the future of monoclonal antibody therapeutics - s. riley (2006) ww
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H E A L T H C A R E
The Future of Monoclonal AntibodyTherapeuticsInnovation in antibody engineering, key growth
strategies and forecasts to 2011
By Sarah Riley
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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 LtdThis Management Report is published by Business Insights Ltd. All rights reserved.Reproduction or redistribution of this Management Report in any form for anypurpose is expressly prohibited without the prior consent of Business Insights Ltd.
The views expressed in this Management Report are those of the publisher, not ofBusiness Insights. Business Insights Ltd accepts no liability for the accuracy or
completeness of the information, advice or comment contained in this ManagementReport nor for any actions taken in reliance thereon.
While information, advice or comment is believed to be correct at the time ofpublication, no responsibility can be accepted by Business Insights Ltd for itscompleteness 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 21Biogeneric regulations 22
Key trends in the market 23Advancements in innovation 23Diversification of therapy areas 24Big Pharma entering the mAb market 25
Chapter 2 Antibody engineering andinnovation in the market 28
Summary 28
Introduction 29
The move from murine to fully human mAbs 30Whole IgG monoclonal antibodies 31
Murine 31Chimeric 31Humanized 32
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Human 32
Innovations in antibody structures 33Fab fragments 34Single chain variable fragments 35
Extended release formulations 36
Innovation in antibody conjugation 37Types of conjugation 37
Direct arming: antibody conjugation 37Indirect arming: Bispecific monoclonal antibodies 37Pre-targeting 38
Marketed conjugated monoclonal antibodies 38Conjugation technology 39
Seattle Genetics antibody technology 39ImmunoGen mAb technology 40Peregrine mAb technology 41
Enhancing monoclonal antibody potency 41
Drug discovery 42Cambridge Antibody Technology 44Dyax 45Morphosys 46
Innovation in drug delivery 47Drug delivery devices 47Inhaled monoclonal antibodies 48Oral monoclonal antibodies 49
Chapter 3 The current monoclonal antibody
market 52
Summary 52
Introduction 53
Strategic analysis 53Drivers 54
Pipeline drugs 54Immature market 54Big Pharma entering the mAb market 55High level of innovation 55Approval of new indications 56
Combination therapies 56Resistors 56Publicized side effects 56Drugs suspended from market 57Competition from small molecule drugs 57Pricing and reimbursement schemes 57
Analysis of launched drugs 58Oncology 60
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Rituxan 61Herceptin 63Avastin 65Erbitux 67Campath 69
Zevalin 70MyloTarg 72Bexxar 74
AIID 76Remicade 76Humira 79Raptiva 81Simulect 83Zenapax 84OrthoClone OKT3 84
Hemostasis 86ReoPro 86
Anti-infectives 87Synagis 88
Respiratory 89Xolair 89
Marketed monoclonal antibody forecasts 90
Chapter 4 The antibody pipeline andforecasts to 2011 94
Summary 94
Introduction 95Strategic analysis 95
Opportunities 97Clinical trials 97
Erbitux and Avastin 98Simulect, Zenapax and Campath 98Campath 98Others 99
Innovation in antibody engineering 99New indications 100
Challenges 101Generic biologics 101Adverse reactions in clinical trials, side effects and termination ofdevelopment 102High attrition rates 103
Analysis of pipeline drugs 104AIID 109
Cimzia 109MRA/Actemra 110
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Eculizumab 112AMG-162 113
Cardiovascular 115Pexelizumab 115
Infectious diseases 116
Numax 116Oncology 117
ABX-EGF 117MDX-010+MDX-1379 119Humax 120
Ophthalmology 121Lucentis 121
Late stage pipeline forecasts 123
The antibody market in 2011 124
Chapter 5 Competitive landscape andfuture growth strategies 128
Summary 128
Introduction 129
Key players in the monoclonal antibody market 130
M&A and licensing activity 130Big Pharma acquiring biotechs and antibody companies 133
AstraZeneca and CAT 134Novartis and NeuTec 134
Amgen and Abgenix 135Roche and GlycArt 135MedImmune and Cellective Therapeutics 136Pfizer and Bioren 136
Company profiles 137
Big Pharma 137Roche 137
Company overview 137Strategic and growth analysis 137Marketed products 139Pipeline 140
Novartis 141
Company overview 141Strategic and growth analysis 141Marketed products 142Pipeline 143
Pfizer 144Company overview 144Strategic and growth analysis 144Pipeline 146
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Large biotech 147Genentech 147
Company overview 147Strategic and growth analysis 147Marketed products 148
Pipeline 149MedImmune 150
Company Profile 150Strategic and growth analysis 150Marketed products 152Pipeline products 152
Biogen Idec 153Company overview 153Strategic analysis 153Marketed products 156Pipeline products 157
UCB-Celltech 157Company overview 157Strategic and growth analysis 158Marketed products 159Pipeline products 160
Small biotech/antibody companies 161Medarex 161
Company overview 161Strategic and growth analysis 161Marketed products 163Pipeline products 163
XOMA 165Company overview 165Strategic and growth analysis 165Marketed products 167Pipeline products 167
Technology companies 169BioWa 169
Company overview 169Strategic and growth analysis 169Pipeline products 171
Crucell 172Company overview 172Strategic and growth analysis 172Pipeline products 174
Chapter 6 Appendix 178
Sales data 178
Index 179
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List of FiguresFigure 1.1: History of monoclonal antibodies 21Figure 2.2: Current marketed monoclonal antibodies, 2006 31Figure 2.3: Therapeutic mAbs entering clinical study, 1980-2004 33Figure 2.4: Whole antibody and fragment structures 34Figure 3.5: Drivers and resistors to growth in the monoclonal antibody market 54Figure 3.6: Market dynamics of current marketed drugs, 2004-5 58Figure 3.7: Marketed monoclonal antibodies by therapy area, 2006 60Figure 4.8: Opportunities and challenges in the mAb market 97Figure 4.9: Antibody structure analysis of forecasted monoclonal antibody sales ($m), 2004-11106Figure 4.10: Therapy area analysis in monoclonal antibody drug development, 2006 107Figure 4.11: Therapy area analysis of forecasted monoclonal antibody sales ($m), 2004-11 108Figure 5.12: Key growth strategies in the monoclonal antibody market, 2005-6 133Figure 5.13: Roches SWOT analysis in the mAb market 138Figure 5.14: Novartis SWOT analysis in the mAb market 141Figure 5.15: Pfizers SWOT analysis in the mAb market 145
Figure 5.16: Genentechs SWOT analysis in the mAb market 148Figure 5.17: MedImmunes SWOT analysis in the mAb market 150Figure 5.18: Biogen Idecs SWOT analysis in the mAb market 154Figure 5.19: UCB Celltechs SWOT analysis in the mAb market 159Figure 5.20: Medarexs SWOT analysis in the mAb market 162Figure 5.21: XOMAs SWOT analysis in the mAb market 166Figure 5.22: BioWas SWOT analysis in the mAb market 170Figure 5.23: Crucells SWOT analysis in the mAb market 173
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List of TablesTable 1.1: Current marketed drugs, 2006 24Table 1.2: Key players in the monoclonal antibody market, 2006 25Table 2.3: Marketed therapeutic monoclonal antibodies, 1986-2006 30Table 2.4: Antibody fragment pipeline, 2006 36Table 2.5: Conjugated antibody engineering technology 39Table 2.6: Drug development technology 42Table 2.7: Monoclonal antibody drug discovery technology 43Table 3.8: Marketed therapeutic monoclonal antibodies, 2004-5 59Table 3.9: Marketed monoclonal antibody sales forecasts, 2005-11 91Table 4.10: Other post-marketing clinical trials, 2005-6 99Table 4.11: Late stage monoclonal antibody pipeline, 2006 105Table 4.12: Late stage monoclonal antibody pipeline sales forecast to 2011 124Table 5.13: Key players in the monoclonal antibody market, 2006 130Table 5.14: Monoclonal antibody collaborations, manufacturing, development and supply
agreements, 2005-6 131Table 5.15: Key acquisitions in the monoclonal antibody market, 2005-6 134Table 5.16: Roches marketed monoclonal antibodies, 2006 139Table 5.17: Roches monoclonal antibody pipeline, 2006 140Table 5.18: Novartis marketed monoclonal antibodies, 2006 143Table 5.19: Novartis monoclonal antibody pipeline, 2006 143Table 5.20: Pfizers monoclonal antibody pipeline, 2006 146Table 5.21: Genentechs marketed monoclonal antibodies, 2006 149Table 5.22: Genentechs monoclonal antibody pipeline, 2006 149Table 5.23: MedImmunes marketed monoclonal antibodies, 2006 152Table 5.24: MedImmunes monoclonal antibody pipeline, 2006 152
Table 5.25: Biogen Idecs marketed monoclonal antibodies, 2006 156Table 5.26: Biogen Idecs monoclonal antibody pipeline, 2006 157Table 5.27: UCB-Celltech monoclonal antibody pipeline, 2006 160Table 5.28: Medarexs monoclonal antibody pipeline, 2006 163Table 5.29: XOMAs monoclonal antibody pipeline, 2006 167Table 5.30: BioWas monoclonal antibody pipeline, 2006 171Table 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 frommurine 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 expectedto 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, infectiousdiseases 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: inRSV 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, withsales 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 introducedalong 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
Khler and Milstein developed the hybridomamethod of murine antibody production
The first mAb reached the market: Johnson &Johnsons Orthoclone OKT3
Chimeric antibodies (60% human and 40% mouse)were first reported
Humanized antibodies (over 90% human) were firstreported
Medimmunes Synagis was launched for theindication of anti-infective disease.
The first radionucleotide conjugated mAb waslaunched: Corixas Bexxar (tositomomab-I131)
1975
1984
1986
1986
1998
2003
Khler and Milstein developed the hybridomamethod of murine antibody production
The first mAb reached the market: Johnson &Johnsons Orthoclone OKT3
Chimeric antibodies (60% human and 40% mouse)were first reported
Humanized antibodies (over 90% human) were firstreported
Medimmunes Synagis was launched for theindication of anti-infective disease.
The first radionucleotide conjugated mAb waslaunched: Corixas Bexxar (tositomomab-I131)
1975
1984
1986
1986
1998
2003
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 1986ReoPro abciximab Centocor/Lilly hemostasis 1995Rituxan/MabThera rituximab Biogen Idec oncology 1997Zenapax daclizumab Hoffman-La Roche AIID 1997Herceptin trastuzumab Genentech oncology 1998Remicade infliximab Centocor AIID 1998Simulect basiliximab Novartis AIID 1998
Synagis palivizumab MedImmune anti-infective 1998MyloTarg gemtuzumab Celltech Group, Wyeth oncology 2000
ozogamicinCampath alemtuzumab Genzyme oncology 2001Zevalin ibritumomab tiuxetan Biogen Idec oncology 2002Bexxar tositumomab-I131 Corixa oncology 2003Erbitux cetuximab ImClone oncology 2003Humira adalimumab Abbott/CAT AIID 2003Raptiva efalizumab Genentech/Xoma AIID 2003Xolair omalizumab Genentech/Novartis respiratory 2003Avastin bevacizumab Genentech oncology 2004Tysabri* 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 Share2004 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 analysisCAT = 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 andinnovation in the market
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Chapter 2 Antibody engineering andinnovation 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.
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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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 sideeffects, 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 dateUS EU
Orthoclone OKT3 muromonab-CD3 Johnson & Johnson murine 06/1986 n/aReoPro abciximab Centocor, Lilly chimeric 12/1994 n/a
Rituxan/ MabThera rituximab Genentech, Roche chimeric 11/1997 06/1998Zenapax daclizumab Hoffman-La Roche humanized 12/1997 02/1999Simulect basiliximab Novartis chimeric 05/1998 10/1998Synagis palivizumab MedImmune humanized 06/1998 08/1999Remicade infliximab Centocor chimeric 08/1998 08/1999Herceptin Trastuzumab Genentech, Roche humanized 09/1998 08/2000MyloTarg gemtuzumab Celltech Group, Wyeth humanized 05/2000 n/a
ozogamicinCampath alemtuzumab Genzyme humanized 05/2001 07/2001Zevalin ibritumomab Biogen Idec murine 02/2002 01/2004
tiuxetanHumira adalimumab Abbott, CAT human 12/2002 09/2003Bexxar tositumomab-I131 Corixa murine 05/2003 n/aXolair omalizumab Genentech, Novartis humanized 06/2003 n/a
Raptiva efalizumab Genentech, XOMA humanized 10/2003 09/2004Avastin bevacizumab Genentech, Roche humanized 02/2004 01/2005Erbitux cetuximab ImClone chimeric 02/2004 06/2004Tysabri 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
3
9
5
1
0
1
2
3
4
5
6
7
89
10
murine humanized chimeric human
NumberofmarketedmAbs
3
9
5
1
0
1
2
3
4
5
6
7
89
10
murine humanized chimeric human
NumberofmarketedmAbs
Source: Business Insights; Company websites Business Insights Ltd
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, whichmounts 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
0
2
4
6
8
10
12
14
1980 1982 1984 19861988 1990 1992 1994 19961998 2000 2002 2004
NumberofmAbsenteringclinicalstudy
Murine
Chimeric
Humanized
Human
0
2
4
6
8
10
12
14
1980 1982 1984 19861988 1990 1992 1994 19961998 2000 2002 2004
NumberofmAbsenteringclinicalstudy
Murine
Chimeric
Humanized
Human
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
Full-size antibody Antigen-bindingfragment (Fab)
Single-chain
Variable region ofheavy chain
Constant region 1 ofheavy chain
Variable region oflight chain
Constant region oflight chain
Full-size antibody Antigen-bindingfragment (Fab)
Single-
antibody (SCA)
Variable region ofheavy chain
Constant region 1 ofheavy chain
Variable region oflight chain
Constant region oflight chain
Constantregion (Fc)
Full-size antibody Antigen-bindingfragment (Fab)
Single-chain
Variable region ofheavy chain
Constant region 1 ofheavy chain
Variable region oflight chain
Constant region oflight chain
Full-size antibody Antigen-bindingfragment (Fab)
Single-
antibody (SCA)
Variable region ofheavy chain
Constant region 1 ofheavy chain
Variable region oflight chain
Constant region oflight chain
Constantregion (Fc)
Source: Business Insights Business Insights Ltd
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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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,90
yttrium;
GlaxoSmithKlines Bexxar, radioimmunoconjugate,131iodine;
Peregrines Cotara, radiolabeled tumor necrosis therapy, 131iodine (approved in
China only).
Marketed conjugated mAbs have relatively low sales compared to the leading
unconjugated mAbs, which is attributed to limited efficacy and difficulty in
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administration. Conjugated drugs need to be administered in the presence of a
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 toConjugate (ADC) be internalized, which result in cell type specific cell death.Antibody directed mAb fragments are fused to enzymes and accumulate inenzyme prodrug tumor tissues once administered. A relatively inactive formtherapy (ADEPT) of an anti-cancer drug (prodrug) is then given and is
converted by the targeted enzymes to a potent cell-killingdrug.
ImmunoGens Tumor-Activated TAP allows cytotoxic agents to be delivered to specificProdrug 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 tumorPharmaceuticals Therapy (TNT) cells. Radioisotopes are conjugated to these antibodies,
which are carried into tumors to kill them.
Source: Business Insights; Company websites; MedTRACK Business Insights Ltd
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
Company Technology Description
Roche GlycoMAb technology Genetically engineering cells to produce bisected non-fucosylated oligosaccharides. GlycoMAb antibodiesbind with higher affinity immune effector cells, thusleading to more efficient killing of the antibody-targeted cells by ADCC.
BioWa Potelligent technology Proprietary technology used to create fucose-freemonoclonal antibodies, with a marked increase inantibody dependent cellular cytotoxicity (ADCC).
Xencor xmAb engineered Fc xmAb engineered Fc domains can be inserted into andomains antibody candidates to improve ADCC, improve half-
life and structural stability.
Source: Business Insights; Company websites; MedTRACK Business Insights Ltd
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
Company Technology Description
CAT Phage Display and Phage Display and Ribosome Display technologies forRibosome Display fully human antibody selection and optimization. CAT
has a vast phage antibody library with over 100bndistinct antibodies.
Dyax Phage display technology Bacteriophage libraries are used to select and producehigh affinity Fab fragments and antibodies, using anautomated screening system.
Morphosys Human Combinatorial HuCAL generates highly specific antibody fragmentsAntibody Library and fully human mAb drug candidates. HuCAL
GOLDhas the added benefit of CysDisplay screeningtechnology.
Symphogen Symplex Platform for the discovery and identification ofmonoclonal and polyclonal drug leads.
Ablynx Nanobody platform Single-domain antibody technology used to discoverand develop high-affinity drug leads.Vaccinex Library-based antibody Two discovery platforms for antibody discovery: the
discovery technology first based on membrane-bound antibody expressionand the second employing secreted antibodies.
Curagen Genomics Potential drug targets are selected and systematicallyprioritized using more detailed expression analysis.
UCB Celltech SLAM (selected SLAM generates a diverse range of high-affinitylymphocyte antibody antibodies against targets which have provenmethod) difficult to raise antibodies against by conventional
hybridoma technology
Source: Business Insights; Company websites; MedTRACK Business Insights Ltd
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 optimizationof 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 HuCALtechnology 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, forexample 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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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 anincrease 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 monoclonalantibody market
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Chapter 3 The current monoclonalantibody 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 VirexxsOvaRex, 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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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 bothanticipated 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% ($556.5m), which is mainly due to approval for use a range of indications:
renal cell carcinoma, NSCLC and breast cancer, and for use with a wider range of
cytotoxics and approval for adjuvant therapy. The largest decline in sales growth was
for Orthoclone OKT3 (-23.7% in 2005), which is primarily because of Orthoclones
murine composition leading to adverse reactions such as fever, nausea and vomiting.
Figure 3.6: Market dynamics of current marketed drugs, 2004-5
-100%
-50%
0%
50%
100%
150%
200%
-1000 -500 0 500 1000 1500 2000 2500 3000 3500 4000
Sales, 2005 ($m)
Salesgrowth,
200
4-5(%)
Bexxar
Tysabri
Orthoclone OKT3
Mylotarg
Zenapax
Simulect
Campath
Rituxan/MabThera
Herceptin
Remicade
Humira
Avastin
Synagis
Zevalin
Erbitux
Xolair
ReoPro
Raptiva
Bubble size represents market share
AIID Oncology Anti-infective Respiratory Hemostasis
-100%
-50%
0%
50%
100%
150%
200%
-1000 -500 0 500 1000 1500 2000 2500 3000 3500 4000
Sales, 2005 ($m)
Salesgrowth,
200
4-5(%)
Bexxar
Tysabri
Orthoclone OKT3
Mylotarg
Zenapax
Simulect
Campath
Rituxan/MabThera
Herceptin
Remicade
Humira
Avastin
Synagis
Zevalin
Erbitux
Xolair
ReoPro
Raptiva
Bubble size represents market share
AIID Oncology Anti-infective Respiratory HemostasisAIID Oncology Anti-infective Respiratory Hemostasis
Sourc