`Cognos Study #9
`
`A PharmacorService
`
`[ULTIPLE SCLEROSIS 2005-2020
`
`April 2007
`
`
`For questions regarding the report content and analysis, contact:
`Analyst: Bethany A. Kiernan, Ph.D.
`
`Tel + 1.781.296.2631 4 E-mail bkiernan@dresources.com
`
`Epidemiologist: Jessica Goelz Welch, M.P.H,
`Tel + 1.781.296.2617 # E-matl jwelch@dresources.com
`
`For questions regarding consulting, contact: Jim McDermott Tel + 1.781.296.2522 # E-mail jmedermott@dresources.com
`
`For questions regarding Sales, service, and technical support, contact:
`Japan
`United States
`Europe
`Tel +81.3.5401.2615 @ Fax +81.35401.2617
`Tel + 1.787.296.2537 # Fax + 1.781.296.2550
`Jel +32.2.357.06.16 4 Fax +32.2.381.2347
`
`
`P(LIy 9-01408
`
`DEPOSITION
`
`rioo
`
`a22 32oF
`
`ee
`A DECISION RESOURCESpublication__AAO
`DECISION RESOURCESis registered in lhe U.S. Patent and Trademark Office.
`This material, prepared specifically for clients of Decision Resources,inc., is furnished in confidence andis not to be duplicated outside of
`subscriber organizations in any form without our prior permission in wriling. The opinions stated represent our interpretation and analysis of
`information generally available to the public or released by responsible individuals in the subjecl companies, We believe that the sources of
`information an which our material is based are reliable and we have applied our best professional judgment to [he dala obtained. We do nat
`assume any liability for the accuracy, comprehensiveness, or use of [he information presented.
`© 2007 Decision Resources,Inc. ¢ 260 Charles Sireet ¢ Waltham, Massachusetis 02453 ¢ Tel +1.781.296.2500 # Fax +1.781,.296,2550
`
`Torrent et al. v. Novartis
`1 of 314 IPR2014-00784/IPR2015-00518—rcor-co-o.0-1
`Novartis 2130
`
`Page 1 of 314
`
`Biogen Exhibit 2210
`Mylanv. Biogen
`IPR 2018-01403
`
`Page 1 of 314
`
`Biogen Exhibit 2210
`Mylan v. Biogen
`IPR 2018-01403
`
`

`

`Multiple Sclerosis 2005-2020
`
`Table of Contents
`
`Executive Summary ... 0.2.2. eee eee ees2
`Whatare the key parameters of the multiple sclerosis market? ...... 20... c cece eee eee 2
`What factors are driving the market for multiple sclerosis therapies? ..................00. 3
`What factors are constraining the marketfor multiple sclerosis therapies? ................. 4
`Whatare the drug developmentactivities of note in multiple sclerosis?.................... 5
`What do the experts Say? 00... cee cette ne eee entrees 6
`What key challenges and opportunities remain?. 00.0... ce eee ees 7
`1. Introduction .. 0... cece nee eee enes 10
`Report Coverage... ccc ete net tee enn n ere ete ee een aes 11
`Report Fealures. 00. cc ee eed een te bbe t eee een ttre ees 11
`2. Current and Emerging Drug TargetS ........ 000. eee eee 13
`OVEIVIOW ooee ten nee nent eee eed 15
`The Autoimmune Attack in Multiple Sclerosis... 0.02. ee etter ees 17
`9 =)|a 17
`T-Cell Activation. 0.0.00... ccc tence eet e eee ennnes 17
`Tyland Ty2 Cells oi. eee tener eter trees 20
`T-Cell Seli-Recognition and the Autoimmune Response in Multiple Sclerosis ...... 21
`T-Cell Migration and Entry into the Central Nervous System ..............0.... 22
`The T-Cell-Mediated Inflammatory Reaction in the Central Nervous System....... 24
`BCells........ Cee ene e Ener ene EEE Ee nee 25
`Antibodies in Multiple Sclerosis... 0.0.00... cc cece cect cent tet nee e eee 26
`Complement Cascade... 2.0.0... 2c cette tenner n ees 26
`CHEMOKINES. 6.ee nee eee een eden eg 26
`Demyelination .. 0... cee eter eee renee eee etn ed 2t
`Inhibition of Remyelination 20... cect ete tenet n tnt ees 27
`Axonal Degeneration and Neuronal Cell Death... 0.0.00... cece ccc ee eee e eens 29
`Neuroprotective Role of the Immune Response ........... 0.0: cect ee een e ees 30
`
`3. Epidemiology and Disease Populations.......... 00.0 cece eee eee eee ee33
`OVEIVIEW 0... nent ene rented eben ett nett n eens 34
`Disease Definition... cette entree bet bene 35
`Methodology OvervieW .... 000 tteteteteeee eet 36
`Major-Market Profiles 2.0... cece eee een n tet enae 4]
`United States ce eee eee te rete eet nett eres Af
`C= 43
`GOIMANY ooee en nee eee 44
`a 45
`SPAIN cent e tented ene tenets 46
`United Kingdom... ccc eet ett ete eee 47
`AE=] 48
`Subpopulations 0... cece cette n tenet tebe beens 49
`Diagnosis and Drug-Treatment Rates
`....0 0.02.22 eee eee ee 50
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`Multiple Sclerosis 2005-2020:
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`4, Current Therapies and Treatment TrendS....... 0.0000 ecceeee eee eenteeaes 54
`Overview of Current TherapieS . 0... icc ccc ete ee eee eee bee tte ees 56
`Recombinant Interferons ..... 0.0.0e eter ent ee ee eneenns 60
`OVEIVIOW cect ee eee net eee te eden teen e enn anee 60
`Mechanism Of Action... 0.0... ccc ccc cece ete etree eee t etn tenet eens 80
`FOrMUlation o.oo et eben b teen eee ete tenn e neta eeeens 60
`Interferon Beta-1D 0... eee tet eterna teense eetners 61
`Interferon Beta-1a (IM) oo... cece etre terete teen etre teens 67
`Interferon Beta-1a (SC)... eee een e eet e een ees 69
`Altered Peptide Ligands .... 0.0... 0c. c ccc ccc creer tener nate e een ee teas 42
`Glatiramer Acetate... 6... cece cence eee een etree etter nnn 72
`Monoclonal Antibodies. 2.2.2... ccc cect ener ee nett e teen nee eterna 74
`Natalizumab. .. 0. cette eet t nett e tnt e ete eees 74
`Chemotherapeutics 0... eect t nee enter ten tenes 80
`OVEVIEW0 cee cence etter ere etree eben tiene rte een need 80
`Mechanism of ACHON 2.0... ccc ccc c eee eet een etre t eden ett tees 84
`Formulation... 0... cece ent net n ep erent nee e eens 81
`Mitoxantrone 0.6.eet tere e teen n teenie nena 81
`Mycophenolate Motetil. 0... eect rents teen eee 83
`Treatment Trends 0.0.0.0...cent tenant ene ents 84
`OVEVIOW0c ee eee een beeen ne tenet teen nett eas 84
`Diagnosis and Referral .........0. 02.2200 e erect ne ete teen e eee enes 84
`Treatment Guidelines 2.0... 0. cece eee teeters pete eens 87
`Pharmacological Treatment...... 0. cece ccc cece e etre ebatees 87
`Economic ISSuU@S oo... 6. ect ett t ett e nett ee tnaes 89
`Major-Market Profiles 20.0.0... e eect eee ete een ea ee 89
`United States... cece ee netted 89
`SLU 0)6, 92
`JAPAN.nnn tenet eee nnee 95
`5. Development Hurdles and Treatment Challenges .......... 0.00 c eee eee 98
`Evolution of Unmet Needs in Multiple Sclerosis... 20.0... 00.0. eee cee eee ees 99
`Reversing Neuronal Damage ... 0.2.0...e tenn e netted 101
`Preventing Disease Progression ....... cc cect teeter ee ene ened 102
`Improved Therapy for Chronic-Progressive Multiple Sclerosis .......... 0... e eee eee eee. 102
`More-Convenient Drug Delivery... 0.0.0.t teen e nes 104
`Improved Diagnostic Criteria................. eee cette teeta 105
`Improved Animal ModelS ..... 0... cece cece cece eee een eet teen net ens 106
`6. Emerging Oral Immunomodulatory TherapieS..........00 0c cece eee eee 108
`OVEIVIEW center n ee ene ttn t eee beeen eed 109
`Emerging Oral Therapies Positioning ......... 0.0.00 ccc cee cette eee ees 110
`Oral Immunomodulators ........0 200e eee tenet eens 113
`OQVEIVIEW0 eee een ener etree eee tense eres 113
`Mechanism of Action... 0.0.0... c cc cece ce ener eee teen e teen nnenas 116
`a 117
`B12 ce eee nn tener tebe tenet e eens 121
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`Multiple Sclerosis 2005-202
`
`Laquinimod 2.0... cee eee tenet tent e knee etnies 122
`Simvastatin... ec cece e deeb eee e eee nee eeeeennnees 125
`Oral ImmunosuppressantS 22.0... cece et needed 127
`OVEIVIGW oo cece cee nett pede nee e eee een besten beeen 127
`Mechanism of Action... 00... ccc ccc cree eee tere eet eee cece een e nena. 127
`TeriflunOMide 0. cece ene eee eee eee etn e eet eebead 127
`Oral CladribIng. 20... eee e eee e ete ter eee nbn enna teagan 130
`
`7. Emerging Injectable Immunomodulatory Therapies .........-..--.-.00000- 135
`OVENVIEW Foc cece eee nee e deb Ebene teen tee e eee teehee tgs 136
`Emerging Injectable Immunomodulatory Therapies Posifioning..................-.4.0- 137
`Monoclonal Antibodies, . 0... 000.00. cece cece ee eect eee e nt w ee te nas 139
`OVENVIOW cee nee ee teed aed bette nent eee t eta 139
`Mechanism of Action. ....0 00... ccc eee cece teen eben nbn ee etennee 142
`RiUXIMAD. cc cere nce ee edd teen ete eee nen nee nes 143
`OTe NT 0=]©rr 145
`Al@MmtuZUMAD occ eee e eee een eee ete een tener tenes 147
`Altered Peptide Ligands 0.0... 0... cece ccc cece tn tenet eee need 150
`OVEDVIEW ccc eee ee eden eee e eee bebe bebe teen res 450
`Mechanism of Action... 0... ccc cece ee etree bene eee teen eee etneeyan 154
`MBP-B298 00. ccc cece cree nee e rn e denn tetera net yteneees 151
`Chemokine Receptor AntagonistS.. 2.0.0.0... cece eect e eet eect renee ten nnaes 155
`OVENVIOW 0.0 cc erect eee eee ede t teen e beeen tree aes 155
`Mechanism of Action... 0.0... ccc cette cet eee nee n nent gir etn yes 156
`MLN-1202 occ cere nee ee nee tb beta cent bebe ene nes 157
`T-Cell Receptor VaccineS 2.0... cece tern nent tne n etre sd 158
`OVEVIEW ccc eee eee tebe teen n bbb be bane pease eentnreny 158
`Mechanism of Action... 0... 0 ccc ccc cece ee eter etree etn t ene bb ees 158
`NGUIOVAX, occ ence ee eect eee bbb ent ete eee eeentenneg 158
`TOVAXIN ccc ence nett eee e bene een e eee teeteeane 160
`Peptide-Encoding DNA Plasmids ........0. 00. c cee cece teen ene e ed 162
`OVEVIOW cc ccc ee eee beer een eter ebb t bbe e sped ete nes 162
`Mechanism of Action... 0.00.00. c cece eect e erence eee etn nee nny 163
`BHT-3009 000c cet beeen nee een ene ee ntten ns 163
`
`8. Emerging Neuroprotective and Remyelinating Therapies .................. 166
`OVEMVIOW cee ene n nn ee nee beeen bed thee eet etseue 167
`Emerging Therapies Positioning.......... 0.0... c cee cece cee eet 169
`Glial Growth Factors . 00.00.00 cence nn eben beeen eee ivy ee 170
`Mechanism Of Action... 0.0.0.0... 0c cece ccc tee eect e eee ene e ene etretens 170
`Recombinant Human Glial Growth Factor-2 200.0000 171
`AMPA Receptor Antagonists 2.2.00... 0. cece cece rte e nate rr naes 172
`OVOIVIEWoc cc ct ee ee tte teen e nde eee een eaterbaans 172
`Mechanism of Action 200.0... c cence tect e een nee nees 173
`A00 173
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`Multiple Sclerosis 2005-2020
`
`
`
`9. Market Outlook 2.0.0.0. cee ee eee eee eee eee eens 177
`
`OVOIVIEW eee een eee n tenet be eek rte e eet been ern eg as 178
`Emerging Therapies ..... 0... ccc cece cect centre eee eter nee nnn teens 200
`Emerging Oral mmunomodulatory Therapies.............. cence eee aes 201
`Emerging Injectable Immunomodulatory Therapies ....... 0. ccc eee eee eee 201
`Emerging Follow-On Products to Current Therapies. ......... 2.00. e cue eeees 202
`Market Segmentation of Emerging Therapies... .......- 0.0. s cece eee eens 202
`Oral vs. Parenteral Formulations. .... 0.00... ccc cece e eee terre e eens 203
`Frequency of Administration and Compliance... 0.0.0... 0.0. e cece eee eee teens 204
`Drug-Class-Specific Trends . 0.0... cece ccc ete ee ete ene net eee nee es 205
`Recombinant Interferons. ..... 0... cc cece tebe etn teed 205
`Branded Interferons... . 6... occ eee cece e nent eens 205
`Biogeneric Interferons22. ees 208
`Altered Peptide Ligands ... 2... ccc ccc ent nett e eens 210
`Chemotherapeutics 00.0.eee eben es 211
`Oral ImmunosuppressantS . 00.0... cc cece ee tenet eee eens 211
`Monoclonal Antibodies... 0... cece ete tenet nee nes 212
`Oral Immunomodulators... 0. cee eter nee teenies 213
`Ragion-Specific Trends... 0... eee eee teen eect eee n nent eens 214
`Appendix A. Bibliography—Multiple Sclerosis .............. 000.0 eee eee 217
`
`Appendix B. Market Forecast Methodology ........0.... 2.2 cece eee eee eens233
`General Sources of Data... 0c cnt e tne teen tnes 233
`Diagnosed and Drug-Treated Populations ......... 0... cece eee eee ees 233
`Percentage Diagnosed ........ 2.0... c ccc et terete teen tes 233
`Percentage Drug-Treated 2.0.0.0 ccc tect tee teen eet ngs 234
`Agents Included in Our MarketAnalysis ..... 0.000... ccc cece cece e eee eeeeees 234
`General Statements About Pricing 2.2... 0... cee eee tenet eee eens 235
`Pricing ASSUMPTIONS 2.0... cece te teen nett e nee een enees 235
`Japanese Price AdjustmentS 0.0.0... ceca reece eee een etter ene enes 236
`Dosing, Days of Therapy, and Compliance
`..... 0.0... cece cece eee eres 236
`Generic EroSion. 22. eee een ee tenet ent beeen ened 237
`Emerging Therapy Prices... 2... eect tte nee ee et ates 240
`Appendix C. Experts Interviewed—Multiple Sclerosis..................--.000. 303
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`Multiple Sclerosis 2005-2020
`
`Tables and Figures
`
`Table 3-1. Number of Diagnosed Prevalent Cases of Multiple Sclerosis and Drug-Treated Population
`in the Major Pharmaceutical Markets, 2005-2020 0.0.0... ccc cece crete ete n een 37
`
`Table 3-2,
`
`Key Sources for Epidemiology Estimates—Multiple Sclerosis... 0.0... eee eee eae39
`
`Table 4-1.
`
`Comparison of Current Therapies for Multiple Sclerosis, 2007 0.0.0.0... 0.00. e eee eee57
`
`Table 4-2.
`
`Key Patent and Exclusivity Expiries of Drugs Used to Treat Multiple Sclerosis, 2007......... 59
`
`Table 4-3.
`
`Key Facts: BetaSeron. 2... ee ence eee n teen erent een eennnes61
`
`Table 4-4.
`
`Comparative Efficacy of Multiple Sclerosis Therapies in PhaseIll Trials for RR-MS, 2007 ..... 62
`
`Table 4-5.
`
`Comparative Efficacy of Multiple Sclerosis Therapies in PhaseIll Trials for SP-MS, 2007 ..... 64
`
`Table 4-6.
`
`Comparative Efficacy of Multiple Sclerosis Therapiesin Clinical Trials for Early-Stage
`S20065
`
`Table 4-7,
`
`Comparative Efficacy of Multiple Sclerosis Therapies in Clinical Trials for PP-MS, 2007 ......87
`
`Table 4-8.
`
`Key Facts: AVOneX 2.0 ccc eee nett beet n enn es 68
`
`Key Facts: Rebif. cece eee ret ttre70
`Table 4-9.
`Table 4-10. Key Facts: GlatiramerAcetate ... 0.0.00... c teen ete tenn nent eeanens73
`
`Table 4-11. Key Facts: Natalizumab 2.0.0.0... ccc cece cece treet tees neste eeenteeens75
`
`Table 4-12. Natalizumab Pivotal Trial Highlights ........0. 0.0.0.0 cee cece eee een et tere neea7
`
`Table 4-13, Key Facts: Mitoxantrone. 0.6... ccc een ttt eee bennett ener enas 82
`
`Table 4-14, Key Facts: Mycophenolate Mofetil ... 0.00.00... cece cece teen ees 83
`
`Table 6-1.
`
`Emerging Oral Immunomodulatory Therapies in Development for Multiple Sclerosis, 2007 .. .114
`
`Table 6-2.
`
`Estimated Launch Dates for Key Late-Stage Emerging Therapies for the Treatmentof
`Multiple Sclerosis, 2007 00.0... ccc cece ccc ene cette deen een eet eben tenes 115
`
`Table 7-1
`
`Emerging Injectable Immunomodulatory Therapies in Development for Multiple Sclerosis,
`200ee ee nee n eben eee b etn eee nes 140
`
`Table 8-1.
`
`Emerging Neuroprotective Therapies in Developmentfor Multiple Sclerosis, 2007.......... 169
`
`Table 9-1.
`
`Sales of Drugs to Treat Multiple Sclerosis (All Populations) in the Major Pharmaceutical
`Markets, 2005-2020 000. ieee en ener een tenn teeta 179
`
`Table 9-2.
`
`Table 9-3,
`
`Sales of Drugs to Treat Relapsing-Remitting Multiple Sclerosis in the Major Pharmaceutical
`Markets, 2005-2020 00.2. eee etn tenner ee tent es 185
`
`Sales of Drugs to Treat Chronic-Progressive Multiple Sclerosis in the Major Pharmaceutical
`Markets, 2005-2020 000. ccc ee tence nna e ete nett eens 191
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` Multiple Sclerosis 2005-2020
`
`Table B-1. Assumptions Behind the 2005 Multiple Sclerosis Market (All Populations) ..............04242
`
`Table B-2. Assumptions Behind the 2010 Multiple Sclerosis Market(All Populations} ................247
`
`Table B-3. Assumptions Behind the 2015 Multiple Sclerosis Market (All Populations) ................252
`
`Table B-4. Assumptions Behind the 2020 Multiple Sclerosis Market(All Populations) ................257
`
`Table B-5.. Assumptions Behind the 2005 Relapsing-Remitting Multiple Sclerosis Market.............262
`
`Table B-6. Assumptions Behind the 2010 Relapsing-Remitting Multiple Sclerosis Market.............267
`
`Table B-7, Assumptions Behind the 2015 Relapsing-Remitting Multiple Sclerosis Market.............2f2
`
`Table B-8. Assumptions Behind the 2020 Relapsing-Remitting Multiple Sclerosis Market.............277
`
`Table B-§. Assumptions Behind the 2005 Chronic-Progressive Multiple Sclerosis Market ............282
`
`Table B-10. Assumptions Behind the 2010 Chronic-Progressive Multiple Sclerosis Market ............ 287
`
`Table B-11. Assumptions Behind the 2015 Chronic-Progressive Multiple Sclerosis Market ............292
`
`Table B-12. Assumptions Behind the 2020 Chronic-Progressive Multiple Sclerosis Market ............ 297
`
`Figure 2-1. Multiple Sclerosis Immune Pathophysiolagy .0.00.2... 0.0.00 cee cece eee een eae 18
`
`Figure 2-2. Two IndependentSignals in T-Cell Activation. ... 0.0.0... 0.0 ccc cre eee eee een eee 19
`Figure 2-3, Migration of Activated T Cells into the Central Nervous System........-. 00.00. c eee e eas23
`Figure 2-4. Demyelinating Plaques in Multiple Sclerosis 6... 0.0.00... eee eee cee eee ees28
`
`Figure 5-1. Unmet Needs: Attainment and Remaining Opportunity in Multiple Sclerosis............... 100
`
`Figure 6-1. Select Multiple Sclerosis Franchises, 2007 2.00.00... cca cece cece eee ee ened 111
`
`Figure 6-2, Multiple Sclerosis Patient Populations, 2007 2.0.02. 0... cee cc eee eet teens 112
`
`Figure 6-3, Pipeline Status of Oral Drugs by Class for Multiple Sclerosis... 00... 0... eee eee 115
`
`Figure 7-1, Multiple Sclerosis Patient Populations, 2007 ©2002. 0 0.000 cee cee ec n eee 136
`
`Figure 7-2. Early-Stage Pipeline Status of Injectable Immunomodulatory Drugs by Class for Multiple
`SCIOTOSISoer e ete ner nner teen tt ener e es 139
`
`Figure 7-3. Late-Stage Pipeline Status of Injectable Immunomodulatory Drugs by Class for Multiple
`SCIEMOSISone ene e eee t ent dnt e abet beens 139
`
`Figure 9-1. Multiple Sclerosis Therapies by Class, 2005 and 2020: Market Share.................4.. 198
`
`Figure 92, Drug Class Sales for Multiple Sclerosis, 2005-2020... 2.00.0... cece cece eee eens 199
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`

`
`
`Pharmacor
`
`[ULTIPLE SCLEROSIS 2005-2020
`
`April 2007
`
`Executive Summary
`
`
`
`
`For questions regarding the report content and analysis, contact:
`Analyst: Bethany A, Kiernan, Ph.D.
`Tel +1.787.296.2631 # E-mail bkiernan@dresources.com
`
`Epidemiologist: Jessica Goetz Welch, M.P.H.
`Tel + 1.781.296.2617 # E-mail jwelch@dresources.com
`
`For questions regarding consulting, contact: Jim McDermott Tel + 1.781.296.2522 # E-mail jmedermott@dresources.com
`
`Far questions regarding sales, service, and technical support, contact:
`Japan
`United States
`Europe
`Tel +81.3.5401.2615 @ Fax +81.3.5401.2617
`Fax +32.2.351.2347
`Tel + 1.781.296.2537 # Fax +1.781.296.2550
`Tel +32.2.357.06.16
`
`
`A DECISION RESOURCESpublication
`DECISION RESOURCESis registered in the U.S. Patent and Trademark Office.
`This material, prepared specifically for clients of Decision Resources, inc., is furnished in confidence and is not to be duplicaied outside of
`subscriber organizations in any form without our prior permission in wriling. The opinions staled represent our interpretation and analysis of
`information generally available to the public or released by responsible individuals in the subject companies. We believe thai the sources of
`information on which our material is based are reliable and we have applied our bes! professional judgment to the data oblained. We do nat
`assume any liability for the accuracy, comprehensiveness, or use of the information presented.
`© 2007 Decision Resources,Inc. + 266 Charles Street ¢ Waltham, Massachusetts 02453 ¢ Tel +1.781.296.2500 + Fax +1.781.296.2550
`
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` Multiple Sclerosis 2005-2020:
`
`Executive Summary
`
` Key Findings
`
`
`
`* Weforecast modest sustained annual growth—2.7%W—ofthe MS marketfrom 2005 to 2015, Annual
`market growth will slow to 0.9%from 2015 fo 2020. Emerging oral agents will contribute substantially
`to market growth, accounting for 25% of major-market sales in 2020. Overall, all emerging agents will
`garner 32% of major-market salesin that year.
`
`* Adrug's safety profile nas becomeinstrumental to its market success. The history of fatal opportunistic
`infections associated with natalizumab (Biogen Idec/Elan's Tysabri) has not only impaired its once-
`promising market success but also made physicians much more cautious about emerging therapies.
`FTY-720 (Novartis/Mitsubishi Pharma's fingolimod) holds the greatest market potential of all emerging
`therapies for MS, Becauseof its moderate safety profile, improved efficacy over current therapies,
`and oral formulation, we expect FTY-720 to capture significant patient and market share by 2020 and
`achieve peak-year sales of $750 million to $1 billion.
`
`*
`
`
`
`
`
`
`
`
`
`
`
`
`
`* Although emerging agents will offer more therapeutic options to M5 patients, significant opportunity
`remains in this market, The MS community continuesto call for drugs that halt disease progression,
`promote remyelination and neuroprotection, and demonstrate improvedsafety, efficacy, tolerability,
`dosing regimens, and formulations.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`What are the key parameters of the multiple sclerosis market?
`
`
`
`
`
`
`© 524,700
`Diagnosed patients::
`$3,497.3MM
`Treated patients:
`
`T [== 316,000/eu:
`
`
`
`Phase Il drugs:
`=
`
`PSTora|—_4,036.0mmTota|96,87. mm}
`Phase III/PR drugs:
`
`
`
`‘Current
`Market.
`PatentiExclusivityExpiry.
`20056
`
`
`~.) $1,359/2 MM
`Interferon-§-1a (Biogen Idec’s Avenex)
`2013 (US); 2005 (EU); 2005 (JA)
`,
`
`Glatiramer acetate (Teva Pharmaceutical’s Copaxone)|2014 (US); 2015 (EU) 2015 (JA) : $1,006,9 MM
`
`
`
`Mostimportant
`Unmet
`Need
`‘CurrentAttainment
`
`
`
`
`Low
`Reversing neuronal damage
`
`
`Low
`Preventing disease progression pn,
`
`Low
`Improved therapy for chronic-progressive MS
`
`Low
`More-convenient drug delivery
`
`au| Launeh Date oe?
`ein Shy oe) PéakeVear
`Sales-Poteni
`Most’PromisingEmergingTherapies:
`
`FT¥-720 (Novartis/Mitsubishi Pharma’‘s fingolimod)
`2010
`$750-1,000 MM
`‘
`
`
`MB8P-8298 (BioMS Medical)
`.| 2011
`$250-500 MM
`
`
`Fi
`::| Impacton Market”
`Relaunch of natalizumab (Biogen Idec/Elan’s Tysabri)|+++
`in the United States and launch in Europe (2006}
`q
`Launch of FTY-720 (2010)
`Launchoffirst oral agent {cladribine, 2010)
`Launch of follow-on products to interferon-B agents
`and glatiramer acetate (2007-2009)
`Launch of MBP-8298 for chronic-progressive MS
`(2011)
`
`
`
`
`
`
`++
`
`+
`
`+
`
`20
`
`
`
`
`
`
`
`i
`High
`
`Moderate
`
`E
`E
`E
`
`i
`
`High
`
`Launchof biogeneric versions of the interferon-B
`agents (2012-2014)
`
`-
`
`E
`
`© Decision Resources, Inc., 2007
`
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` Multiple Sclerosis 2005-202:
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`Chemotherapeutics 1%
`
`Other? <1%
`
`Altered
`peptide ligands
`
`Recombinant
`interferons
`
`2020
`Total:$5,531.3 MM
`
`Oral
`immunomodulators
`
`Other <1%
`
`
`
`Moncclonal antibodies 1%
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` Note:Percentagesmays
`
`
`
`
`
`Oral
`immunosuppressanis
`
`Recombinant
`Interferons
`
`Monoclonal
`antibodies
`
`Altered
`peptide ligands
`
`a. "Other"‘includes corticasteroids: azathioprine, and mycophenolate mofetil.
`b.Other” includes.corticosterdids‘and.chemotherapeutics.-
`
`
`eDeksinResoowse jie bar
`
`
`Whatfactors are driving the market for multiple sclerosis
`therapies?
`* The MS market is growing as a result of increased diagnosis rates, which
`are fueled by increased use of the McDonald criteria and magnetic
`resonance imaging (MRI) as well as diagnosis occurring earlierin the
`disease process.
`
`*
`
`Increasing drug-treatmentrates will drive growth of the MS market
`through 2020 as expert opinion shifts in favor of prescribing therapy
`early in the disease. Indeed, patients with early forms of MS represent
`a significant commercial opportunity, and the interferon beta (IFN-(3)
`agents are now approved for use in this population. In addition, therapies
`that launch during ourstudy period will provide new therapeutic options,
`particularly to patients underserved by current therapies, including early-
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`Multiple Sclerosis 2005-2020 :.
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`stage MS patients, chronic-progressive MS (CP-MS}patients, and patients
`whose MSis refractory to or who cannottolerate current therapies. The
`convenience provided by emerging oral agents will also promote use in
`patients who cannot tolerate or who do not want injectable therapies.
`
`The lack of cost-sensitivity in the MS markethashistorically driven
`emerging agents to be priced at a premium to current therapies. We
`expect this trend to continue during our study period; emerging therapies
`will command higherprices thanks to improvements in convenience or
`efficacy. As emerging agents compete with current therapies forpatient
`share, their higher price points will drive sales growth.
`
`Two therapiesin particular will contribute significantly to market growth
`through 2020: natalizumab (Biogen Idec/Elan’s Tysabri) and FTY-720
`(Novartis/Mitsubishi Pharma's fingolimod). With natalizumab’s relaunch
`in the United States and launch in Europe in 2006 and FT'Y-720’s
`expected launch in 2010 in the United States and 2011 in Europe, these
`drugs will garner substantial patient share because of their demonstrated
`efficacy and, in the case of FT'Y-720, availability in an oral formulation.
`However, these drugs’ potential to trigger severe side effects will hamper
`uptake so that neither agent will achieve blockbusterstatus during our
`study period,
`
`Despite the parenteral formulation of current therapies, patient compliance
`is extremely high in MS, and the launch of agents in more-convenient
`oral formulations will only increase compliance. As the drug-treated
`population increases because of the availability of additional novel
`therapies, the percentage of patients who arc compliant with treatment
`will increase, driving market growth,
`
`Whatfactors are constraining the market for multiple
`sclerosis therapies?
`* Despite experts’ demand for agents that are moreefficacious at delaying
`disease progression, the majority of MS agents that we expect to launch
`during ourstudy period have yet to demonstrate significant improvement
`in efficacy over most current therapies. As a result, most elnerging
`therapies will capture limited patient shares and gameronly modest
`marketsales.
`
`Drug safety has becomea primary consideration in medical practice
`following the unexpected developmentof fatal opportunistic infections in
`patients taking natalizumab, a development that prompted its temporary
`withdrawal from the U.S. market. Experts continue to be leery of
`natalizumab, and this guardedness oversafety has extended to emerging
`therapies, even thoughthese therapies have demonstrated adequate
`safety profiles thus far in development. This heightened awareness of
`the possibility of severe side effects will constrain uptake of new agents,
`relegating many of them to third- or fourth-line therapies.
`
`Reimbursement of MS therapies continues to constrain the market,
`particularly in Europe. Indeed, although natalizumab has been approved
`in all European markets we cover, reimbursement has bcen approved only
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`Multiple Sclerosis 2005-2020 :
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`in Germany. This problem is due to the high cost per year of the drug, and
`until reimbursement issues are resolved, the drug will not be administered
`unless patients are willing to pay out-of-pocket, as has occurred in the
`United States. Given the obstacles that natalizumab is facing, emerging
`“me-too” agents with similar safety and cost issues may also have
`difficulty receiving reimbursement approval.
`
`The launch of biogeneric versions of the IFN-B agents will contribute
`to losses in market and patient shares of the respective branded forms.
`However, biogenerics face developmental and regulatory hurdles that
`will delay their entry into the market, especially in the United States,
`where regulatory fraineworks have yet to be established. Once available
`on the market, their uptake will be modest; physician concerns over
`bioequivalence will likely be offset by the push from reimbursement
`agencies for biogeneric use.
`
`Whatare the drug developmentactivities of note in multiple
`sclerosis?
`
`Several drugs in the MSpipeline will fulfill a significant unmet need by
`offering the convenience of an oral formulation. The first oral agent to
`market will be Merck Serono’s oral cladribine, launching in the United
`States and Europe in 2010, but four otheroral agents will also launch
`during our study period: FTY-720, Sanofi-Aventis’s teriflunomide,
`Biogen Idec’s BG-12, and Teva/Active Biotech’s laquinimod, Despite the
`convenience oftheir oral formulations, their efficacy in MSis the key to
`their market success.
`
`The ost promising emerging agent is FTY-720. With its demonstrated
`efficacy (which appears superiorto that of the IFN-Bs and glatiramer
`acetate [Teva’s Copaxone] in PhaseII trials thus far), acceptable safety
`profile, and oral formulation, the drug will garner significant market and
`patient share following its launch, but it will not outperform all current
`therapies by 2020 because of concerns overits safety.
`
`Therapeutic options for CP-MS, which encompasses secondary-
`progressive MS (SP-MS) and primary-progressive MS (PP-MS),are
`limited because current therapies do not adequately address the neuronal
`degeneration characteristic of this type of MS. Two emerging agents are
`being positioned forthis patient population--BioMS Medical’s MBP-8298
`and rituximab (Biogen Idec/Genentech’s Rituxan)--although we do not
`expect rituximab to launchfor this indication.
`
`Current therapies face patent and exclusivity expiries during our forecast
`period. To temper the market decline of their branded agents, Bayer
`Schering Pharma/Berlex, Merck Serono, and Teva are developing follow-
`on products that are expected to offer comparable or improved efficacy,
`safety, and tolerability.
`
`Experts continue to clamor for agents that promote remyelination and/
`or provide neuroprotection. This prolonged interest in such drugs has
`prompted extensive researchthat is slowly translating into clinical trials.
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`Multiple Sclerosis 2005-2020
`
`
`Executive Summary
`
`What do the experts say?
`Highlights of the expert opinion that informs our analyses:
`
`* At the forefront of the minds ofall experts interviewed are concermms over
`the safety of natalizamab following the developmentoffatal opportunistic
`infections in patients taking natalizumab/Avonex combination therapy.
`These safety concers have led to restrictions in prescribing and
`administration of the drug and, in turn,are hurting its market uptake.
`Experts expect such heightened caution to continue. As one neurologist
`explains, ‘Now that it’s been re-released with new wamings, there are
`probably risks we haven’t seen yet. 1 think the use of Tysabri is going to
`be much, muchless than it would have been.”
`
`According to one Spanish expert, “In the future, the most important
`challenge is safety,” Natalizumab’s history has made experts acutely
`sensitive to the potential for severe side effects, and this concern has
`extended to emerging therapies. Most experts are withholding judgment
`on emerging therapies until clinical trial data are available. As one U.S.
`expert explains, “There is still going to be some caution. It’s going to
`depend on the safety during the clinical trial. Even if there aren’t any real
`safety issues that come up during the studies, I’m going to be cautious
`about using the drug because we don’t know what the long-tenn risks
`are.” Warns a U.K. expert, “Just because the drug gets through all of the
`very expensive and carefully controlled hurdles, it’s no guarantee that it is
`safe,”
`
`Experts are excited about FTY-720 because, as one expertstates, the
`drug is “probably the most promising and it’s the most interesting new
`mechanism.” The drug has demonstrated efficacy in clinical trials and has
`an oral formulation, but experts are wary of potentially severe side effects.
`This expert continues, “The only problemis the mechanismofaction
`indicates it blocks lymphocytes from migrating out of the lymph nodes
`and J think they’re going to run into the very sameset of problems that
`they ran into with Tysabri, namely opportunistic infections.”
`
`Oral formulations would provide patients with a more-convenient
`formulation, a significant advantage in a market of injectables. Although
`experts acknowledge the advantages oforal therapies, the majority of
`experts interviewed state that convenience is not the most important
`driving factorin their