The Future of Monoclonal Antibody Therapeutics

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
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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 Ltd This Management Report is published by Business Insights Ltd. All rights reserved. Reproduction or redistribution of this Management Report in any form for any purpose is expressly prohibited without the prior consent of Business Insights Ltd. The views expressed in this Management Report are those of the publisher, not of Business Insights. Business Insights Ltd accepts no liability for the accuracy or completeness of the information, advice or comment contained in this Management Report nor for any actions taken in reliance thereon. 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
Introduction Antibody engineering and innovation in the market The current monoclonal antibody market The antibody pipeline and forecasts to 2011 Competitive landscape and future growth strategies
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12 13 14 15 16
Chapter 1
Summary Introduction
Introduction
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18 19 20 21 21 22 23 23 24 25
History of monoclonal antibodies Monoclonal antibody approval process Current approval process Biogeneric regulations Key trends in the market Advancements in innovation Diversification of therapy areas Big Pharma entering the mAb market
Chapter 2
Antibody engineering and innovation in the market
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28 29 30 31 31 31 32
The move from murine to fully human mAbs Whole IgG monoclonal antibodies Murine Chimeric Humanized iii
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Human Innovations in antibody structures Fab fragments Single chain variable fragments Extended release formulations Innovation in antibody conjugation Types of conjugation Direct arming: antibody conjugation Indirect arming: Bispecific monoclonal antibodies Pre-targeting Marketed conjugated monoclonal antibodies Conjugation technology Seattle Genetics antibody technology ImmunoGen mAb technology Peregrine mAb technology Enhancing monoclonal antibody potency Drug discovery Cambridge Antibody Technology Dyax Morphosys Innovation in drug delivery Drug delivery devices Inhaled monoclonal antibodies Oral monoclonal antibodies
32 33 34 35 36 37 37 37 37 38 38 39 39 40 41 41 42 44 45 46 47 47 48 49
Chapter 3
Summary Introduction Strategic analysis Drivers
The current monoclonal antibody market
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52 53 53 54 54 54 55 55 56 56 56 56 57 57 57 58 60
Pipeline drugs Immature market Big Pharma entering the mAb market High level of innovation Approval of new indications Combination therapies Resistors Publicized side effects Drugs suspended from market Competition from small molecule drugs Pricing and reimbursement schemes Analysis of launched drugs Oncology
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Rituxan Herceptin Avastin Erbitux Campath Zevalin MyloTarg Bexxar AIID Remicade Humira Raptiva Simulect Zenapax OrthoClone OKT3 Hemostasis ReoPro Anti-infectives Synagis Respiratory Xolair Marketed monoclonal antibody forecasts
61 63 65 67 69 70 72 74 76 76 79 81 83 84 84 86 86 87 88 89 89 90
Chapter 4
Summary Introduction Strategic analysis Opportunities Clinical trials
The antibody pipeline and forecasts to 2011
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94 95 95 97 97 98 98 98 99 99 100 101 101 102 103 104 109 109 110
Erbitux and Avastin Simulect, Zenapax and Campath Campath Others Innovation in antibody engineering New indications Challenges Generic biologics Adverse reactions in clinical trials, side effects and termination of development High attrition rates Analysis of pipeline drugs AIID Cimzia MRA/Actemra
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Eculizumab AMG-162 Cardiovascular Pexelizumab Infectious diseases Numax Oncology ABX-EGF MDX-010+MDX-1379 Humax Ophthalmology Lucentis Late stage pipeline forecasts The antibody market in 2011
112 113 115 115 116 116 117 117 119 120 121 121 123 124
Chapter 5
Competitive landscape and future growth strategies
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128 129 130 130 133 134 134 135 135 136 136 137 137 137 137 137 139 140 141 141 141 142 143 144 144 144 146
Key players in the monoclonal antibody market M&A and licensing activity Big Pharma acquiring biotechs and antibody companies AstraZeneca and CAT Novartis and NeuTec Amgen and Abgenix Roche and GlycArt MedImmune and Cellective Therapeutics Pfizer and Bioren Company profiles Big Pharma Roche Company overview Strategic and growth analysis Marketed products Pipeline Novartis Company overview Strategic and growth analysis Marketed products Pipeline Pfizer Company overview Strategic and growth analysis Pipeline
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Large biotech Genentech Company overview Strategic and growth analysis Marketed products Pipeline MedImmune Company Profile Strategic and growth analysis Marketed products Pipeline products Biogen Idec Company overview Strategic analysis Marketed products Pipeline products UCB-Celltech Company overview Strategic and growth analysis Marketed products Pipeline products Small biotech/antibody companies Medarex Company overview Strategic and growth analysis Marketed products Pipeline products XOMA Company overview Strategic and growth analysis Marketed products Pipeline products Technology companies BioWa Company overview Strategic and growth analysis Pipeline products Crucell Company overview Strategic and growth analysis Pipeline products
147 147 147 147 148 149 150 150 150 152 152 153 153 153 156 157 157 157 158 159 160 161 161 161 161 163 163 165 165 165 167 167 169 169 169 169 171 172 172 172 174
Chapter 6
Sales data Index
Appendix
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178 179
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List of Figures
Figure 1.1: Figure 2.2: Figure 2.3: Figure 2.4: Figure 3.5: Figure 3.6: Figure 3.7: Figure 4.8: Figure 4.9: Figure 4.10: Figure 4.11: Figure 5.12: Figure 5.13: Figure 5.14: Figure 5.15: Figure 5.16: Figure 5.17: Figure 5.18: Figure 5.19: Figure 5.20: Figure 5.21: Figure 5.22: Figure 5.23: History of monoclonal antibodies 21 Current marketed monoclonal antibodies, 2006 31 Therapeutic mAbs entering clinical study, 1980-2004 33 Whole antibody and fragment structures 34 Drivers and resistors to growth in the monoclonal antibody market 54 Market dynamics of current marketed drugs, 2004-5 58 Marketed monoclonal antibodies by therapy area, 2006 60 Opportunities and challenges in the mAb market 97 Antibody structure analysis of forecasted monoclonal antibody sales ($m), 2004-11106 Therapy area analysis in monoclonal antibody drug development, 2006 107 Therapy area analysis of forecasted monoclonal antibody sales ($m), 2004-11 108 Key growth strategies in the monoclonal antibody market, 2005-6 133 Roches SWOT analysis in the mAb market 138 Novartis SWOT analysis in the mAb market 141 Pfizers SWOT analysis in the mAb market 145 Genentechs SWOT analysis in the mAb market 148 MedImmunes SWOT analysis in the mAb market 150 Biogen Idecs SWOT analysis in the mAb market 154 UCB Celltechs SWOT analysis in the mAb market 159 Medarexs SWOT analysis in the mAb market 162 XOMAs SWOT analysis in the mAb market 166 BioWas SWOT analysis in the mAb market 170 Crucells SWOT analysis in the mAb market 173
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List of Tables
Table 1.1: Table 1.2: Table 2.3: Table 2.4: Table 2.5: Table 2.6: Table 2.7: Table 3.8: Table 3.9: Table 4.10: Table 4.11: Table 4.12: Table 5.13: Table 5.14: Table 5.15: Table 5.16: Table 5.17: Table 5.18: Table 5.19: Table 5.20: Table 5.21: Table 5.22: Table 5.23: Table 5.24: Table 5.25: Table 5.26: Table 5.27: Table 5.28: Table 5.29: Table 5.30: Table 5.31: Current marketed drugs, 2006 Key players in the monoclonal antibody market, 2006 Marketed therapeutic monoclonal antibodies, 1986-2006 Antibody fragment pipeline, 2006 Conjugated antibody engineering technology Drug development technology Monoclonal antibody drug discovery technology Marketed therapeutic monoclonal antibodies, 2004-5 Marketed monoclonal antibody sales forecasts, 2005-11 Other post-marketing clinical trials, 2005-6 Late stage monoclonal antibody pipeline, 2006 Late stage monoclonal antibody pipeline sales forecast to 2011 Key players in the monoclonal antibody market, 2006 Monoclonal antibody collaborations, manufacturing, development and supply agreements, 2005-6 Key acquisitions in the monoclonal antibody market, 2005-6 Roches marketed monoclonal antibodies, 2006 Roches monoclonal antibody pipeline, 2006 Novartis marketed monoclonal antibodies, 2006 Novartis monoclonal antibody pipeline, 2006 Pfizers monoclonal antibody pipeline, 2006 Genentechs marketed monoclonal antibodies, 2006 Genentechs monoclonal antibody pipeline, 2006 MedImmunes marketed monoclonal antibodies, 2006 MedImmunes monoclonal antibody pipeline, 2006 Biogen Idecs marketed monoclonal antibodies, 2006 Biogen Idecs monoclonal antibody pipeline, 2006 UCB-Celltech monoclonal antibody pipeline, 2006 Medarexs monoclonal antibody pipeline, 2006 XOMAs monoclonal antibody pipeline, 2006 BioWas monoclonal antibody pipeline, 2006 Crucells monoclonal antibody pipeline, 2006 24 25 30 36 39 42 43 59 91 99 105 124 130 131 134 139 140 143 143 146 149 149 152 152 156 157 160 163 167 171 174
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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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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 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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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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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
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 ophthalmology. therapy areas including infectious disease and
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) were first reported The first mAb reached the market: Johnson & Johnsons Orthoclone OKT3 Humanized antibodies (over 90% human) were first reported Medimmunes Synagis was launched for the indication of anti-infective disease. The first radionucleotide conjugated mAb was launched: Corixas Bexxar (tositomomab-I131)
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 noninvasive 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 Orthoclone OKT3 ReoPro Rituxan/MabThera Zenapax Herceptin Remicade Simulect Synagis MyloTarg Campath Zevalin Bexxar Erbitux Humira Raptiva Xolair Avastin Tysabri* Generic muromonab-CD3 abciximab rituximab daclizumab trastuzumab infliximab basiliximab palivizumab gemtuzumab ozogamicin alemtuzumab ibritumomab tiuxetan tositumomab-I131 cetuximab adalimumab efalizumab omalizumab bevacizumab natalizumab Originator Johnson & Johnson Centocor/Lilly Biogen Idec Hoffman-La Roche Genentech Centocor Novartis MedImmune Celltech Group, Wyeth Genzyme Biogen Idec Corixa ImClone Abbott/CAT Genentech/Xoma Genentech/Novartis Genentech Biogen Idec Therapy area Launch year AIID hemostasis oncology AIID oncology AIID AIID anti-infective oncology oncology oncology oncology oncology AIID AIID respiratory oncology AIID 1986 1995 1997 1997 1998 1998 1998 1998 2000 2001 2002 2003 2003 2003 2003 2003 2004 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 2004 Genentech Hoffman-La Roche Centocor Abbott MedImmune Schering-Plough ImClone Lilly Merck KGaA Genzyme Novartis CAT* Biogen Idec Wyeth Biogen Idec/Elan Johnson & Johnson Corixa Total 2,838.0 1,862.7 2,145.0 829.1 942.3 746.0 244.1 362.8 99.7 51.5 49.7e 22.9 24.0 26.0 2.4 17.3e 3.8e 10,267.3 Sales ($m) 2005 4,116.4 2,704.7 2,535.0 1,362.4 1,060.9 942.0 533.7 296.7 218.0 60.8 54.9e 37.6 28.4 25.6 21.2 13.2e 8.2e 14,019.8 Sales Growth 2004-05 45.2% 45.0% 18.2% 64.3% 12.6% 26.3% 118.7% -18.2% 118.7% 18.1% 10.5% 64.3% 18.3% -1.5% 783.3% -23.7% 115.8% 36.5% Market Share 2005 29.4% 19.3% 18.1% 9.7% 7.6% 6.7% 3.8% 2.1% 1.6% 0.4% 0.4% 0.3% 0.2% 0.2% 0.2% 0.1% 0.1% 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
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Chapter 2
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 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 Orthoclone OKT3 ReoPro Rituxan/ MabThera Zenapax Simulect Synagis Remicade Herceptin MyloTarg Campath Zevalin Humira Bexxar Xolair Raptiva Avastin Erbitux Tysabri Generic muromonab-CD3 abciximab rituximab daclizumab basiliximab palivizumab infliximab Trastuzumab gemtuzumab ozogamicin alemtuzumab ibritumomab tiuxetan adalimumab tositumomab-I131 omalizumab efalizumab bevacizumab cetuximab natalizumab Company Johnson & Johnson Centocor, Lilly Genentech, Roche Hoffman-La Roche Novartis MedImmune Centocor Genentech, Roche Celltech Group, Wyeth Genzyme Biogen Idec Abbott, CAT Corixa Genentech, Novartis Genentech, XOMA Genentech, Roche ImClone Biogen Idec Description Approval date US EU murine chimeric chimeric humanized chimeric humanized chimeric humanized humanized 06/1986 12/1994 11/1997 12/1997 05/1998 06/1998 08/1998 09/1998 05/2000 n/a n/a 06/1998 02/1999 10/1998 08/1999 08/1999 08/2000 n/a
humanized 05/2001 07/2001 murine 02/2002 01/2004 human murine humanized humanized humanized chimeric humanized 12/2002 05/2003 06/2003 10/2003 02/2004 02/2004 11/2004 09/2003 n/a n/a 09/2004 01/2005 06/2004 n/a
Source: Business Insights; Company websites; FDA
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Figure 2.2: Current marketed monoclonal antibodies, 2006

10 Number of marketed mAbs 9 8 7 6 5 4 3 2 1 0 murine humanized chimeric human 1 3 5 9
Source: Business Insights; Company websites
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

Number of mAbs entering clinical study 14 12 10 8 6 4 2 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
Murine Chimeric Humanized Human
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 region of light chain
Constant region (Fc)
Full-size antibody
SingleSingle-chain antibody (SCA)
Antigen-binding 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 ReoPro (abciximab) Lucentis (ranibizumab) Pexelizumab CDP870 CDP791 SGN-17 Company Centocor/Lilly Genentech/Novartis Alexion/Procter & Gamble UCB Celltech UCB Celltech Seattle Genetics Fragment type Fab/chimeric Fab/humanized Single chain Fv (scFv)/humanized Fab/PEGylated humanized Fab/PEGylated humanized (ScFv) fused to b-lactamase, human Stage Indication
FDA approved Cardiovascular Filed Phase 3 Phase 3 Phase 2 Preclinical Ophthalmology Cardiovascular Crohn's disease Cancer Cancer
Source: Business Insights; Company websites; MedTRACK
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; Peregrines Cotara, radiolabeled tumor necrosis therapy, China only).
131
iodine (approved in
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 ADC technology allows mAbs linked to cytotoxic drugs to be internalized, which result in cell type specific cell death. mAb fragments are fused to enzymes and accumulate in tumor tissues once administered. A relatively inactive form of an anti-cancer drug (prodrug) is then given and is converted by the targeted enzymes to a potent cell-killing drug.
Seattle Genetics Antibody drug Conjugate (ADC) Antibody directed enzyme prodrug therapy (ADEPT)
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. TNT utilizes mAbs directed to dead and dying tumor cells. Radioisotopes are conjugated to these antibodies, which are carried into tumors to kill them.
Peregrine Tumor Necrosis Pharmaceuticals Therapy (TNT)
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 nonprotein-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 Roche Technology Description
BioWa Xencor
GlycoMAb technology Genetically engineering cells to produce bisected nonfucosylated oligosaccharides. GlycoMAb antibodies bind with higher affinity immune effector cells, thus leading to more efficient killing of the antibodytargeted cells by ADCC. Potelligent technology Proprietary technology used to create fucose-free monoclonal antibodies, with a marked increase in antibody dependent cellular cytotoxicity (ADCC). xmAb engineered Fc xmAb engineered Fc domains can be inserted into an domains antibody candidates to improve ADCC, improve halflife 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

Company CAT Technology Phage Display and Ribosome Display Phage display technology Human Combinatorial Antibody Library Description Phage Display and Ribosome Display technologies for fully human antibody selection and optimization. CAT has a vast phage antibody library with over 100bn distinct antibodies. Bacteriophage libraries are used to select and produce high affinity Fab fragments and antibodies, using an automated screening system. HuCAL generates highly specific antibody fragments and fully human mAb drug candidates. HuCAL has the added benefit of CysDisplay screening technology. Platform for the discovery and identification of monoclonal and polyclonal drug leads. Single-domain antibody technology used to discover and develop high-affinity drug leads. Two discovery platforms for antibody discovery: the first based on membrane-bound antibody expression and the second employing secreted antibodies. Potential drug targets are selected and systematically prioritized using more detailed expression analysis. SLAM generates a diverse range of high-affinity antibodies against targets which have proven difficult to raise antibodies against by conventional hybridoma technology
Dyax Morphosys GOLD Symphogen Ablynx Vaccinex Curagen UCB Celltech
Symplex Nanobody platform Library-based antibody discovery technology Genomics SLAM (selected lymphocyte antibody method)
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 lessinvasive, 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 autoinjector) 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
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Chapter 3
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 sideeffects, 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 Pricing and reimbursement
molecule drugs
Resistors
Source: Business Insights Business Insights Ltd
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 autoinjector) 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 Sales growth, 2004-5 (%) 150% Bexxar 100% Tysabri Zevalin Mylotarg 0% -1000 -500 -50% -100% Sales, 2005 ($m) AIID Oncology Anti-infective Respiratory Hemostasis 0 Zenapax 50% Xolair Raptiva Campath Simulect 500 1000 Erbitux Humira Herceptin Remicade
Rituxan/ MabThera
Synagis 1500 2000 2500 3000 3500 4000
ReoPro Orthoclone OKT3
Bubble size represents market share

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Table 3.8: Marketed therapeutic monoclonal antibodies, 2004-5

Brand Generic Company Therapy area AIID Sales ($m) Sales Market 2004 2005 Growth Share 2004-5 2005 2,891.0 3,477.0 3,323.2 1,730.6 1,400.0 1,332.0 1,060.9 751.7 326.4 296.7 79.0 60.8 54.9 29.9 28.4 25.6 13.2 11.0 8.2 20.3% 24.8% 22.0% 23.7% 50.8% 12.4% 64.3% 10.0% 139.4% 9.5% 12.6% 7.6% 118.6% 5.4% 73.6% -18.2% 51.9% 18.1% 10.5% -6.9% 18.3% -1.5% -23.7% 71.9% 115.8% 2.3% 2.1% 0.6% 0.4% 0.4% 0.2% 0.2% 0.2% 0.1% 0.1% 0.1%
Remicade infliximab
Centocor, Schering Plough Rituxan rituximab Genentech, Roche Herceptin trastuzumab Genentech, Roche Humira adalimumab Abbott, CAT Avastin bevacizumab Genentech, Roche Synagis palivizumab MedImmune Erbitux cetuximab Merck KGaA, ImClone Xolair omalizumab Genentech ReoPro abciximab Lilly Raptiva efalizumab Genentech Campath alemtuzumab Genzyme Simulect basiliximab Novartis Zenapax daclizumab Roche Zevalin ibritumomab Biogen Idec tiuxetan MyloTarg gemtuzumab Wyeth ozogamicin Orthoclone muromonab- Johnson & OKT3 CD3 Johnson Tysabri natalizumab Biogen Idec, Elan Bexxar tositumomab Corixa -I131 Total
Source: Business Insights; Annual reports; IMS
Oncology 2,724.2 Oncology 1,148.0 AIID 852.0 Oncology 556.5 Anti-infective 942.3 Oncology 343.8 Respiratory Hemostasis AIID Oncology AIID AIID Oncology Oncology AIID AIID Oncology 188.0 362.8 52.0 51.5 49.7 32.1 24.0 26.0 17.3 6.4 3.8
10,271.3 14,009.5 36.4% 100.0%

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 Erbitux Herceptin Mylotarg Rituxan/MabThera Zevalin
AIID: Humira Orthoclone OKT3 Raptiva Remicade Simulect Tysabri Zenapax
Marketed mAbs
39%
43%
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 MDX010 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 chemoresistant 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 firstto-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 HER2overexpressing 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 BristolMyers 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 antiangiogenesis 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 chemotherapynaive 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 (BCLL) 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 BCLL 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 halflife. 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 WyethAyerst 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 firstline 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 venoocclusive 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-tosevere 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 CTLA4Ig 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 (antiangiogenesis) 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 Remicade Company Therapy area AIID Sales ($m) CAGR 2008 2011 2005-11 4,023.6 3,828.3 1,946.6 2,709.5 3,032.4 547.3 1,728.9 523.5 362.5 259.2 98.9 65.4 28.4 49.1 41.2 219.1 10.1 18.4 4,120.9 4,122.3 2,025.4 4,009.3 3,741.4 282.3 2,177.2 755.4 442.8 447.9 160.8 77.9 27.0 84.8 66.3 440.0 7.7 41.1 2.9% 3.7% 2.7% 19.2% 18.8% -19.8% 19.4% 15.0% 6.9% 33.5% 17.6% 6.0% -1.7% 20.0% 17.2% 65.8% -8.5% 30.8% 8.6%
2005 3,477.0
Centocor, Johnson & Johnson Rituxan/MabThera Genentech, Roche Herceptin Genentech, Roche Humira Abbott, CAT Avastin Genentech, Roche Synagis MedImmune, Abbott Erbitux ImClone, BMS Xolair Genentech, Novartis ReoPro Centocor, Lilly Raptiva Genentech, XOMA Campath Genzyme, Bayer AG Simulect Novartis Zenapax Roche Zevalin Biogen Idec, Bayer AG MyloTarg Celltech group, Wyeth Tysabri Biogen Idec, Elan Orthoclone OKT3 Johnson & Johnson Bexxar Corixa, GSK Total
Source: Business Insights; Annual reports; IMS
Oncology 3,323.2 Oncology 1,730.6 AIID 1,400.0 Oncology 1,332.0 Anti-infective1,060.9 Oncology 751.7 Respiratory 326.4 Hemostasis 296.7 AIID 79.0 Oncology 60.8 AIID 54.9 AIID 29.9 Oncology 28.4 Oncology 25.6 AIID 21.2 AIID 13.2 Oncology 8.2
14,019.8 19,492.2 23,030.6
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CHAPTER 4
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Chapter 4
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. 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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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 AbESTT-II. Abciximab in Emergent Stroke Treatment Trial-II. 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. AFFIRM and SENTINEL. Phase III Multiple Sclerosis studies 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.
10/2005 ReoPro Lilly (abciximab)
04/2006 Tysabri Biogen (natalizumab) Idec
Source: Business Insights; Clinicaltrials.org
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, MDX010+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 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. 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-tomid 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 lifethreatening 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 AIID Cimzia (certolizumab) MRA/Actemra (tocilizumab) Soliris (eculizumab) Ticilimumab Nuvion (visilizumab) Denosumab (AMG 162) CNTO 1275 CNTO 148 (golimumab) Cardiovascular Pexelizumab Infectious disease Numax TNX-355 Aurograb Oncology ABX-EGF (panitumumab) OvaRex MDX-010 + MDX-1379 IGN-101 Humax (Zanolimumab) MLN-2704 Rencarex (WX-G250) LymphoCide (epratuzumab) MT201 Ophthalmology Lucentis (ranibizumab) Company Type Stage Launch date 2006 2007 2007 2008 2008 2010 2010 2010 2007 2008 2009 >2011 2007 2007 2007 2007 2008 2008 2009 >2011 >2011 2006
Nektar/UCB Roche Alexion Pfizer PDL Amgen Medarex/Centocor Centocor/Shering-Plough Alexion/Procter & Gamble MedImmune/Abbott Biogen Idec/Tanox Novartis/ NeuTec Abgenix/Amgen United Therapeutics/ViRexx Medarex/BMS Igeneon Genmab/Medarex Millennium Esteve/Wilex Immunomedics/Amgen CAT/Micromet/Serono Genentech/Novartis
Humanized Humanized Humanized Human Humanized Human Human Human Humanized Humanized Humanized Human Human Murine Human Murine Human Humanized Chimeric Humanized Human Humanized
Filed Phase III Phase III Phase III Phase III Phase III Phase III Phase III Phase III Phase III Phase III Phase III Filed Phase III Phase III Phase III Phase III Phase III Phase III Phase III Phase III Approved
Source: Business Insights; Company reports; FDA
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 ABXEGF. 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 ($m), 2004-11
14,000
12,000
10,000 Sales ($m) chimeric
8,000
6,000 humanized 4,000
2,000
human murine 2004 2005 2006 2007 2008 2009 2010 2011
Source: Business Insights; company reports; IMS
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 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 Phase I Phase II Phase III
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 6000 Sales ($m) 4000 AIID 2500 2000 1500 Infectious disease 1000 500 0 2004 2005 AIID 2006 Oncology 2007 2008 2009 2010 2011 Hemostasis Respiratory Cardiovascular Ophthalmology Oncology
Infectious disease Hemostasis
Respiratory
Cardiovascular
Source: Business Insights; company reports; IMS
Ophthalmology
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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 ABXEGF 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 ABXEGF 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 $1,155m, respectively. High sales are forecast for Numax as it has been shown to be highly efficacious: in RSV neutralization studies it is 20 times more potent than Synagis, and approximately 50 times more effective in reducing RSV in the lungs of cotton rats. Therefore Numax, forecast to launch in 2008, has the competitive advantage over Synagis and has the potential to enable expansion into additional indications further boosting sales; Cimzia is expected to gain high sales due to its advantageous dosing regimen (once every 4 weeks), in addition to its low manufacturing costs compared to fully human mAbs. However, Cimzia will be threatened by competition from established drugs Remicade and Humira in its RA and Crohns disease indications; MDX-010+MDX-1379 is indicated for oncology and has high forecasted sales in 2011, as a result of its fully human structure and superior dosing regimen compared to its competitor Erbitux.
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Table 4.12: Late stage monoclonal antibody pipeline sales forecast to 2011
Drug Numax (MedImmune) Cimzia (CDP 870) MDX-010 + MDX-1379 Lucentis MRA/Actemra (tocilizumab) Eculizumab ABX-EGF TNX-355 CNTO 148 (golimumab) Denosumab (AMG 162) Humax-CD4 (Zanolimumab) CNTO 1275 OvaRex Nuvion IGN-101 Rencarex (WX-G250) MLN-2704 Aurograb (anti-MRSA mAb) Lymphocide (Epratuzumab) MT201 Total
Source: Business Insights; company reports
Company
Therapy area
Sales ($m) 2008 2011 594.0 710.0 436.0 320.0 86.4 103.4 82.0 22.6 22.0 13.0 13.0 7.5 1,512.0 1,266.0 1,155.8 685.0 413.5 415.7 179.8 158.4 94.6 70.0 69.8 53.9 38.9 32.0 32.9 26.7 19.7 6,650.7
MedImmune, Abbott Infectious disease UCB AIID Medarex, BMS Oncology Genentech, Novartis Ophthalmology Chugai, Roche AIID Alexion AIID Abgenix, Amgen Oncology Biogen Idec, Tanox Infectious disease Centocor, Shering -Plough AIID Amgen AIID Genmab, Medarex Oncology Medarex, Centocor AIID United Therapeutics, ViRexx Oncology PDL AIID Igeneon Oncology Esteve, Wilex Oncology Millennium Oncology Novartis, NeuTec Infectious disease Immunomedics, Amgen AIID Micromet, Serono, CAT Oncology
2,601.9
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
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Chapter 5
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 2004 Genentech Hoffman-La Roche Centocor Abbott MedImmune Schering-Plough ImClone Lilly Merck KGaA Genzyme Novartis Biogen Idec CAT Wyeth Johnson & Johnson Corixa Total 2,838.0 1,862.7 2,145.0 829.1 942.3 746.0 244.1 362.8 99.7 51.5 49.7e 26.4 22.9 26.0 17.3e 3.8e 10,267.3 Sales ($m) 2005 4,116.4 2,704.7 2,535.0 1,362.4 1,060.9 942.0 533.7 296.7 218.0 60.8 54.9e 49.6 37.6 25.6 13.2e 8.2e 14,019.8 Sales Growth 2004-5 45.2% 45.2% 18.2% 64.3% 12.6% 26.3% 118.7% -18.2% 118.7% 18.1% 10.5% 87.9% 64.3% -1.5% -23.7% 115.8% 36.5% Market Share 2005 29.4% 19.3% 18.1% 9.7% 7.6% 6.7% 3.8% 2.1% 1.6% 0.4% 0.4% 0.4% 0.3% 0.2% 0.1% 0.1% 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 Xoma, Schering Plough Deal Date
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. ScheringPlough to develop Centocors CNTO 148. (08/16/2005 Acquisition e.g. AZ acquisition of CAT. 05/12/2006
Big Pharma
Technology companies
*
#
Technology license e.g. Crucell license STAR technology to Millennium. 04/06/2006
In-house development e.g. Genentech
Large biotech
Small biotech/ Development Antibody company collaborations e.g. Abmaxis, 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
* Acquisitionacquire GlyArt Biotech (gain technology). e.g. Roche

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
Source: Business Insights; MedTRACK Business Insights Ltd
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 announced June 2006 May 2006 Dec 2005 Oct 2005 Sept 2005 Aug 2005 Jul 2005 Acquirer Novartis AstraZeneca Amgen Novartis MedImmune Pfizer Roche Target NeuTec CAT Abgenix Chiron Cellective Therapeutics Bioren GlycArt Biotechnology Therapeutic/strategic focus Development of recombinant antibodies mAb: Humira and pipeline drugs CAT 3888 and CAT 354 Monoclonal antibodies Vaccines mAb drug discovery and developer Optimizing antibody technology Swiss biotech, focused on antibodies
Source: Business Insights; Company websites
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 LookThrough 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 Majority equity holding of Genentech Strong licensing and collaboration strategy Weaknesses Lack of product diversity in terms of therapy area Lack of in-house antibody technology
Opportunities Capitalise on links with Genentech Expansion into other therapy areas e.g. infectious disease
Threats Competition from companies launching drugs in similar areas to Roche/Genentechs marketed 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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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 Avastin Herceptin Rituxan/MabThera Zenapax Therapy area Oncology Oncology Oncology AIID Indication Colorectal cancer Breast cancer NHL Kidney transplant Launch date 2005 1999 1997 1997
Source: Business Insights; MedTRACK
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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 Atlizumab (MRA) Omnitarg R1594 (PRO70769) R1594 (PRO70769) Therapy area AIID Oncology AIID Oncology Indication Rheumatoid arthritis Solid tumors Rheumatoid arthritis Hematologic malignancies Phase Phase II Phase II Phase I Pre-clinical Launch date 2009 >2011 >2011 >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.
Strategic and growth analysis 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
Strengths Strong sales and marketing abilities. 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 Opportunities Large R&D spend, which will facilitate in licensing of antibody technology Further acquisitions to broaden its mAb pipeline. Key late stage pipeline products Weaknesses Lack of early stage mAb pipeline products
Threats Competition from companies experienced in antibody development.
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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

Name Xolair Simulect Therapy area Respiratory AIID Indication Severe allergic asthma Renal transplant rejection Launch date 2005 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

Name Lucentis Mycograb Aurograb Therapy area Ophthalmology Infectious disease Infectious disease Indication Macular degeneration Systemic candidiasis anti-MRSA Phase Approved Filed (EU) III Launch date 2006 2008 >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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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.
Strategic and growth analysis 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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Figure 5.15: Pfizers SWOT analysis in the mAb market
Pfizer
Strengths Strong sales and marketing abilities. Acquisition of Bioren in August 2005 to gain a late stage mAb pipeline. Weaknesses Lack of antibody experience. No currently marketed mAbs.
Opportunities Large R&D spend, which will facilitate in licensing of antibody technology Further acquisitions to broaden its mAb pipeline.
Threats Competition from companies experienced in antibody development.
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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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 inhouse 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

Name CP-675,206 (ticilimumab) CP-571,871 RN1219 (Rinat) Undisclosed Therapy area Indication Oncology Oncology CNS Unknown Metastatic melanoma Multiple myeloma (Relapsed/refractory) Alzheimers Unknown Phase Phase III Phase I Phase I Phase I Launch date >2011 >2011 >2011 >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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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.
Strategic and growth analysis 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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strategy, such as its long established collaboration with Roche, will help drive longterm growth. Genentechs strategic position is analyzed in Figure 5.13.
Figure 5.16: Genentechs SWOT analysis in the mAb market
Genentech
Strengths Leading mAb company Strong marketed mAb portfolio Established collaboration with Roche Weaknesses Lack of mid and late phase pipeline drugs
Opportunities Acquisitions to expand mAb pipeline
Threats Competition from companies 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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Table 5.21: Genentechs marketed monoclonal antibodies, 2006

Name Avastin Raptiva Xolair Herceptin Rituxan/MabThera Therapy area Oncology AIID Respiratory Oncology Oncology Indication Colorectal cancer Psoriasis Asthma Breast cancer NHL Launch date 2005 2003 2003 1999 1997
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

Name Lucentis PRO70769 RI 624 TRX-1 Therapy area Ophthalmology AIID CNS Hematology Indication Macular degeneration Rheumatoid arthritis Pain Hemophilia A Phase Approved Phase I Phase I Phase I Launch date 2006 >2011 >2011 >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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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.
Strategic and growth analysis MedImmunes SWOT analysis in the mAb market is shown in Figure 5.17.
Figure 5.17: MedImmunes SWOT analysis in the mAb market
MedImmune
Strengths Fully integrated biotech company Sales of the marketed drug Synagis and subsequent pipeline product Numax, which has high forecast sales Collaboration to gain technology (PDL) Weaknesses Unlikely to be able to diversify its mAb portfolio beyond the RSV market
Opportunities Switching patients from Synagis to Numax Establish more R&D collaborations and seek to license early-stage mAbs to broaden its pipeline further
Threats Patient reluctance to switch to Numax Competition from other drugs in the RSV market
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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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Marketed products MedImmunes marketed mAb portfolio is shown in Table 5.23.
Table 5.23: MedImmunes marketed monoclonal antibodies, 2006

Name Synagis Therapy area Infectious disease Indication RSV Launch date 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

Name Numax Vitaxin Anti-IL-9 MT103 Anti-EphA2 Anti-EphA4 Anti-hMPV HMGB-1 MEDI-507 MDX-1103 MDX-1333 Therapy area Infectious disease Oncology Respiratory disease Oncology Oncology Oncology Infectious disease AIID Oncology AIID AIID Indication RSV refractory solid tumors asthma B-cell tumors pancreatic cancer meta-pneumo virus infection auto-immune diseases T-cell lymphoma auto-immune diseases auto-immune diseases Phase Phase III Phase II Phase I Phase I Pre-clinical Pre-clinical Pre-clinical Pre-clinical Pre-clinical Pre-clinical Pre-clinical Launch date 2008 >2011 >2011 >2011 >2011 >2011 >2011 >2011 >2011 >2011 >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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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
Strengths Fully integrated antibody company Two marketed antibodies: Rituxan and Zevalin Strong manufacturing capabilities Weaknesses Voluntary suspension of Tysabri, however has been allowed back onto the market by FDA Limitation of in-house technology base
Opportunities Further in-licensing deals
Threats Other product launches in niche therapy areas (MS/NHL)
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Biogen Idec has strong manufacturing capabilities, with two licensed biological bulkmanufacturing 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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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 tumortargeting 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

Name Rituxan/MabThera Zevalin Tysabri Therapy area Oncology Oncology AIID Indication NHL NHL MS Launch date 1997 2002 2004
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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

Name Rituxan Tysabri Anti-CD80 mAb (galiximab) Anti-CD23 mAb (lumiliximab) VLA-1 mAb Anti-Lymphotoxin Beta Receptor Anti-CD20 mAb CH2 Domain Deleted mAb IDEC-151 IDEC-114 IDEC-131 Therapy area AIID AIID Oncology Oncology/AIID AIID Oncology Oncology Oncology Indication Rheumatoid Arthritis Crohns / RA NHL CLL (cancer), asthma Phase Phase III PhaseIII Phase II Phase I Launch date 2008 2008 >2011 >2011 >2011 >2011 >2011 >2011 Business Insights Ltd
Inflammatory disorders Pre-clinical Solid tumors Pre-clinical B-cell cancers Solid tumors Pre-clinical Pre-clinical Suspended Suspended 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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Strategic and growth analysis UCBs acquisition of Celltech during 2004 has provided the company with the opportunity to become a leading biopharmaceutical company. UCB now has unique inhouse 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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Figure 5.19: UCB Celltechs SWOT analysis in the mAb market
UCB Celltech
Strengths Celltechs pipeline drugs benefit from the financial backing from UCB In-house technology (PEGylation of mAb fragments) Wide range of collaborations Weaknesses Gap in mAb pipeline now that Cimzia has been submitted for approval High dependence on Cimzia
Opportunities Expand into other therapy areas such as anti-infectives In-license products to fill gap in pipeline
Threats Consolidation in the market Other companies developing more innovative mAb technology
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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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

Name Cimzia (CDP 870) CDP 484 CDP 791 CMC 544 anti-OX40R Therapy area AIID AIID Oncology Oncology AIID Indication RA/Crohns RA MS, Lupus Phase Filed Phase I Phase I Phase I Preclinical Launch date 2006 >2011 >2011 >2011 >2011
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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.
Strategic and growth analysis 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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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
Strengths Proprietary technology: UltiMab platform Broad early stage pipeline Extensive collaborations Weaknesses Lack of sales and marketing experience
Opportunities Further out -licensing deals (technology and pipeline products) To become more fully integrated by marketing their own products rather than forming collaborations
Threats Other companies with technology similar to Medarex
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 mAbrelated 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 MDX-010 + MDX-13792 MDX-0102 MDX-060 MDX-018 MDX-010 + peptides MDX-070 MDX-214 MDX-010 + GVAX MDX-066 MDX-1307 MDX-1100 MDX-1303 Amrad Ab1 SARS Ab1 PRIMABioMed Ab1 Ferric Technologies Ab1 diaDexus Ab1 Abbott Ab 11 Abbott Ab 21 Therapy area Oncology Oncology Oncology AIID Oncology Oncology Oncology Oncology Infectious disease Oncology Indication Phase Phase III Phase II Phase II Phase II Phase II Phase II Phase II Phase I Phase I Phase I Preclinical Preclinical Preclinical Preclinical Preclinical Preclinical Preclinical Preclinical Preclinical Launch date 2007 2007 2009 2009 >2010 >2010 >2010 >2010 >2010 >2010 >2010 >2010 >2010 >2010 >2010 >2010 >2010 >2010 >2010
Melanoma Melanoma, breast cancer Lymphoma Melanoma Prostate Cancer EGFr-positive cancers Prostate cancer C. difficile Colorectal, pancreatic and bladder cancers AIID Infectious disease Anthrax Respiratory Asthma Infectious disease SARS Oncology Infectious disease Bacterial infections Oncology Lung cancer AIID Oncology Cancer
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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.
Strategic and growth analysis 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.
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Figure 5.21: XOMAs SWOT analysis in the mAb market
XOMA
Strengths Advanced in-house antibody technology Deals and alliances based on out-licensing of its technology Strong early stage pipeline Weaknesses No marketed products No late stage pipeline products
Opportunities Further out-licensing deals of its antibody technology Collaborations to gain late stage pipeline mAbs
Threats Other companies with advanced antibody technology, such as BioWa or Crucell
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 ScheringPlough 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 upfront license fee, development milestones and royalties. AVEO retains all development and commercialization rights to AV-299;
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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

Name HCD 122 (chir12.12) (Novartis) Anti-gastrin mAb (Aphton) XOMA 052 MAb Therapy area Oncology GI disorders AIID Indication B-cell cancers GI cancers Phase Phase I preclinical preclinical Launch date >2011 >2011 >2011
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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
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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.
Strategic and growth analysis 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.
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Figure 5.22: BioWas SWOT analysis in the mAb market
BioWa
Strengths Advanced antibody technology Licensing deals to apply its POTELLIGENT technology to range a range of mAbs Weaknesses No currently marketed mAb
Opportunities Become more integrated and develop its own mAb portfolio Further out-licensing deals for its proprietary technology
Threats Competition from other antibody companies that also have advanced antibody 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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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

Name KW-2871 Potelligent-IL5R Potelligent-Flt-1 Potelligent-GM2 Potelligent-GD2 Therapy area Oncology Respiratory Oncology Oncology Oncology Indication Melanoma Asthma VEGF-R/FLT-1 Lung cancer, glioblistoma Solid tumor Phase Phase II Phase I Phase I Phase I Phase I Launch date <2011 <2011 <2011 <2011 <2011
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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.
Strategic and growth analysis

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.
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Figure 5.23: Crucells SWOT analysis in the mAb market
Crucell
Strengths Outlicensing its PER.C6 technology to pharmaceutical and biotechnology companies Weaknesses No currently marketed mAb
Opportunities Become more integrated and develop its own mAb portfolio Further out-licensing deals for its proprietary technology
Threats Competition from other antibody companies that also have advanced antibody 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.
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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 diseasespecific 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

Name Anti-rabies Therapy area Infectious disease Indication Rabies Phase preclinical Launch date >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
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virus). Crucell plans to initiate Phase I clinical testing of its rabies antibody product late in 2006.
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Chapter 6
Appendix
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Chapter 6
Sales data
Appendix
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.
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Index
Abbott, 24, 25, 28, 30, 32, 44, 59, 77, 79, 80, 88, 91, 105, 109, 113, 116, 117, 124, 130, 163 Abgenix, 43, 52, 61, 105, 117, 124, 132, 134, 135 ABX-EGF, 52, 61, 66, 67, 94, 99, 104, 105, 106, 117, 118, 124, 125, 148 ADCC, 41, 42, 61, 131, 135, 168, 169, 170, 171 AIID, 18, 19, 24, 25, 52, 59, 76, 91, 94, 100, 105, 106, 107, 109, 124, 137, 139, 140, 143, 147, 149, 152, 153, 156, 157, 160, 163, 164, 167 Amgen, 32, 52, 57, 61, 62, 66, 77, 80, 82, 105, 110, 113, 114, 117, 118, 120, 121, 124, 132, 134, 135, 159 antibody fragments, 20, 23, 28, 33, 35, 43, 45, 46, 49, 94, 100, 104 Anti-infective, 59, 87, 91, 105, 116, 124, 143, 152, 163, 174 AstraZeneca, 20, 25, 26, 44, 45, 129, 132, 134 Bexxar, 24, 30, 37, 38, 59, 60, 62, 71, 72, 74, 75, 91 Bioequivalent, 22, 95, 96, 101, 102, 151 Biogen Idec, 24, 25, 30, 31, 37, 38, 45, 57, 59, 61, 62, 71, 72, 75, 78, 82, 91, 105, 124, 130, 151, 153, 154, 155, 156, 157 Bioren, 134, 136, 144, 145, 146 BioWa, 42, 131, 132, 165, 169, 170, 171 Campath, 24, 30, 59, 61, 69, 70, 91, 98 CAT, 20, 24, 25, 28, 30, 32, 42, 43, 44, 45, 59, 79, 91, 104, 105, 124, 129, 130, 132, 134 Cellective, 134, 136 Celltech, 24, 30, 34, 36, 40, 42, 43, 49, 73, 76, 80, 91, 95, 109, 155, 157, 158, 159, 160 Centocor, 24, 25, 30, 31, 36, 46, 59, 76, 86, 87, 91, 105, 124, 130, 131, 132 Chimeric, 31, 105, 106 Cimzia, 36, 55, 58, 76, 78, 79, 80, 82, 91, 94, 95, 100, 104, 105, 109, 110, 113, 123, 124, 125, 157, 158, 160 Crucell, 128, 131, 139, 159, 165, 167, 172, 173, 174 Eculizumab, 100, 112, 113, 124 Elan, 25, 59, 91, 154, 155 Erbitux, 24, 30, 56, 59, 61, 66, 67, 68, 69, 91, 98, 118, 123 Food and drug administration, 101 Fully human, 32 Genentech, 18, 24, 25, 28, 30, 32, 33, 36, 40, 55, 59, 61, 62, 63, 64, 65, 66, 78, 81, 82, 89, 91, 94, 101, 105, 118, 122, 124, 128, 130, 131, 132, 137, 138, 140, 142, 143, 147, 148, 149, 153, 156, 165, 167, 170, 171 Genzyme, 24, 25, 30, 59, 69, 70, 91, 130, 131 GlycArt, 20, 132, 134, 135 HAMA, 18, 20, 23, 29, 31, 84 Hemostasis, 59, 86 Herceptin, 24, 30, 32, 41, 56, 57, 59, 60, 63, 64, 65, 91, 125, 139, 149 Humanized, 32, 105, 125 Humax, 94, 99, 105, 120, 121, 124 Humira, 23, 24, 28, 30, 32, 44, 52, 55, 57, 58, 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, 46, 76, 82, 84, 86, 91, 130 Lucentis, 28, 33, 36, 55, 94, 100, 104, 105, 122, 124, 125, 134, 141, 142, 143, 149 Medarex, 52, 61, 64, 88, 105, 119, 120, 124, 131, 132, 161, 162, 163, 164, 165 MedImmune, 24, 25, 30, 32, 40, 49, 59, 88, 91, 105, 116, 117, 124, 130, 131, 134, 136, 150, 151, 152, 153, 165 Merck KGaA, 25, 59, 66, 67, 130, 131 MRA, 55, 62, 100, 105, 110, 111, 124, 140 murine, 18, 20, 23, 28, 29, 30, 31, 32, 58, 62, 76, 79, 83, 84, 85, 99 Mylotarg, 61 Neutec, 20, 105, 124, 134, 141, 142, 143, 144 Novartis, 20, 24, 25, 26, 30, 36, 55, 57, 59, 66, 83, 89, 90, 91, 105, 122, 124, 128, 130, 131, 134, 141, 142, 143, 149, 167, 168 Numax, 52, 87, 88, 94, 104, 105, 107, 116, 117, 123, 124, 151, 152, 153 oncology, 18, 19, 24, 25, 37, 52, 59, 60, 61, 69, 76, 94, 100, 105, 106, 107, 119, 123, 124, 135, 137, 146, 147, 153, 158, 160, 163, 164, 171 Orthoclone OK3, 18, 19, 20, 24, 30, 58, 59, 76, 83, 84, 85, 91, 142 Pexelizumab, 36, 105, 115 Pfizer, 26, 32, 89, 101, 105, 118, 122, 134, 136, 144, 145, 146, 147, 161 Potelligent, 42, 131, 169, 170, 171 Raptiva, 24, 30, 57, 59, 78, 81, 82, 91, 147, 149, 165, 167
Remicade, 24, 30, 31, 52, 57, 58, 59, 62, 76, 77, 78, 79, 80, 82, 90, 91, 100, 103, 109, 110, 123 Reopro, 31, 86 Respiratory, 59, 89, 91, 143, 149, 152, 163, 164, 171 Rituxan, 24, 30, 31, 41, 52, 56, 58, 59, 60, 61, 62, 63, 71, 72, 78, 90, 91, 128, 137, 139, 148, 149, 153, 155, 156, 157 Roche, 20, 24, 25, 30, 32, 42, 46, 59, 61, 62, 63, 65, 78, 84, 87, 91, 105, 110, 111, 118, 124, 128, 130, 131, 132, 134, 135, 137, 138, 139, 140, 147, 148, 156 Sandoz, 102 Simulect, 24, 30, 59, 83, 91, 98, 131, 142, 143, 159 Synagis, 24, 25, 30, 32, 52, 59, 87, 88, 91, 94, 106, 116, 117, 123, 151, 152, 153 Tysabri, 24, 30, 57, 59, 91, 99, 154, 155, 156, 157 UCB, 34, 36, 40, 42, 43, 55, 58, 76, 78, 80, 82, 91, 95, 105, 109, 110, 113, 124, 157, 158, 159, 160, 173 Wyeth, 24, 25, 30, 37, 57, 59, 72, 73, 77, 82, 91, 130, 159 Xencor, 41, 42, 131, 132, 139 Xolair, 24, 30, 59, 89, 90, 91, 142, 143, 149 XOMA, 30, 78, 81, 91, 128, 165, 166, 167, 168, 173 Zenapax, 24, 30, 32, 59, 76, 83, 84, 91, 98, 139, 142 Zevalin, 24, 30, 37, 38, 59, 60, 62, 70, 71, 72, 75, 91, 154, 155, 156
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The Future of Monoclonal Antibody Therapeutics - S. Riley (2006) WW

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The Future of Monoclonal Antibody Therapeutics - S. Riley (2006) WW

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H E A LT H C A R E

Antibody engineering and innovation in the market

The current monoclonal antibody market

The antibody pipeline and forecasts to 2011

Competitive landscape and future growth strategies

Antibody engineering and innovation in the market

The current monoclonal antibody market

The antibody pipeline and forecasts to 2011

Competitive landscape and future growth strategies

History of monoclonal antibodies

Figure 1.1: History of monoclonal antibodies

Source: Business Insights

Business Insights Ltd

Monoclonal antibody approval process

Key trends in the market

Table 1.1: Current marketed drugs, 2006

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

Antibody engineering and innovation in the market

Antibody engineering and innovation in the market

The move from murine to fully human mAbs

Table 2.3: Marketed therapeutic monoclonal antibodies, 1986-2006

Source: Business Insights; Company websites; FDA

Business Insights Ltd

Figure 2.2: Current marketed monoclonal antibodies, 2006

Source: Business Insights; Company websites

Business Insights Ltd

Figure 2.3: Therapeutic mAbs entering clinical study, 1980-2004

Murine Chimeric Humanized Human

Innovations in antibody structures

Figure 2.4: Whole antibody and fragment structures

Variable region of light chain Constant region of light chain

Constant region (Fc)

SingleSingle-chain antibody (SCA)

Antigen-binding fragment (Fab)

Source: Business Insights

Table 2.4: Antibody fragment pipeline, 2006

Source: Business Insights; Company websites; MedTRACK

Business Insights Ltd

Innovation in antibody conjugation

Table 2.5: Conjugated antibody engineering technology

Peregrine Tumor Necrosis Pharmaceuticals Therapy (TNT)

Source: Business Insights; Company websites; MedTRACK

Enhancing monoclonal antibody potency

Table 2.6: Drug development technology

Source: Business Insights; Company websites; MedTRACK

Table 2.7: Monoclonal antibody drug discovery technology

Dyax Morphosys GOLD Symphogen Ablynx Vaccinex Curagen UCB Celltech

Source: Business Insights; Company websites; MedTRACK

Innovation in drug delivery

The current monoclonal antibody market

The current monoclonal antibody market

Analysis of launched drugs

Figure 3.6: Market dynamics of current marketed drugs, 2004-5

Synagis 1500 2000 2500 3000 3500 4000

ReoPro Orthoclone OKT3

Bubble size represents market share

Table 3.8: Marketed therapeutic monoclonal antibodies, 2004-5

10,271.3 14,009.5 36.4% 100.0%

Figure 3.7: Marketed monoclonal antibodies by therapy area, 2006

Anti-infective: Synagis Hemostasis: ReoPro

AIID: Humira Orthoclone OKT3 Raptiva Remicade Simulect Tysabri Zenapax

Source: Business Insights