`Cognoswgmdy #9
`
`A Phatmacor Sewice
`
` ULHPLE gunman 2005—2020
`April 2007
`
`
`For questions regarding the report content and analysis. contact:
`Analyst: Bethany A. Kiernan, Ph.lJ.
`
`Tel +1.781.296.2631 it E-mail bkiernan@dresources.com
`
`Epidemiologist: Jessica Goelz Welch, M.P.H.
`Tel +1.781.296.2617 0 E-mail iwelch@dresources.com
`
`For questions regarding consulting, contact: Jim McDermott Tel +1.781.ZQE.2522 0 Email jmcdermotl@dresoutces.com
`
`For questions regarding sales. service, and technical support, contact:
`United States
`Europe
`Tel +1.781.296.2537 0 Fax +1.781.29h‘.2550
`Tel +32.2.357.UE.16 9 Fax +32.2.351.234Il
`
`Japan
`Tel +81.3.540L2615 0 Fax + 81354012517
`
`
`
`3i g
`
`3
`
`
`
`DEPOSITION
`as
`—LQ
`
`A DEClSlON RESOURCES publication
`DECISION RESOURCES is registered in the U. 3. Patent and Trademark Office.
`This material, prepared specifically for clients of Decision Resources, lnc., is furnished in confidence and is not to be duplicated outside of
`subscriber organizations in any form without our prior permission in writing. The opinions stated represent our interpretation and analysis of
`information generally available to the public or released by responsible individuals in the subject companies, We believe that the sources of
`information on which our material is based are reliable and we have applied our best professional judgment to the data obtained. We do not
`assume any liability for the accuracy, comprehensiveness, or use of the information presented.
`© 2007 Decision Resources, Inc. 0 260 Charles Street 0 Waltham, Massachusetts 02453 0 Tel +1 181.206.2500 0 Fax +1.781.206.2550
`
`Page 1 of 314
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`Torrent et at. v. Novartis
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`1 of314 |PR2014—00784/lPR2015-00518
`Novartis 2130
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`MGR-comm
`
`Biogen Exhibit 2210
`Mylan v. Biogen
`IPR 2018-01403
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`Page 1 of 314
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`Biogen Exhibit 2210
`Mylan v. Biogen
`IPR 2018-01403
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`

`

`Multiple Selero sis 2005—2020
`
`Table of Contents
`
`Executive Summary .....................................................2
`
`What are the key parameters of the multiple sclerosis market? .......................... 2
`What factors are driving the market for multiple sclerosis therapies? ..................... 3
`What factors are constraining the market for multiple sclerosis therapies? ................. 4
`What are the drug development activities of note in multiple sclerosis? .................... 5
`What do the experts say? ....................................................... 6
`What key challenges and opportunities remain? ...................................... 7
`
`1. Introduction ......................................................... 10
`
`Report Coverage ............................................................. 11
`Report Features .............................................................. 11
`
`2. Current and Emerging Drug Targets ..................................... 13
`
`Overview ................................................................... 15
`
`The Autoimmune Attack in Multiple Sclerosis ....................................... 17
`T Cells ................................................................. 17
`T-Cell Activation ...................................................... 17
`
`TH1 and TH2 Cells .................................................... 2U
`T—Cell Sell—Recognition and the Autoimmune Response in Multiple Sclerosis ...... 21
`T-Cell Migration and Entry into the Central Nervous System ................... 22
`The T-Cell—Mediated Inflammatory Reaction in the Central Nervous System ....... 24
`B Cells ........ , ........................................................ 25
`Antibodies in Multiple Sclerosis .............................................. 26
`Complement Cascade ..................................................... 26
`Chemokines ............................................................. 26
`
`Demyelination ............................................................... 2?
`Inhibition of Remyelination ................................................. 2?
`Axonal Degeneration and Neuronal Cell Death .................................. 29
`Neuroprotective Role of the immune Response ................................. 30
`
`3. Epidemiology and Disease Populations ..................................33
`Overview ................................................................... 34
`Disease Definition ............................................................ 35
`
`Methodology Overview ........................................................ 36
`Major-Market Profiles ......................................................... 41
`United States ............................................................ 41
`France ................................................................. 43
`
`Germany ............................................................... 44
`Italy ................................................................... 45
`Spain .................................................................. 46
`United Kingdom .......................................................... 47
`Japan .................................................................. 48
`Subpopulations .............................................................. 49
`Diagnosis and Drug—Treatment Rates ............................................ 50
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`Multiple Sclerosis 2005—2020
`
`4. Current Therapies and Treatment Trends .' ................................ 54
`
`Overview of Current Therapies .................................................. 56
`Recombinant Interferons ....................................................... 60
`Overview ............................................................... 60
`Mechanism of Action ...................................................... 60
`Formulation ............................................................. 60
`Interferon Beta-1b ........................................................ 61
`
`Interferon Beta—1a(IM) .................................................... 67
`Interferon Beta—1 a (SC) .................................................... 69
`Altered Peptide Ligands ....................................................... 72
`Glatiramer Acetate ........................................................ T2
`Monoclonal Antibodies ......................................................... 74
`Natalizumab ............................................................. 74
`
`Chemotherapeutics ........................................................... 80
`Overview ............................................................... 80
`Mechanism of Action ...................................................... 81
`Formulation ............................................................. 81
`Mitoxantrone ............................................................ 81
`
`Mycophenolate Mofelil ..................................................... 83
`Treatment Trends ............................................................ 84
`Overview ............................................................... 84
`
`Diagnosis and Referral ................................................ 84
`Treatment Guidelines ...................................... , .......... 87
`Pharmacological Treatment ............................................. 87
`Economic Issues ..................................................... 89
`
`Major-Market Profiles ..................................................... 89
`United States ........................................................ 89
`
`Europe ............................................................. 92
`Japan .............................................................. 95
`
`5. Development Hurdles and Treatment Challenges .......................... 98
`
`Evolution of Unmet Needs in Multiple Sclerosis ..................................... 99
`Reversing Neuronal Damage .................................................. 101
`Preventing Disease Progression ............................................... 102
`Improved Therapy for Chronic-Progressive Multiple Sclerosis ......................... 102
`More-Convenient Drug Delivery ................................................ 104
`Improved Diagnostic Criteria ................. -.................................. 105
`Improved Animal Models ..................................................... 106
`
`6. Emerging Oral Immunomodulatory Therapies ............................ 108
`
`Overview .................................................................. 109
`
`Emerging Oral Therapies Positioning ............................................ 110
`Oral Immunomodulators ...................................................... 113
`Overview .............................................................. 113
`Mechanism of Action ..................................................... 116
`FTY—720 ............................................................... 117
`BG—12 ................................................................ 121
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`Multiple Sclerosis 2005—202
`
`Laquinimod ............................................................ 122
`Simvastatin ............................................................ 125
`
`Oral Immunosuppressants .................................................... 127
`Overview .............................................................. 127
`Mechanism of Action ..................................................... 127
`Teritlunomide ........................................................... 127
`Oral Cladribine .......................................................... 130
`
`7. Emerging lnjectable lmmunomodulatory Therapies ....................... 135
`Overview .................................................................. 136
`
`Emerging Injectable Immunomodulatory Therapies Positioning ........................ 137
`Monoclonal Antibodies ........................................................ 139
`Overview .............................................................. 139
`Mechanism of Action ..................................................... 142
`Rituximab .............................................................. 143
`Daclizumab ............................................................ 145
`Alemtuzumab .......................................................... 147
`
`Altered Peptide Ligands ...................................................... 150
`Overview .............................................................. 150
`Mechanism of Action ..................................................... 151
`MBP-8298 ............................................................. 151
`
`Chemokine ReceptorAntagonists ............................................... 155
`Overview .............................................................. 155
`Mechanism of Action ..................................................... 156
`MLN~1202 ............................................................. 157
`
`T—Cell Receptor Vaccines ..................................................... 158
`Overview .............................................................. 158
`Mechanism of Action ..................................................... 158
`NeuroVax .............................................................. 158
`Tovaxin ............................................................... 160
`
`Peptide-Encoding DNA Plasmids ............................................... 162
`Overview .............................................................. 162
`Mechanism of Action ..................................................... 163
`BHT—3009 ............................................................. 163
`
`8. Emerging Neuroprotective and Remyelinating Therapies .................. 166
`Overview .................................................................. 167
`
`Emerging Therapies Positioning ................................................ 169
`Glial Growth Factors ......................................................... 170
`Mechanism of Action ..................................................... 170
`Recombinant Human Glial Growth Factor-2 ................................... 171
`
`AMPA Receptor Antagonists ................................................... 172
`Overview .............................................................. 172
`Mechanism of Action .................................................... 173
`E-2007 ................................................................ 173
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` Multiple Sclerosis 2005—2020
`
`9. Market Outlook ..................................................... 177
`
`Overview .................................................................. 178
`
`Emerging Therapies ..................................................... 200
`Emerging Oral lmmunomodulatory Therapies .............. ................. 201
`Emerging Injectable lmmunomodulatory Therapies ......................... 201
`Emerging Follow-On Products to CurrentTherapies ......................... 202
`Market Segmentation of Emerging Therapies .............................. 202
`Oral vs. Parenteral Formulations ............................................ 203
`
`Frequency ofAdministration and Compliance .................................. 204
`Drug-Class-Specific Trends ................................................... 205
`Recombinant lnten‘erons .................................................. 205
`Branded Interferons .................................................. 205
`
`Biogeneric Interlerons ................................................ 208
`Altered Peptide Ligands .................................................. 210
`Chemotherapeutics ...................................................... 211
`Oral Immunosuppressants ................................................ 211
`Monoclonal Antibodies .................................................... 212
`Oral Immunomodulators .................................................. 213
`
`Region-Specific Trends ....................................................... 214
`
`Appendix A. Bibliography—Multiple Sclerosis ............................. 217
`
`Appendix B. Market Forecast Methodology ................................233
`
`General Sources of Data ..................................................... 233
`
`Diagnosed and Drug-Treated Populations ........................................ 233
`Percentage Diagnosed ................................................... 233
`Percentage Drug-Treated ................................................. 234
`Agents lncluded in Our MarketAnalysis .......................................... 234
`General Statements About Pricing .............................................. 235
`Pricing Assumptions ......................................................... 235
`Japanese Price Adjustments ............................................... 236
`Dosing, Days of Therapy, and Compliance ................................... 236
`Generic Erosion ......................................................... 237
`
`Emerging Therapy Prices ................................................. 240
`
`Appendix C. Experts Interviewed—Multiple Sclerosis ......................... 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 .................................... 37
`
`Table 3-2.
`
`Key Sources for Epidemiology Estimates—Multiple Sclerosis ........................... 39
`
`Table 4—1.
`
`Comparison of Current Therapies for Multiple Sclerosis, 2007 ..........................57
`
`Table 4-2.
`
`Key Patent and Exclusivity Expiries of Drugs Used to Treat Multiple Sclerosis, 2007 ......... 59
`
`Table 4-3.
`
`Key Facts: Betaseron .......................................................... 6‘]
`
`Table 4-4.
`
`Comparative Efficacy of Multiple Sclerosis Therapies in Phase III Trials for RR-M S, 2007 ..... 62
`
`Table 4-5.
`
`Comparative Efficacy of Multiple Sclerosis Therapies in Phase III Trials for SP-MS, 2007' ..... 54
`
`Table 4-6.
`
`Comparative Efficacy of Multiple Sclerosis Therapies in Clinical Trials for Early—Stage
`MS, 2007 ................................................................... 65
`
`Table 4—7.
`
`Comparative Efficacy of Multiple Sclerosis Therapies in Clinical Trials for PP-MS, 2007 ...... 67
`
`Table 4—8.
`
`Key Facts: Avonex ............................................................ 68
`
`Table4—9. KeyFactszRebif.............................................: ................70
`
`Table 4-10. Key Facts: Glatiramer Acetate ................................................... 73
`
`Table 4-11. Key Facts: Natalizumab ........................................................75
`
`Table 4-12. Natalizumab Pivotal Trial Highlights ...............................................77
`
`Table 4—13‘ Key Facts: Mitoxantrone ........................................................ 82
`
`Table 4-14. Key Facts: Mycophenolate Mofetil ................................................ 83
`
`Table 6-1.
`
`Emerging Oral lmmunomodulatory Therapies in Development for Multiple Sclerosis, 2007 .
`
`. .114
`
`Table 6-2.
`
`Estimated Launch Dates for Key Late-Stage Emerging Therapies for the Treatment of
`Multiple Sclerosis, 200? ....................................................... 115
`
`Table 7-1
`
`Emerging Injectable lmmunomodulatory Therapies in Development for Multiple Sclerosis,
`2007 ...................................................................... 140
`
`Table 8—1.
`
`Emerging Neuroprotective Therapies in Development for Multiple Sclerosis, 2007 .......... 169
`
`Table 9-1.
`
`Sales of Drugs to Treat Multiple Sclerosis (All Pepulations) in the Major Pharmaceutical
`Markets, 2005-2020 .......................................................... 179
`
`Table 9-2.
`
`Sales of Drugs to Treat Relapsing»Remitting Multiple Sclerosis in the Major Pharmaceutical
`Markets, 2005-2020 .......................................................... 185
`
`Table 9—3.
`
`Sales of Drugs to Treat Chronic-Progressive Multiple Sclerosis in the Major Pharmaceutical
`Markets, 2005-2020 .......................................................... 191
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`Multiple Sclerosis 2005—2020
`
`Table B-1. Assumptions Behind the 2005 Multiple Sclerosis Market (All Populations) ................242
`
`Table B-2. Assumptions Behind the 2010 Multiple Sclerosis Market (All Populations) ................247
`
`Table B-3. Assumptions Behind the 2015 Multiple Sclerosis Market (All Pepulations) ................ 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 .............272
`
`Table B-8. Assumptions Behind the 2020 Relapsing-Remitting Multiple Sclerosis Market .............277
`
`Table B-9. Assumptions Behind the 2005 Chronic-Progressive Multiple Sclerosis Market ............282
`
`Table 8-10. Assumptions Behind the 2010 Chronic—Progressive Multiple Sclerosis Market ............ 287
`
`Table B-11. Assumptions Behind the 2015 Chronic~Progressive Multiple Sclerosis Market ............ 292
`
`Table 8-12. Assumptions Behind the 2020 Chronic-Progressive Multiple Sclerosis Market ............ 297
`
`Figure 2—1. Multiple Sclerosis immune Pathophysiology .
`
`.- ...................................... 18
`
`Figure 22. Two Independent Signals in T-Cell Activation ........................................ 19
`Figure 2-3. Migration of Activated T Cells into the Central Nervous System..........................23
`
`Figure 2-4. Demyelinating Plaques in Multiple Sclerosis ........................................ 28
`
`Figure 5-1. Unmet Needs: Attainment and Remaining Opportunity in Multiple Sclerosis ............... 100
`
`Figure 6-1. Select Multiple Sclerosis Franchises, 2007 ........................................ 111
`
`Figure 6-2. Multiple Sclerosis Patient Populations. 2007 ....................................... 112
`
`Figure 6-3. Pipeline Status of Oral Drugs by Class for Multiple Sclerosis .......................... 115
`
`Figure 7—1. Multiple Sclerosis Patient Populations, 2007 ....................................... 136
`
`Figure 7-2. Early-Stage Pipeline Status of lnjectable lmmunomodulatory Drugs by Class for Multiple
`Sclerosis ................................................................... 139
`
`Figure 7-3. Late-Stage Pipeline Status of lnjectable Immunomodulatory Drugs by Class for Multiple
`Sclerosis ................................................................... 139
`
`Figure 9-1. Multiple Sclerosis Therapies by Class, 2005 and 2020: Market Share .................... 198
`
`Figure 9-2. Drug Class Sales for Multiple Sclerosis, 2005-2020 .................................. 199
`
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`

`
`
`Pharmacor
`
`ULTTPLE SCLEROSis 2005—2020
`
`
`April 2007
`
`Executive Summary
`
`
`For questions regarding the report content and analysis. contact:
`Analyst: Bethany A. Kiernan, Ph.D.
`Tel +1.781.296.263‘| 0 E-mail bkiernan®dresourcescom
`
`Epidemiologist: Jessica Goetz Welch. M.F.H.
`Tel +1.78‘I.296.2617 0 E—mail iwelch@dresources.com
`
`For questions regarding consulting, contact: Jim McDermolt Tel +1.781.296.2522 0 E-mail inicdernlott®dresources.com
`
`For questions regarding sales, service, and technical support. contact:
`United States
`Europe
`Tel +1.781.296.2537 0 Fax +1.781.295.2550
`Tel +32.2357.UB.16 9 Fax +32.2.351.2347
`
`Japan
`Tel +81.3.5401.2615 0 Fax +81.3.54l]1.2617
`
`
`
`A DECISION RESOURCES publication
`DECISION RESOURCES is registered in the US Patent and Trademark Office.
`This materiat, prepared specificatty tor ciients of Decision Resources, Inc., is furnished in confidence and is not to be dupticated outside of
`subscriber organizations in any form without our prior permission in writing. The opinions stated represent our interpretation and analysis of
`in formation generatty avaitabte to the public or reteased by responsibte individuats in the subject companies. We betieve that the sources of
`information on which our materiat is based are reiiabte and we have appIied our best professionai judgment to the data obtained. We do not
`assume any Iiabitity for the accuracy, comprehensiveness, or use of the information presented.
`© 2007 Decision Resources, Inc. 0 260 Charles Street 9 Waltham. Massachusetts 02453 9 Tel +1.781.296.2500 9 Fax +1.781_296.2550
`
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`

` Multiple Sclerosis 2005-2020;
`
`Executive Summary
`
` Key Findings
`- We forecast modest sustained annual growth—2.7%—of the MS market from 2005 to 2015. Annual
`
`
`market growth will slow to 0.9% from 2015 to 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 sales in that year.
`
`' A drug's safety profile has become instrumental 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—72O (NovartisfMitsubishi Pharma's fingolimod) holds the greatest market potential of all emerging
`therapies for MS. Because of 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 MS patients. significant opportunity
`remains in this market. The MS community continues to call fordrugs that halt disease progression,
`promote remyelination and neuroprotection. and demonstrate improved safety, efficacy, tolerability,
`dosing regimens, and formulations.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`What are the key parameters of the multiple sclerosis market?
`
`
`
`
`. 524.700
`.
`Diagnosed patients: -
`
`
`
`316,000 EU:
`Treated patientsi
`
`JA:
`Phase II drugs:
`-
`
`
`
`'
`
`21
`
`
`
`
`
`
`
`4,
`:cja, ,
`A,
`.
`iastsmrrs'sausmtyfses __ ,,
`
`
`interferon—534a (Biagen ldec's Avonex)
`2013 (US); 2005 (EU); 2005 (JA)
`'
`'
`-
`. $13592 MM
`Glatiramer acetate (Teva Pharmace tical’s Copaxone) 2014 (US); 2015 EU); 2015 (JA)
`$1,006.93 MM
`-
`
`
`
`
`"
`' "
`'
`’
`:ctt'r‘rshriisitsifimss;
`'
`'
`
`
`Low
`
`Reversing neuronal damage
`,
`Preventing disease progression '2 ’
`Low
`Improved therapy for-chronic—progressive'MS
`Low
`-
`More—convenient drug delivery
`Low
`4
`
`nastiness, _1iij§;j‘-;jerfiéf§ihtjtrfh'é‘é'éi‘pis ,
`(Lse'hsh Date'fj».
`éé‘I-rao
`
`
`
`FTY—720 tNovartisIMitsubishi Pharma’s fingolimod)
`2010
`$750-‘i,000 MM
`
`MBP-BZQB tBioMS Medical)
`, 2011
`5250-500 MM
`
`
`
`.
`.
`Impact'on Market
`L
`..
`-
`25:2 Probabilit
`
`
`Relaunch of natalizumab (Biogen IdeclElan‘s Tysabri)
`+ + +
`Not applicable
`E
`in the United States and launch in Europe (2006)
`
`20
`
`
`
`
`
`
`
`..::-A$48.0"_MM_
`
`
`
`..,.
`
`G
`
`'
`
`High 4,
`
`-'
`
`-::
`
`3
`
`‘
`
`
`
`
`
`'
`
`
`
`Wow-m r2010: ——
`0. first
`was... 20101——
`Launch of follow-on products to interferon—[3 agents
`+
`High
`'
`and glatiramer acetate [2007-2009)
`E
`Launch of MBP~8298 for chronic-progressive MS
`(2011)
`Launch of biogeneric versions of the interferon«[5
`agents (2012—2014)
`
`+
`
`-
`
`Moderate
`
`High
`
`."
`;
`
`
`
`
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`

` Multiple Sclerosis 2005—202
`ExecutIve Summary
`
`
`
`Othera < 1 %
` Chemotherapeutics 1%
`
`Monoclonal antibodies 1%
`
`
`
`
`
`
`Altered
`peptide ligands
`
`Recombinant
`interferons
`
`2020
`Total:w$5.531h.§ MM
`
`Otherh <1 9%
`
`Oral
`immunomodulators
`
`
`
`
`
`
`
`
`
`
`
`
`Oral
`immunosuppressants
`
`Monoclonal
`antibodies
`
`Flecombinant
`nterferons
`
`Altered
`peptide ligands
`
`
`
`
`
`
`
`
`
`
`
`
`a._“0i:her"includes cortIcosterotds, azathioprine, and mycophenolate mofetil.
`b ’~'Other__" includescorticostéroids:andchemotherapeutics
`
`
`dd to 100 because Iof'rounding.
`gmgimmm, “'1 my
`Note Percentages may,
`
`
`
`
`What factors are driving the market for multiple sclerosis
`therapies?
`
`' The MS market is growing as a result ofincreased diagnosis rates, which
`are fueled by increased use of the McDonald criteria and magnetic
`resonance imaging (MRI) as well as diagnosis occurring earlier in the
`disease process.
`
`'
`
`Increasing drug—treatment rates 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 ofMS represent
`a significant commercial opportunity, and the interferon beta (IFN-B)
`agents are now approved for use in this population. In addition, therapies
`that launch during our study period will provide new therapeutic options,
`particularly to patients undersewed by current therapies, including early-
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`

` Multiple Sclerosis 2005—2020 .. ,. ., .
`
`
`
`
`Executive Summary
`
`stage MS patients, chronic—progressive MS (CF—MS) patients, and patients
`whose MS is refractory to or who cannot tolerate 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 market has historically 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 higher prices thanks to improvements in convenience or
`efficacy. As emerging agents compete with current therapies for patient
`share, their higher price points will drive sales growth.
`
`' Two therapies in particular will contribute significantly to market growth
`through 2020: natalizumab (Biogen ldec/Elan’s Tysabri) and FTY—720
`(Novartis/Mitsubishi Phanna’s fingolimod). With natalizumab’s relaunch
`in the United States and launch in Europe in 2006 and FTY—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 FTY—720, availability in an oral formulation.
`However, these drugs’ potential to trigger severe side effects will hamper
`uptake so that neither agent will achieve blockbuster status 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 are compliant with treatment
`will incrcase, driving market growth.
`
`What factors are constraining the market for multiple
`sclerosis therapies?
`
`' Despite experts’ demand for agents that are more efficacious at delaying
`disease progression, the majority of MS agents that we expect to launch
`during our study period have yet to demonstrate significant improvement
`in efficacy over most current therapies. As a result, most emerging
`therapies will capture limited patient shares and garner only modest
`market sales.
`
`' Drug safety has become a primary consideration in medical practice
`following the unexpected development of 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 over safety has extended to emerging
`therapies, even though these 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 been approved only
`
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`Multiple Sclerosis 2005-2020
`Executive Summary
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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 biogenerie versions of the IFN—B agents will contribute
`to losses in market and patient shares of the respective branded forms.
`However, biegeneries face developmental and regulatory hurdles that
`will delay their entry into the market, especially in the United States,
`where regulatory frameworks 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 biogenerie use.
`
`What are the drug development activities of note in multiple
`sclerosis?
`
`Several drugs in the MS pipeline will fulfill a significant unmet need by
`offering the convenience of an oral formulation. The first oral agent to
`market will be Merck Sereno‘s oral cladribine, launching in the United
`States and Europe in 2010, but four other oral 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 of their oral formulations, their efficacy in MS is the key to
`their market success.
`
`The most promising emerging agent is FTY-720. With its demonstrated
`efficacy (which appears superior to that of the IFN—Bs and glatiramer
`acetate [Teva’s Copaxone] in Phase II 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 outperfonn all current
`therapies by 2020 because of concerns over its safety.
`
`Therapeutic options for CP—MS, which encompasses secondary-
`progressive MS (SP—MS) and primary-progressive MS (PP—MS), ar