of Simulect (for injection) for IBD,
while Novartis will continue to market it in the transplantation indications. Novartis
mainly out licensed Simulect for the indication of IBD due to it being a small
indication, and thus not forecast to reach high sales;
In June 2003 Genentech and Novartis Ophthalmics, the eye health unit of Novartis
AG, entered into an agreement under which Novartis Ophthalmics will receive an
exclusive license to develop and market Lucentis (ranibizumab) outside of the US
for indications related to diseases of the eye.
Marketed products
Novartis marketed mAb portfolio is shown in Table 5.18. Novartis market two mAbs,
Xolair (in collaboration with Genentech) and Simulect. Xolair is the only currently
marketed mAb for asthma and reached sales of $326.4m in 2005, an increase of 73.6%
from the previous year. Sales of Zenapax reached $54.8m in 2005, an increase of
10.5% from 2004 sales. Simulect is indicated for organ transplant rejection, and thus
faces competition from other mAbs with the same indication such as Orthoclone OKT3
and Zenapax.
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Table 5.18: Novartis marketed monoclonal antibodies, 2006
Xolair Respiratory Severe allergic asthma 2005

Simulect AIID Renal transplant rejection 1998
Pipeline
Novartis mAb pipeline includes Lucentis, which is being developed in collaboration

with Genentech and was approved in June 2006. Novartis has also acquired NeuTec
and has subsequently gained its promising pipeline drugs Mycograb and Aurograb, as
shown in Table 5.19.
Table 5.19: Novartis monoclonal antibody pipeline, 2006
Lucentis Ophthalmology Macular degeneration Approved 2006

Mycograb Infectious disease Systemic candidiasis Filed (EU) 2008
Aurograb Infectious disease anti-MRSA III >2011
Aurograb
Aurograb is a mAb targeting staphylococcus aureus including MRSA and the recently
emerged VISA. Given its synergy with vancomycin, NeuTec (now Novartis)
anticipates that Aurograb will be of particular benefit when prescribed in combination
with vancomycin in the treatment of MRSA infections, both increasing efficacy and
inhibiting the emergence of VISA. In May 2004 Aurograb entered a double-blind
placebo-controlled phase III clinical trial. The trial compares the effects of Aurograb in
combination with vancomycin versus vancomycin alone in the treatment of MRSA
infections. Aurograb is not forecast to launch before 2011.
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TLFeBOOK
Mycograb
Mycograb is a mAb targeting the immunodominant antigen heat shock protein 90 for
the treatment of systemic candidiasis. The drug may also be active against other fungal
infections and breast cancer. Additionally, a successful application to the FDA for an
IND has been achieved for a phase III study to assess the efficacy and safety of
Mycograb as adjunctive therapy for cryptococcal meningitis in patients with AIDS. In
September 2005 NeuTec recruited its first patient in a clinical study in breast cancer
patients. The phase Ib, pharmacokinetic, multi-centre, open label study will evaluate
the safety and efficacy of Mycograb administered in combination with Docetaxel in
metastatic or recurrent breast cancer patients. Mycograb is forecast to launch in 2008,
reaching sales of $60m in 2011.
Pfizer
Company overview
Pfizer is the number one pharmaceutical company in the world, with sales of $51,298m
during 2005, a decrease of 2.3% from 2004. Pfizer does not have any marketed mAbs
at present, but has several pipeline mAbs developed in house and gained through
company acquisitions.
Although Pfizer does not have any marketed mAb drugs, they have made several deals
in order to enter the market in recent years. Pfizer has looked to acquire key companies
including Bioren in order to gain a late stage mAb pipeline and gain access into this
high growth market, which is a key growth strategy seen in the mAb market. Further
M&A activity is predicted to extend Pfizers growth in mAbs, with rumored targets
including Genmab (with at least four pipeline anticancer antibodies), which has
recently out-licensed its anti-T-cell lymphoma HuMax-CD4 antibody to Serono for
approximately $215m, or Protein Design Lab with its chimeric antibody's volociximab
currently in Phase II for solid tumors. Pfizer has seen an opportunity in therapeutic
mAbs and is expected to launch a product in the next 5-10 years in this area.
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TLFeBOOK
Figure 5.15: Pfizers SWOT analysis in the mAb market
Pfizer
Strong sales and marketing Lack of antibody experience.

abilities. No currently marketed mAbs.
Acquisition of Bioren in August
2005 to gain a late stage mAb
pipeline.
Large R&D spend, which will Competition from companies

facilitate in licensing of antibody experienced in antibody
technology development.
Further acquisitions to broaden
its mAb pipeline.
Pfizer has been involved in numerous deals regarding therapeutic mAbs, which has
allowed them to gain access to pipeline products and innovative technology. Recent
deals include the acquisition of Bioren and Rinat Neuroscience:
In April 2006 Pfizer announced its agreement to acquire Rinat Neuroscience Corp.,
a privately held biotechnology company that is developing therapeutic proteins for
the treatment of diseases and disorders of the central nervous system. The
acquisition of Rinat allowed Pfizer to gain access to Rinats Alzheimer's pipeline
drug RN1219;
In May 2006, BioSystems and Northeastern University announced that they had
signed a license agreement for the University's mAb based biomarker discovery and
development platform that was developed by scientists at Pfizer Fresnes
Laboratories and Northeastern University. Pfizer retains rights to use the
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TLFeBOOK
technology for its programs and transferred all other rights to Northeastern
University;
Pfizer announced the completion of its acquisition of Bioren in August 2005. Pfizer
purchased all outstanding stock of Bioren for an undisclosed amount. Bioren is a
California-based, privately held company that specializes in optimizing antibodies.
Bioren has developed Walk-Through Mutagenesis (WTMTM) and Look-Through
Mutagenesis (LTMTM) technologies to improve the drug development of
antibodies.
Pipeline
Pfizers mAb pipeline is shown in Table 5.20. Pfizer is developing several mAbs in-
house in addition to the products it has acquired through acquisitions. However, Pfizer
does not have any mAbs forecast to launch before 2011.
Table 5.20: Pfizers monoclonal antibody pipeline, 2006
CP-675,206 (ticilimumab) Oncology Metastatic melanoma Phase III >2011

CP-571,871 Oncology Multiple myeloma Phase I >2011
(Relapsed/refractory)
RN1219 (Rinat) CNS Alzheimers Phase I >2011
Undisclosed Unknown Unknown Phase I >2011
Ticilimab
Ticilimab (CP-675, 206) is an oncology mAb to the CTLA4 antigen, which began
Phase III trials in December 2005. This drug may provide an important new option for
treating metastatic melanoma, which has a 5 year survival rate of less than 10%.
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TLFeBOOK
RN1219
As a result of Pfizers acquisition of Rinat Neuroscience, Pfizer has obtained the

pipeline drug RN1219 for the potential treatment of Alzheimer's disease. RN1219 is a
humanized mAb that has been shown to reduce amyloid plaque in pre-clinical studies.
The buildup of amyloid deposits in the brain contributes to the progressive death of
nerve cells that occurs in Alzheimer's patients.
Large biotech
Genentech
Company overview
Genentech is the leading producer of mAbs and is one of the key bio-oncology
companies. After poor sales of a key cardiovascular product weakened the company,
Roche acquired a 60% majority stake of Genentech in 1990. This stake was 58% at
December 2003. As part of its relationship with Genentech, Roche has the right to
market Genentechs products outside the US.
Genentech is currently the leading producer of mAb therapeutics, with a very strong
bio-oncology franchise and the largest manufacturing capabilities. Genentech is
predicted to grow even stronger within the oncology market. However, Genentech has
an opportunity to boost growth by developing its AIID franchise through products such
as Raptiva (efalizumab), and should consider late-stage partnering to accelerate the
consolidation of its position in this market.
Genentechs continuing evolution as the leading mAb company is set to strengthen the
companys position over the next few years. Its strong product development strategy,
driven by its portfolio management strategy and extensive licensing and collaboration
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TLFeBOOK
strategy, such as its long established collaboration with Roche, will help drive long-
term growth. Genentechs strategic position is analyzed in Figure 5.13.
Figure 5.16: Genentechs SWOT analysis in the mAb market
Genentech
Leading mAb company Lack of mid and late phase

Strong marketed mAb portfolio pipeline drugs
Established collaboration with
Roche
Acquisitions to expand mAb Competition from companies

pipeline launching drugs in similar areas to
Roche/Genentechs marketed
products
Marketed products
Genentech currently has 5 marketed mAbs, as shown in Table 5.21. Genentechs

highest selling mAb is Rituxan, with US sales of $1,574m in 2004, which increased
16.3% in 2005 to $1,831m. However, Genentech pays royalties to Roche for their
marketed mAbs under their long established agreement. Avastin is the most recently
launched mAb by Genentech with sales of $1,133 in 2005 and a rapid growth rate of
107.9% compared to 2004 sales. However, Avastin is set to face competition from the
pipeline drugs PTK787 (vatalanib) and ABX-EGF (panitumumab).
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TLFeBOOK
Table 5.21: Genentechs marketed monoclonal antibodies, 2006
Avastin Oncology Colorectal cancer 2005

Raptiva AIID Psoriasis 2003
Xolair Respiratory Asthma 2003
Herceptin Oncology Breast cancer 1999
Pipeline
Genentechs mAb pipeline is shown in Table 5.17. Genentechs mAb pipeline lacks
late and mid-phase products now that Lucentis has been approved.
Table 5.22: Genentechs monoclonal antibody pipeline, 2006
Lucentis Ophthalmology Macular degeneration Approved 2006

PRO70769 AIID Rheumatoid arthritis Phase I >2011
RI 624 CNS Pain Phase I >2011
TRX-1 Hematology Hemophilia A Phase I >2011
Lucentis
Lucentis (ranibizumab) is a humanized anti-VEGF mAb fragment indicated for

ophthalmology, which is based on Genentechs larger anti-VEGF antibody Avastin.
Lucentis is being co-developed with Novartis Ophthalmics and gained FDA approval
in June 2006. Lucentis is a high-affinity Fab variant, and therefore enables better
penetration of the eye, but has a shorter half-life. It is under development for the
treatment of the wet form of age-related macular degeneration (AMD), a leading cause
of blindness in the elderly, and once launched will be available in both an injectable
and an ophthalmic formulation. Lucentis is forecast to reach sales of 685m in 2011.
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TLFeBOOK
MedImmune
Company Profile
MedImmune, founded in 1988, is a fully integrated biotechnology company

specializing in antibody therapies and vaccines. The companys antibody-based
marketed products include both monoclonal and polyclonal antibodies. In 2004, the
companys monoclonal antibody business accounted for almost 83% of total revenue.
MedImmunes SWOT analysis in the mAb market is shown in Figure 5.17.
Figure 5.17: MedImmunes SWOT analysis in the mAb market
MedImmune
Fully integrated biotech company Unlikely to be able to diversify its

Sales of the marketed drug mAb portfolio beyond the RSV
Synagis and subsequent pipeline market
product Numax, which has high
forecast sales
Collaboration to gain technology
(PDL)
Switching patients from Synagis Patient reluctance to switch to

to Numax Numax
Establish more R&D Competition from other drugs in
collaborations and seek to license the RSV market
early-stage mAbs to broaden its
pipeline further
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TLFeBOOK
MedImmune has established itself as a fully integrated biopharmaceutical company, as
a result of combining its immunology expertise and collaborating with companies that
have vaccine and antibody engineering capabilities. The success of MedImmune to
date is underpinned by the success of its main product, Synagis (palivizumab),
approved for the prevention of respiratory infections associated with respiratory
syncytial virus (RSV). This antibody was developed in-house using Protein Design
Labss SMART Humanization antibody technology. MedImmunes business model is
similar to other biotechnology companies, such as Chiron and Biogen Idec, which have
established themselves as fully integrated players in a similar manner.
Synagis and the follow-up product in development, Numax, are expected to provide
MedImmune with a stable revenue stream for several years, as the products are
unlikely to face competition from new products or generic competition, owing to the
lack of a biogeneric regulatory pathway. It is expected that MedImmunes marketing
strategy will focus on switching the patients from Synagis to Numax, once it is
launched in 2008. The combined revenue from these anti-RSV therapies is forecast to
generate over $1bn in revenue for MedImmune each year. Over the next five years,
MedImmune is unlikely to be able to diversify its mAb portfolio beyond the RSV
market, as Numax is the only product forecast to launch before 2011. However,
MedImmunes early stage pipeline covers a range of therapy areas, which will boost
their long-term growth.
MedImmune has primarily made two types of agreements with companies. Firstly,
MedImmune has licensed antibody engineering technologies from other companies,
such as the deals with Protein Design Labs for its SMART Humanization technology.
MedImmune has relied on such deals to develop mAbs because it lacks any in-house
antibody engineering technology. The second type of deal MedImmune has formed are
early-stage mAb development collaborations, to either discover and develop mAbs or
gain access to antibody engineering technology or antibody targets, and thus broaden
their early-stage pipeline.
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TLFeBOOK
Marketed products
MedImmunes marketed mAb portfolio is shown in Table 5.23.
Table 5.23: MedImmunes marketed monoclonal antibodies, 2006
Synagis Infectious disease RSV 1998
MedImmunes only marketed mAb product is Synagis, which is currently the leading
therapy for respiratory syncytial virus (RSV) on the market. Synagis was the first mAb
therapy to be approved for an infectious disease indication. MedImmune has two
additional marketed antibodies, RespiGam (RSV immunoglobulin) and CytoGam
(Cytomegalovirus immunoglobulin), however these products are not included in the
report as they are polyclonal.
Pipeline products
MedImmunes mAb pipeline products are shown in Table 5.24.
Table 5.24: MedImmunes monoclonal antibody pipeline, 2006
Numax Infectious disease RSV Phase III 2008

Vitaxin Oncology refractory solid tumors Phase II >2011
Anti-IL-9 Respiratory disease asthma Phase I >2011
MT103 Oncology B-cell tumors Phase I >2011
Anti-EphA2 Oncology - Pre-clinical >2011
Anti-EphA4 Oncology pancreatic cancer Pre-clinical >2011
Anti-hMPV Infectious disease meta-pneumo virus Pre-clinical >2011
infection
HMGB-1 AIID auto-immune diseases Pre-clinical >2011
MEDI-507 Oncology T-cell lymphoma Pre-clinical >2011
MDX-1103 AIID auto-immune diseases Pre-clinical >2011
MDX-1333 AIID auto-immune diseases Pre-clinical >2011
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MedImmune has a relatively broad therapeutic focus for its mAbs, which includes four
main areas: AIID, infectious disease, oncology and respiratory. The company appears
to be looking to consolidate its infectious disease portfolio, as it has two mAb R&D
programs underway. MedImmunes R&D programs indicate that in the longer term, the
company is looking to expand its therapeutic focus to incorporate AIID and oncology
in particular.
Numax
MedImmune is developing Numax as a follow-up to its successful RSV therapy,

Synagis. This second-generation anti-RSV antibody product has been shown to be a
potent RSV antibody in preclinical studies, with more than 20 times the potency of
Synagis in neutralizing RSV in tissue culture, and also 50 times more effective in
reducing RSV in the lungs of cotton rats. MedImmune began Phase III trials for the
drug in November 2004, and it is predicted that an application will be filed with the
FDA in 2007, resulting in an approval by 2008. MedImmune is expected to market
Numax to patients on Synagis, and therefore uptake is anticipated to be rapid in its first
year on the market, with sales reaching $300m, rising to $1,266m in 2010.
Biogen Idec
Company overview
Biogen Idec is a leading developer of antibody-based therapies for the treatment of

cancer, autoimmune and inflammatory diseases. Biogen Idecs mAb sales reached
$49.6m in 2005, an increase of 87.9% from the previous year.
Strategic analysis
Biogen Idec is one of the most fully-integrated of the mAb specialists, with three
marketed antibodies. In particular, Biogen Idec benefits from its deal with Genentech
for Rituxan (rituximab), currently the gold standard treatment for non-Hodgkins
lymphoma. In addition, the opportunity to co-promote Rituxan in the US has allowed
Biogen Idec to establish an oncology sales force and launch a second oncology
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TLFeBOOK
antibody Zevalin (ibritumomab tiuxetan) in 2002. Biogen Idecs SWOT analysis is
shown in Figure 5.18.
The growth of Biogen Idecs antibody portfolio in the near and medium term depends
largely on the success of the multiple sclerosis treatment Tysabri (natalizumab).
However, Biogen Idec and Elan voluntarily suspended Tysabri in February 2005,
following two cases of progressive multifocal leukoencephalopathy (PML). In June
2006 the FDA formally agreed to allow Tysabri back on the market. There is still no
known link between Tysabri and PML, but the benefits of the drug are considered to
outweigh the risks. However, the FDA suggested that patients try another MS drug first
and avoid drug combinations while taking Tysabri. The suspension of Tysabri is
expected to have a negative impact on Tysabri sales, due to risks of the drug being
highlighted and its use being limited.
Figure 5.18: Biogen Idecs SWOT analysis in the mAb market
Biogen Idec
Fully integrated antibody Voluntary suspension of Tysabri,

company however has been allowed back
Two marketed antibodies: onto the market by FDA
Rituxan and Zevalin Limitation of in-house technology
Strong manufacturing capabilities base
Further in-licensing deals Other product launches in niche

therapy areas (MS/NHL)
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TLFeBOOK
Biogen Idec has strong manufacturing capabilities, with two licensed biological bulk-
manufacturing facilities that were fully validated and approved to meet worldwide
requirements. In March 2003, Biogen Idec began construction of a large-scale
manufacturing facility in Hillerd, Denmark, which is one of the largest facilities of its
kind in the world, with 90,000 liters of bioreactor capacity.
Biogen Idecs strategy is based around a strong dependence on its own R&D and
utilizing its own expertise in the development of therapeutic proteins. However, the
companys own antibody technology base is limited, and consists primarily of the
antibody primatization technology. Biogen Idec has therefore had to in-license
antibody technologies and products from partners. Its most recently-approved antibody,
Tysabri, was humanized by Aeres Biomedical and more recently Biogen Idec has
collaborated with ImmunoGen and Dyax to gain access to conjugated and fully human
mAb technologies. The collaboration with Celltech to develop antibodies against the
CD40 ligand is a further example of how Biogen intends to leverage the targets that it
researches and discovers.
Biogen Idecs strength is in product development, focusing in niche therapeutic areas,

such as MS and NHL. Biogen Idec has carried out a strategy to build on its existing
therapy areas, by licensing Elans Tysabri to bolster its MS portfolio, and by
developing Zevalin to follow up its success in NHL with Rituxan.
Biogen Idec has signed a number of deals to expand its antibody expertise and gain
antibody technology where the company has limited expertise, for example
commercially important product candidates (e.g. Tysabri from Elan), in addition to
conjugated (ImmunoGen) and fully human (Dyax) technologies. Key deals made by
Biogen Idec include:
Biogens collaboration agreement with Elan in August 2000, to develop and

commercialize Tysabri for multiple sclerosis and various immune disorders. This
deal gave Biogen access to a product that is now key to its future prospects,
however the product is currently facing problems;
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TLFeBOOK
A research collaboration with Dyax to gain their fully human antibody libraries to
identify therapeutic and/or diagnostic antibodies against up to 90 Biogen protein
targets over three years. This major collaboration marks Biogen Idecs entry into
the area of fully human antibodies;
Biogen Idecs license deal of ImmunoGen's Tumor-Activated Prodrug (TAP)

technology in October 2004. The TAP technology is designed to provide tumor-
targeting antibodies with significant anticancer activity. This deal is a key example
of Biogen Idecs strategy to leverage its own research by using partners novel
technologies.
Marketed products
Biogen Idecs mAb marketed products are shown in Table 5.26. Biogen Idec has 3
marketed products, with Rituxan achieving the highest sales ($3,323.2m). However,
Rituxan is marketed by Roche, Genentech and Chugai, therefore Biogen Idec only
receives a proportion of sales.
Table 5.25: Biogen Idecs marketed monoclonal antibodies, 2006

Zevalin Oncology NHL 2002
Tysabri AIID MS 2004
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TLFeBOOK
Pipeline products
Biogen Idecs mAb pipeline is shown in Table 5.26. A key strategy for Biogen Idec is
to expand the indications of current marketed drugs, for example Rituxan in RA.
Biogen Idec has a broad pipeline portfolio, with mAbs at all phases of development.
Table 5.26: Biogen Idecs monoclonal antibody pipeline, 2006
Rituxan AIID Rheumatoid Arthritis Phase III 2008

Tysabri AIID Crohns / RA PhaseIII 2008
Anti-CD80 mAb Oncology NHL Phase II >2011
(galiximab)
Anti-CD23 mAb Oncology/AIID CLL (cancer), asthma Phase I >2011
(lumiliximab)
VLA-1 mAb AIID Inflammatory disorders Pre-clinical >2011
Anti-Lymphotoxin Oncology Solid tumors Pre-clinical >2011
Beta Receptor
Anti-CD20 mAb Oncology B-cell cancers Pre-clinical >2011
CH2 Domain Oncology Solid tumors Pre-clinical >2011
Deleted mAb
IDEC-151 - - Suspended -
UCB-Celltech
Company overview
UCB is a global biopharmaceutical company with global products including the

antihistamine drug Zyrtec and the anti-epileptic drug Keppra. UCB acquired Celltech
for $2.5bn in July 2004, which was a strategic move to enter the mAb market. With the
addition of Celltechs late stage pipeline product, Cimzia, UCB is in a strong position
to compete in the mAb market.
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TLFeBOOK
UCBs acquisition of Celltech during 2004 has provided the company with the
opportunity to become a leading biopharmaceutical company. UCB now has unique in-
house mAb technologies, which include antibody fragment technology, the PEGylation
of antibodies to improve the pharmacological profile of mAbs, and low-cost antibody
manufacturing abilities using bacterial fermentation. These should provide UCB with a
strong platform to develop future mAb products, in addition to attracting new
collaborations to develop mAbs with other companies. In particular, its low-cost
antibody manufacturing capabilities gives UCB the opportunity to focus on developing
treatments in diseases other than cancer and autoimmune diseases, where it can
competitively compete with small molecules on a price basis. An opportunity for UCB
is to expand the therapeutic focus of antibody development beyond its traditional areas
of inflammation, immunology and oncology, to new areas such as viral and bacterial
infections.
UCB is highly dependent on the success of Cimzia, which is in Phase III trials for the
treatment of Crohns disease and RA, for organic growth in the short to long term.
Celltech lacks further pipeline products that will reach the market between 2007 and
2010. UCB will need to look at in-licensing products to plug this gap. UCBs
marketing operations remain focused on European countries and the US. However, the
acquisition allows Celltechs products to be marketed in more countries, as UCB has a
greater geographical presence than Celltech. Celltech has historically grown through
M&A activity and out-licensing. However, UCBs recent takeover bid for Celltech in
May 2004 represents an opportunity for the development of Celltechs pipeline without
bringing in external partners, and directly marketing these products using UCBs
greater financial capacity.
UCB Celltechs SWOT analysis is shown in Figure 5.19.
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TLFeBOOK
Figure 5.19: UCB Celltechs SWOT analysis in the mAb market
UCB Celltech
Celltechs pipeline drugs benefit Gap in mAb pipeline now that

from the financial backing from Cimzia has been submitted for
UCB approval
In-house technology (PEGylation High dependence on Cimzia
of mAb fragments)
Wide range of collaborations
Expand into other therapy areas Consolidation in the market

such as anti-infectives Other companies developing
In-license products to fill gap in more innovative mAb technology
pipeline
UCB has collaborations with numerous other companies to develop mAbs: Amgen,
ImClone Systems, Millennium Pharmaceuticals, Wyeth and Seattle Genetics. UCBs
most recent deal was with Crucell/DSM Biologics in March 2006 to license Crucells
PER.C6 technology. This agreement allows UCB to evaluate the PER.C6 cell line for
research and manufacturing of mAbs.
Marketed products
UCB does not currently market any mAbs and the companys only mAb-related
revenue comes from licensing deals and royalties related to the companys mAb
technology, mAb fragment and Selected Lymphocyte Antibody Method (SLAM).
However, UCB does have experience in the mAb market, due to its collaboration with
Wyeth for the development of Simulect.
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TLFeBOOK
Pipeline products
UCBs therapeutic focus for developing mAb products lies in arthritis, AIID and
oncology, which are the predominant therapy areas of current marketed drugs.
Currently, UCBs most advanced pipeline product, Cimzia (CDP-870), is in Phase III
development in the AIID therapy area, with two further early-stage mAbs in
development. In oncology, the concentration of activity is in Phase I, with two products
currently under development. Another oncology product CDP-860, however, was
terminated during 2004.
Cimzia is expected to reach the market in 2006 and is forecast to achieve high sales.
However, if this fails to successfully gain approval in the US and Europe, or fails to
reach its full market potential, UCB may not be able to become a key mAb player for
many years in its current position, as the rest of its products are at early-stages of
development.
Table 5.27: UCB-Celltech monoclonal antibody pipeline, 2006
Cimzia (CDP 870) AIID RA/Crohns Filed 2006

CDP 484 AIID RA Phase I >2011
CDP 791 Oncology - Phase I >2011
CMC 544 Oncology - Phase I >2011
anti-OX40R AIID MS, Lupus Preclinical >2011
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TLFeBOOK
Small biotech/antibody companies
Medarex
Company overview
Medarex is a US biopharmaceutical company focused on the discovery and the

development of fully human mAbs. Medarex has developed the proprietary UltiMAb
Human Antibody Development System and has formed numerous alliance agreements
for this technology, such as with BMS and Pfizer, as well as developing one of the
most extensive mAb pipelines in the industry. Medarex also has a broad collaboration
with Genmab, which specializes in the discovery and development of mAbs using
Medarexs HuMAb-Mouse technology platform.
Medarex has established an extensive alliance network with major and small
pharmaceutical and biotech companies, as a result of its reputation for developing fully
human mAbs using the UltiMab platform, which has allowed Medarex to develop a
wider range of antibodies. Medarexs deals include collaborative agreements for the
development of mAbs for a given antibody target, which is usually provided by the
partner, using Medarexs UltiMab Human Antibody Development System. An example
of this is the agreement with J&J for CNTO-95, CNTO-148 and CNTO 1275 and
Fibrogen for anti-CTGF antibody.
Medarexs collaborations provide the company with a stream of revenue from contracts
and licensing, and in the future, royalties on any future sales of these products.
Medarex is forecast to continue to attract partners to develop mAb products, on the
basis of its antibody technology. Medarex has used its revenue stream to fund the
development of its own pipeline. As Medarexs own pipeline enters late-stages clinical
trials, there is the opportunity to begin directly marketing its products in order to
maximize sales. Medarex has out-licensed the marketing rights for MDX-010 in
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TLFeBOOK
combination with MDX-1379 to BMS, but has retained an option to co-promote it in
the US.
Medarexs SWOT analysis in the mAb market is shown in Figure 5.18.
Figure 5.20: Medarexs SWOT analysis in the mAb market
Medarex
Proprietary technology: UltiMab Lack of sales and marketing

platform experience
Broad early stage pipeline
Extensive collaborations
Further out -licensing deals Other companies with technology

(technology and pipeline products) similar to Medarex
To become more fully integrated
by marketing their own products
rather than forming collaborations
Medarex has been prominent in licensing over the last few years. Medarexs latest
deals include:
A license and research agreement with Euroscreen announced on 26th June 2006.
The deal was for the exclusive worldwide development and commercialization of
antibody-based products against certain targets for various diseases, including
inflammatory and autoimmune conditions. Medarex intends to use its UltiMAb
technology to create antibodies to targets provided by Euroscreen;
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A strategic collaboration with Celera Genomics announced on June 22nd 2006 to
discover and develop fully human antibodies for the potential treatment of multiple
cancer indications. The collaboration combines Celera's ability to discover and
validate novel targets for oncology with Medarex's expertise in the development of
fully human antibody therapeutics.
Marketed products
Medarex does not currently have any mAbs on the market. However, Medarexs mAb-
related revenue comes from licensing deals and royalties related to the companys mAb
technology.
Pipeline products
Medarexs mAb pipeline products are shown in Table 5.28.
Table 5.28: Medarexs monoclonal antibody pipeline, 2006
Name Therapy area Indication Phase Launch

date
MDX-010 + MDX-13792 Oncology Melanoma Phase III 2007

MDX-0102 Oncology Melanoma, breast cancer Phase II 2007
MDX-060 Oncology Lymphoma Phase II 2009
MDX-018 AIID - Phase II 2009
MDX-010 + peptides Oncology Melanoma Phase II >2010
MDX-070 Oncology Prostate Cancer Phase II >2010
MDX-214 Oncology EGFr-positive cancers Phase II >2010
MDX-010 + GVAX Oncology Prostate cancer Phase I >2010
MDX-066 Infectious disease C. difficile Phase I >2010
MDX-1307 Oncology Colorectal, pancreatic Phase I >2010
and bladder cancers
MDX-1100 AIID - Preclinical >2010
MDX-1303 Infectious disease Anthrax Preclinical >2010
Amrad Ab1 Respiratory Asthma Preclinical >2010
SARS Ab1 Infectious disease SARS Preclinical >2010
PRIMABioMed Ab1 Oncology - Preclinical >2010
Ferric Technologies Ab1 Infectious disease Bacterial infections Preclinical >2010
diaDexus Ab1 Oncology Lung cancer Preclinical >2010
Abbott Ab 11 AIID - Preclinical >2010
Abbott Ab 21 Oncology Cancer Preclinical >2010
163
TLFeBOOK
Medarexs focus is within the oncology therapy area, mainly targeting niche cancer
indications where there is a high unmet need. However, Medarex appears to be
widening its therapeutic focus, with early-stage mAb programs underway for infectious
disease, respiratory and AIID-related indications. In-line with its strategy in the
oncology therapy area, Medarex appears to be mainly focusing on developing mAbs
for diseases with high unmet need, such as Severe Acute Respiratory Syndrome
(SARS) and HIV.
MDX-010
MDX-010 is a fully human mAb in development as a monotherapy and in combination

with other therapies for the treatment of several cancers and HIV. MDX-010 was
developed using Medarexs fully human antibody engineering technology platform,
UltiMab. MDX-010s most advanced trials are for use in the treatment of advanced
metastatic melanoma, in combination with a peptide vaccine based on gp100
melanoma-associated antigens, known as MDX-1379. In addition, Phase III trials are
underway for the use of MDX-010 as a monotherapy in melanomas, as well as breast
and prostate cancer. MDX-010, in combination with MDX-1379, is forecast to launch
in mid-2007 in Europe and the US. Sales of the combination therapy are forecast at
$1,155.8m in 2011.
MDX-060
MDX-060 is a fully human mAb that is being developed by Medarex as a treatment for
CD30 positive lymphomas, such as Hodgkins disease and anaplastic large cell
lymphomas. MDX-060 targets CD30, found to be over expressed on malignant cells in
Hodgkins disease and anaplastic large cell lymphomas. In October 2004, the FDA
designated MDX-060 orphan drug status for the treatment of Hodgkins disease.
MDX-060 is forecast to launch in 2009, but its use is expected to be limited to a small
population. The mAb is expected to be marketed at a high price premium, which is
estimated in the region of $25,000 per treatment cycle and is forecast to achieve sales
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of $15m sales in 2009, its first year on the market, rising to $50m in 2011, as approval
is gained for the additional indication of ALCL in the US.
XOMA
Company overview
XOMA is a leading biopharmaceutical company, focusing on therapeutic antibody

discovery and development. XOMA was founded in 1981 with the aim of synthesizing
and manufacturing immunotoxins and other monoclonal antibodies used in the
treatment of a variety of human diseases. XOMA receives royalties from Genentech for
Raptiva (efalizumab), which was developed in collaboration between XOMA and
Genentech. XOMAs pipeline includes both proprietary products and collaborative
programs at various stages of preclinical and clinical development, primarily directed
toward treatments for cancer and immune disorders.
XOMAs main strength is its antibody technology, which it has used to form
collaborations with other companies. Threats come from other antibody companies that
also have advanced antibody technology, including larger biotechs like Medarex and
MedImmune or more specialized companies like BioWa or Crucell.
XOMAs SWOT analysis for the mAb market is shown in Figure 5.21.
165
TLFeBOOK
Figure 5.21: XOMAs SWOT analysis in the mAb market
XOMA
Advanced in-house antibody No marketed products

technology No late stage pipeline products
Deals and alliances based on
out-licensing of its technology
Strong early stage pipeline
Further out-licensing deals of its Other companies with advanced

antibody technology antibody technology, such as
Collaborations to gain late stage BioWa or Crucell
pipeline mAbs
XOMA has established a range of collaborative and licensing deals, with the most
recent and key deals summarized below:
In May 2006 XOMA announced the formation of a collaboration with Schering-

Plough through its research and development arm, Schering-Plough Research
Institute, for therapeutic mAb discovery and development. The collaboration is
intended to capitalize on XOMA's antibody technologies and expertise, which
include phage display libraries and optimization technologies;
In April 2006 XOMA and AVEO announced an agreement for XOMA to utilize its
Human Engineering technology to humanize AV-299, AVEO's novel anti-HGF
mAb. For work conducted and licenses granted, AVEO will pay XOMA an up-
front license fee, development milestones and royalties. AVEO retains all
development and commercialization rights to AV-299;
166
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In January 2006, Crucell announced that it had signed a non-exclusive STAR
(antibody technology) research license agreement for the production of mAbs and
other proteins with XOMA;
In September 2005, XOMA announced that it had signed an agreement with Cubist
Pharmaceuticals to develop new processes to manufacture a novel two-antibody
biologic (HepeX-B). XOMA has agreed to develop manufacturing processes for
two mAbs, which together make up the HepeX-B product. XOMA intends to
commence work on the project immediately, and to negotiate a longer-term
definitive agreement with Cubist later in 2006. If these trials are successful, the
parties may extend the relationship to a commercial supply agreement for product
launch.
Marketed products
XOMA does not have any currently marketed mAb products, but does receive royalties
for Raptiva from Genentech. XOMA also receives revenue for their proprietary
technology that has been outlicensed or used in collaborations with other companies. In
addition XOMA has in licensed technology to further enhance its capabilities.
Pipeline products
XOMAs mAb pipeline products are shown in Table 5.29. XOMA lacks a late stage
pipeline, but has established collaboration deals with Novartis and Aphton for 2 of its
early stage products.
Table 5.29: XOMAs monoclonal antibody pipeline, 2006
HCD 122 (chir12.12) Oncology B-cell cancers Phase I >2011

(Novartis)
Anti-gastrin mAb GI disorders GI cancers preclinical >2011
(Aphton)
XOMA 052 MAb AIID - preclinical >2011
167
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HCD122
In 2004 XOMA and Chiron entered into a collaborative agreement for the development
and commercialization of antibody products for the treatment of cancer. In April of
2006, Novartis acquired Chiron and the corresponding collaborative agreement.
HCD122 (formerly known as CHIR-12.12) is the first lead product candidate to come
out of the collaboration.
HCD122 is a fully human, antagonist antibody that targets the CD40 antigen. HCD122
has been shown experimentally to bind to tumor cells that express CD40 and
antagonizes CD40 ligand-mediated growth and survival of malignant B cells. Based on
preclinical data, HCD122 also induces ADCC, killing CD40 expressing tumor cells by
immune effector cells. This dual mechanism of action makes HCD122 a drug candidate
with potential for the treatment of B-cell malignancies. The first IND application
submission took place in December of 2004. In April of 2005, XOMA and Chiron
announced the initiation of Phase I clinical testing of HCD122, in patients with
advanced chronic lymphocytic leukemia. In October 2005, the clinical program was
extended to a Phase I trial in patients with multiple myeloma.
Anti-gastrin mAb
In September of 2004, XOMA and Aphton Corporation announced a worldwide

collaboration to develop treatments for gastrointestinal and other gastrin-sensitive
cancers using anti-gastrin monoclonal antibodies. The aim of the mAbs in development
is to bind and neutralize the hormone gastrin that is known to be involved in tumor
progression in GI cancers. XOMA and Aphton are collaborating to develop mAbs to
inhibit the pathological functions of gastrin as a novel treatment for GI cancers. This
program is currently in preclinical development.
XOMA 052
XOMA 052 is a proprietary mAb being developed as an anti-inflammatory molecule

for use in a variety of auto-immune and inflammatory diseases. This mAb is a high
affinity antibody with a very potent inhibitory activity against its target. XOMA 052 is
168
TLFeBOOK
currently in preclinical development and Phase I clinical studies are anticipated to
begin in early 2007.
Technology companies
BioWa
Company overview
BioWa focuses on discovery and development of technology that has the potential to
improve the effectiveness of antibody-based treatments across many therapeutic
categories. BioWa is the exclusive worldwide licensor of Potelligent Technology, a
proprietary technology that creates fucose-free monoclonal antibodies that demonstrate
a marked increase in ADCC, and thus enhances the ability of antibodies to kill tumor
cells. With BioWas technology, enhancement of mAb potency has been shown to
increase up to 100 fold.
BioWa aims to maximize the therapeutic efficacy of biopharmaceuticals by applying its

proprietary Potelligent Technology, and other advancements, developed alone or in
collaboration with future partners.
BioWas SWOT analysis for the mAb market is shown in Figure 5.22.
169
TLFeBOOK
Figure 5.22: BioWas SWOT analysis in the mAb market
BioWa
Advanced antibody technology No currently marketed mAb

Licensing deals to apply its
POTELLIGENT technology to
range a range of mAbs
Become more integrated and Competition from other antibody

develop its own mAb portfolio companies that also have
Further out-licensing deals for its advanced antibody technology
proprietary technology
BioWa has established collaborations with a variety of companies including Aphton,

OncoTherapy Science and Genentech:
In February 2006 BioWa and Aphton Corporation announced that BioWa has
granted a non-exclusive license to Apthon's wholly-owned subsidiary, Igeneon, to
use BioWa's Potelligent technology for the development of IGN312, a humanized
monoclonal Lewis Y-specific antibody. Aphton, through Igeneon, develops
IGN312 as a next-generation antibody based on IGN311, which is currently in a
Phase I/II clinical trial in patients with Lewis Y-positive cancers (breast, colon,
gastric and pancreatic). Aphton plans to use BioWa's Potelligent technology for the
development of a next-generation Lewis Y-specific antibody with enhanced
ADCC;
BioWa and OncoTherapy Science announced that the two companies have entered
into a collaboration to identify and develop cancer focused mAbs. OncoTherapy
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TLFeBOOK
Science will employ its technology for identification of the cancer antigens and
generation of mAbs against those antigens, and BioWa will apply its Potelligent
technology to the mAbs for the enhancement of ADCC. Under this collaboration,
BioWa and OncoTherapy Science will carry out research and development
activities collaboratively and will share profits gained from future antibody
products;
In March 2006 BioWa announced that it had licensed its Potelligent technology to
Genentech for use in researching and developing antibodies for potential
therapeutic applications that may include enhancement of ADCC. Under the terms
of the agreement, BioWa will provide Genentech with rights to use the technology
for multiple antibodies. In return, BioWa will receive technology access fees, and
may receive milestone payments and royalties in the event that products are
developed by Genentech.
Pipeline products
BioWas mAb pipeline is shown in Table 5.30. BioWas pipeline products are focused
on oncology, with one product (Potelligent-IL5R) indicated for Asthma.
Table 5.30: BioWas monoclonal antibody pipeline, 2006
KW-2871 Oncology Melanoma Phase II <2011

Potelligent-IL5R Respiratory Asthma Phase I <2011
Potelligent-Flt-1 Oncology VEGF-R/FLT-1 Phase I <2011
Potelligent-GM2 Oncology Lung cancer, glioblistoma Phase I <2011
Potelligent-GD2 Oncology Solid tumor Phase I <2011
171
TLFeBOOK
Crucell
Company overview
Crucell is a biotechnology company focused on developing products that prevent and

treat infectious diseases. Crucell utilizes its proprietary PER.C6 technology to develop
and produce novel vaccines and antibodies, which makes developing biologics faster,
easier, safer and more cost-effective than conventional methods. In addition, Crucell
outlicenses PER.C6 technology to pharmaceutical and biotechnology companies
worldwide.
A key strength of Crucell is its proprietary technology, which the company uses to
establish collaborations through outlicensing. Crucells licensee portfolios encompass
all types of biologics including vaccines, monoclonal antibodies, therapeutic proteins
and gene therapy vectors. The licensing program provides an on-going revenue stream
in the form of upfront payments and annual fees, and may provide future revenue in the
form of royalties on product sales.
Crucells SWOT analysis in the mAb market is shown in Figure 5.23.
172
TLFeBOOK
Figure 5.23: Crucells SWOT analysis in the mAb market
Crucell
Outlicensing its PER.C6 No currently marketed mAb

technology to pharmaceutical and
biotechnology companies
Become more integrated and Competition from other antibody

develop its own mAb portfolio companies that also have
Further out-licensing deals for its advanced antibody technology
proprietary technology
Crucell has recently made several key licensing deals:
In April 2006, Crucell announced that it had signed a non-exclusive STAR research
license agreement for the production of mAbs with Millennium Pharmaceuticals;
In March 2006, Crucell and allied contract manufacturer DSM Biologics

announced that they had signed a PER.C6 research license agreement with global
biopharmaceutical leader UCB. This agreement allows UCB to evaluate the
PER.C6 cell line for research and manufacturing of monoclonal antibodies;
In January 2006, Crucell announced that it had signed a non-exclusive STAR

research license agreement for the production of mAbs and other proteins with
XOMA.
173
TLFeBOOK
Pipeline products
MAbstract technology is used to identify strong binding and neutralizing antibodies for
specific disease targets. Antibodies discovered in this way can then be produced on
PER.C6 technology. MAbstract technology is Crucells proprietary technology for the
discovery of antibodies binding to disease-specific proteins, viruses and even whole
cells and tissues. The fully human mAbs produced with the MAbstract technology are
highly sought-after for the development of prophylactic or therapeutic antibodies.
MAbstract technology is ideally suited for identifying protein-specific and disease-
specific antibodies. It can be applied in diverse biomedical areas in which detection,
eradication or neutralization of targets is important, including the area of infectious
diseases. Crucells mAb pipeline is shown in Table 5.31.
Table 5.31: Crucells monoclonal antibody pipeline, 2006
Anti-rabies Infectious disease Rabies preclinical >2011
Crucell is developing a mAb product for protection against rabies. Discovered using
MAbstract technology and produced on PER.C6 technology, the product is a
combination of two human anti-rabies antibodies. As an alternative, Crucell has
conceived an antibody product that is produced using PER.C6 technology, which offers
large-scale manufacturing capabilities and production under serum-free culture
conditions. Crucells Antibody Discovery Group has developed a human mAb product
in collaboration with two leaders in the rabies antibody field, the Thomas Jefferson
University (TJU) based in Philadelphia and the US Centers for Disease Control and
Prevention (CDC) in Atlanta. Crucells MAbstract technology was used in the program
resulting in a combination of two human anti-rabies antibodies. mAbs are produced on
Crucells PER.C6 technology, whereby the PER.C6 cells are adapted to produce large
amounts of a specific antibody that binds to a specific antigen (in this case the rabies
174
TLFeBOOK
virus). Crucell plans to initiate Phase I clinical testing of its rabies antibody product
late in 2006.
175
TLFeBOOK
176
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Chapter 6
Appendix
177
TLFeBOOK
Chapter 6 Appendix
Sales data
Sales figures were taken from company reports, with the exception of companies that
did not provide detailed sales breakdowns. Estimated sales were based on IMS health
data and adjusted according to the difference seen between other company reported
sales. Sales provided in this report are in US dollars and cover the global mAb market.
178
TLFeBOOK
Index
Abbott, 24, 25, 28, 30, 32, 44, 59, 77, 79, 80, Celltech, 24, 30, 34, 36, 40, 42, 43, 49, 73, 76,
88, 91, 105, 109, 113, 116, 117, 124, 130, 80, 91, 95, 109, 155, 157, 158, 159, 160
163
Centocor, 24, 25, 30, 31, 36, 46, 59, 76, 86,
Abgenix, 43, 52, 61, 105, 117, 124, 132, 134, 87, 91, 105, 124, 130, 131, 132
135
Chimeric, 31, 105, 106
ABX-EGF, 52, 61, 66, 67, 94, 99, 104, 105,
106, 117, 118, 124, 125, 148 Cimzia, 36, 55, 58, 76, 78, 79, 80, 82, 91, 94,
95, 100, 104, 105, 109, 110, 113, 123, 124,
ADCC, 41, 42, 61, 131, 135, 168, 169, 170, 125, 157, 158, 160
171
Crucell, 128, 131, 139, 159, 165, 167, 172,
AIID, 18, 19, 24, 25, 52, 59, 76, 91, 94, 100, 173, 174
105, 106, 107, 109, 124, 137, 139, 140, 143,
147, 149, 152, 153, 156, 157, 160, 163, 164, Eculizumab, 100, 112, 113, 124
167
Elan, 25, 59, 91, 154, 155
Amgen, 32, 52, 57, 61, 62, 66, 77, 80, 82, 105,
110, 113, 114, 117, 118, 120, 121, 124, 132, Erbitux, 24, 30, 56, 59, 61, 66, 67, 68, 69, 91,
134, 135, 159 98, 118, 123
antibody fragments, 20, 23, 28, 33, 35, 43, Food and drug administration, 101
45, 46, 49, 94, 100, 104
Fully human, 32
Anti-infective, 59, 87, 91, 105, 116, 124, 143,
152, 163, 174 Genentech, 18, 24, 25, 28, 30, 32, 33, 36, 40,
55, 59, 61, 62, 63, 64, 65, 66, 78, 81, 82, 89,
AstraZeneca, 20, 25, 26, 44, 45, 129, 132, 134 91, 94, 101, 105, 118, 122, 124, 128, 130,
131, 132, 137, 138, 140, 142, 143, 147, 148,
Bexxar, 24, 30, 37, 38, 59, 60, 62, 71, 72, 74, 149, 153, 156, 165, 167, 170, 171
75, 91
Genzyme, 24, 25, 30, 59, 69, 70, 91, 130, 131
Bioequivalent, 22, 95, 96, 101, 102, 151
GlycArt, 20, 132, 134, 135
Biogen Idec, 24, 25, 30, 31, 37, 38, 45, 57, 59,
61, 62, 71, 72, 75, 78, 82, 91, 105, 124, 130, HAMA, 18, 20, 23, 29, 31, 84
151, 153, 154, 155, 156, 157
Hemostasis, 59, 86
Bioren, 134, 136, 144, 145, 146
Herceptin, 24, 30, 32, 41, 56, 57, 59, 60, 63,
BioWa, 42, 131, 132, 165, 169, 170, 171 64, 65, 91, 125, 139, 149
Campath, 24, 30, 59, 61, 69, 70, 91, 98 Humanized, 32, 105, 125
CAT, 20, 24, 25, 28, 30, 32, 42, 43, 44, 45, 59, Humax, 94, 99, 105, 120, 121, 124
79, 91, 104, 105, 124, 129, 130, 132, 134
Humira, 23, 24, 28, 30, 32, 44, 52, 55, 57, 58,
Cellective, 134, 136 59, 76, 77, 79, 80, 81, 82, 90, 91, 94, 99,
103, 109, 111, 113, 123, 134
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Johnson & Johnson, 18, 19, 20, 24, 25, 30, Remicade, 24, 30, 31, 52, 57, 58, 59, 62, 76,
46, 76, 82, 84, 86, 91, 130 77, 78, 79, 80, 82, 90, 91, 100, 103, 109,
110, 123
Lucentis, 28, 33, 36, 55, 94, 100, 104, 105,
122, 124, 125, 134, 141, 142, 143, 149 Reopro, 31, 86
Medarex, 52, 61, 64, 88, 105, 119, 120, 124, Respiratory, 59, 89, 91, 143, 149, 152, 163,
131, 132, 161, 162, 163, 164, 165 164, 171
MedImmune, 24, 25, 30, 32, 40, 49, 59, 88, Rituxan, 24, 30, 31, 41, 52, 56, 58, 59, 60, 61,
91, 105, 116, 117, 124, 130, 131, 134, 136, 62, 63, 71, 72, 78, 90, 91, 128, 137, 139,
150, 151, 152, 153, 165 148, 149, 153, 155, 156, 157
Merck KGaA, 25, 59, 66, 67, 130, 131 Roche, 20, 24, 25, 30, 32, 42, 46, 59, 61, 62,
63, 65, 78, 84, 87, 91, 105, 110, 111, 118,
MRA, 55, 62, 100, 105, 110, 111, 124, 140 124, 128, 130, 131, 132, 134, 135, 137, 138,
139, 140, 147, 148, 156
murine, 18, 20, 23, 28, 29, 30, 31, 32, 58, 62,
76, 79, 83, 84, 85, 99 Sandoz, 102
Mylotarg, 61 Simulect, 24, 30, 59, 83, 91, 98, 131, 142, 143,
159
Neutec, 20, 105, 124, 134, 141, 142, 143, 144
Synagis, 24, 25, 30, 32, 52, 59, 87, 88, 91, 94,
Novartis, 20, 24, 25, 26, 30, 36, 55, 57, 59, 66, 106, 116, 117, 123, 151, 152, 153
83, 89, 90, 91, 105, 122, 124, 128, 130, 131,
134, 141, 142, 143, 149, 167, 168 Tysabri, 24, 30, 57, 59, 91, 99, 154, 155, 156,
157
Numax, 52, 87, 88, 94, 104, 105, 107, 116,
117, 123, 124, 151, 152, 153 UCB, 34, 36, 40, 42, 43, 55, 58, 76, 78, 80, 82,
91, 95, 105, 109, 110, 113, 124, 157, 158,
oncology, 18, 19, 24, 25, 37, 52, 59, 60, 61, 159, 160, 173
69, 76, 94, 100, 105, 106, 107, 119, 123,
124, 135, 137, 146, 147, 153, 158, 160, 163, Wyeth, 24, 25, 30, 37, 57, 59, 72, 73, 77, 82,
164, 171 91, 130, 159
Orthoclone OK3, 18, 19, 20, 24, 30, 58, 59, Xencor, 41, 42, 131, 132, 139
76, 83, 84, 85, 91, 142
Xolair, 24, 30, 59, 89, 90, 91, 142, 143, 149
Pexelizumab, 36, 105, 115
XOMA, 30, 78, 81, 91, 128, 165, 166, 167,
Pfizer, 26, 32, 89, 101, 105, 118, 122, 134, 168, 173
136, 144, 145, 146, 147, 161
Zenapax, 24, 30, 32, 59, 76, 83, 84, 91, 98,
Potelligent, 42, 131, 169, 170, 171 139, 142
Raptiva, 24, 30, 57, 59, 78, 81, 82, 91, 147, Zevalin, 24, 30, 37, 38, 59, 60, 62, 70, 71, 72,
149, 165, 167 75, 91, 154, 155, 156
180
TLFeBOOK

The Future of Monoclonal Antibody

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H E A LT H C A R E

The Future of Monoclonal Antibody

Copyright 2006 Business Insights Ltd

While information, advice or comment is believed to be correct at the time of

Chapter 2 Antibody engineering and

Chapter 3 The current monoclonal antibody

Chapter 4 The antibody pipeline and

Chapter 5 Competitive landscape and

Chapter 6 Appendix 178

Khler and Milstein developed the hybridoma method of murine antibody

Current marketed antibody fragments include ReoPro and CEA-scan (diagnosis),

Advancements in antibody engineering and technology act as a huge opportunity

Lucentis (ranibizumab) is a humanized anti-VEGF mAb fragment, which is based

Technology players, for example Crucell, are developing proprietary antibody

A key theme of this report is the high level of innovation, as demonstrated by

History of monoclonal antibodies

1975 Khler and Milstein developed the hybridoma

Chimeric antibodies (60% human and 40% mouse)

The first mAb reached the market: Johnson &

Humanized antibodies (over 90% human) were first

Medimmunes Synagis was launched for the

The first radionucleotide conjugated mAb was

Source: Business Insights Business Insights Ltd

Monoclonal antibody approval process

Current approval process

mAbs conjugated with other drugs or radionucleotides is another technique to improve

mAbs currently have to be subcutaneously or intravenously injected because their

Diversification of therapy areas

Table 1.1: Current marketed drugs, 2006

Brand Generic Originator Therapy area Launch year

Orthoclone OKT3 muromonab-CD3 Johnson & Johnson AIID 1986

*Voluntary suspension February 2005, relaunched in June 2006;

Source: Business Insights; Company websites Business Insights Ltd

Big Pharma entering the mAb market

Table 1.2: Key players in the monoclonal antibody market, 2006

Company Sales ($m) Sales Growth Market Share

Genentech 2,838.0 4,116.4 45.2% 29.4%

Total 10,267.3 14,019.8 36.5% 100.0%

Source: Business Insights; Company reports; IMS Business Insights Ltd

Antibody engineering and

The last 5 therapeutic mAbs launched in the US were humanized or chimeric,

Table 2.3: Marketed therapeutic monoclonal antibodies, 1986-2006

Brand Generic Company Description Approval date

Orthoclone OKT3 muromonab-CD3 Johnson & Johnson murine 06/1986 n/a

Source: Business Insights; Company websites; FDA Business Insights Ltd

Source: Business Insights; Company websites Business Insights Ltd

Whole IgG monoclonal antibodies

Data are presented as two-year moving averages

Source: Tufts CSDD Business Insights Ltd

Innovations in antibody structures

Full-size antibody Single-chain

Source: Business Insights Business Insights Ltd

UCB Celltech is an innovator in Fab fragment engineering technology, and use

Single chain variable fragments

Drug Company Fragment type Stage Indication

ReoPro Centocor/Lilly Fab/chimeric FDA approved Cardiovascular

Source: Business Insights; Company websites; MedTRACK Business Insights Ltd

Extended release formulations

A method of improving a drugs pharmacological profile is to apply technology to

Another method of sustained release is to attach polyethylene glycol compound(s) to

Conjugated mAbs can be used as carrier agents of chemotherapy drugs, radioactive

Antibody conjugation can be categorized into 3 types:

Direct arming: antibody conjugation

Conjugated mAbs can be used as carrier agents of chemotherapy drugs, radioactive