Report: Pipeline Insight: Multiple Sclerosis

CHAPTER 1 EXECUTIVE SUMMARY
- Scope of the analysis
- Key metrics
CHAPTER 2 MULTIPLE SCLEROSIS PIPELINE OVERVIEW AND DYNAMICS
- Pipeline overview
  - Oral disease-modifying drugs feature heavily in the late-stage MS pipeline
  - The majority of products are in development for RRMS
  - Oral formulations aiming to succeed in a solely injectable market
- Key companies involved in the multiple sclerosis pipeline
  - Current MS players look to offset mass competition with follow-up products
  - Biogen Idec committed to maintaining MS market leader status
    - Avonex and Tysabri provide Biogen Idec with leader status in MS market
    - Rituxan and BG-12 Phase III MS developments lead the way
    - Early-stage development products add depth to Biogen Idec' s MS pipeline
    - Biogen Idec' s MS pipeline products are split by class and delivery mechanism
    - In-licensing and collaborations essential to Biogen Idec' s future MS advancements
  - Teva looks to supplement its Copaxone franchise
    - Copaxone represents Teva' s first branded product and now boasts blockbuster status
    - Oral Copaxone is still many years away from market
    - Laquinimod replaces oral Copaxone developments as Teva' s front-running oral MS focus
    - Teva licenses Vaccinex' s VX-15 to strengthen its long-term MS developments
- Key R&D company strategies
  - Combination of oral administration with novel mechanism provides major competitive edge
  - Targeting SPMS and PPMS can reduce competition but will increase R&D challenge
  - In-licensing is increasingly important to secure long-term franchise growth
CHAPTER 3 MULTIPLE SCLEROSIS DISEASE OVERVIEW AND MARKET POTENTIAL
- Definition of multiple sclerosis
  - There is no universal course for multiple sclerosis
- Segmentation of multiple sclerosis
  - Researchers have attempted to classify multiple sclerosis according to the clinical course of the disease
- Epidemiology of multiple sclerosis
  - Young female adults are most at risk of developing MS
  - Genetic and environmental factors appear to play a role in the onset of MS
  - Over 800,000 individuals in the US, Japan and 5EU markets are estimated to suffer from MS
    - US
    - Japan
    - 5EU
  - The majority of patients suffer from relapse remitting multiple sclerosis
- Unmet needs in multiple sclerosis
  - Prevention and discovery of a cure are the ultimate goals in MS
  - Unmet need 1: improved efficacy
    - Improved disease modifying efficacy is the top unmet need in MS
    - The need for improved symptomatic efficacy remains an issue
  - Unmet need 2: improved side-effect profile
    - Improved side-effect profile is in joint second place as the highest unmet need below improved efficacy.
  - Unmet need 3: approval for a wider range of MS disease severities
    - Approval for a wider range of MS disease severities is regarded as a high unmet need
  - Unmet need 4: improved delivery method
    - The MS market is a solely injectable domain in need of a more less-invasive and user-friendly delivery method
  - Unmet need 5: fewer drug interactions
    - The ability to combine treatments depends on the drug-drug interactions
CHAPTER 4 R&D APPROACH
- Current treatment options
- Current treatment options
  - There are only six disease-modifying agents currently on the market
  - Across all stages of MS, 45% of total diagnosed patients do not receive disease-modifying therapy
  - RRMS and SPMS patients are most likely to recieve disease-modifying therapy
- Classification of pipeline products
  - Novel drug classes look to capitalize in a largely undifferentiated market
  - Cytokines
    - Interferons
    - Interleukin antibodies
    - Other cytokines
  - Immunomodulators
  - Myelin basic protein modulators
  - Dehydrogenase inhibitors
  - Human immunoglobulins
  - Therapeutic vaccines
  - Others
- Clinical trial design in multiple sclerosis
  - Approved MS disease-modifying drugs set the standard for future trial design
  - The revised McDonald criteria allows trials to include patients earlier in the course of their disease
  - Placebo-controlled MS trials might be considered unethical
  - A placebo control arm is essential in Phase III trials but less of an issue in Phase II trials
  - The SENTINEL and BEYOND trials provide alternative trial design
- Clinical trial endpoints in multiple sclerosis
  - Relapse rate
  - Disability/progression measures
    - Fatigue
    - Expanded disability status scale
    - Multiple Sclerosis Functional Composite
  - Health-related quality-of-life assessments
    - The Multiple Sclerosis Quality of Life-54 instrument
    - Multiple Sclerosis Impact Scale
    - Multiple Sclerosis Symptom and Impact Diary
  - MRI measures
    - Conventional MRI techniques to assess lesions
    - Advanced MRI techniques
    - Brain atrophy
CHAPTER 5 CYTOKINE LATE-STAGE DRUG ANALYSIS & FORECASTS
- Cytokine pipeline Overview
  - Pipeline summary
- Definition of current comparator therapy
  - MS disease-modifier ' gold-standard' is Avonex
    - Two key studies evaluated the clinical effectiveness of Avonex in MS
    - Contraindications and adverse reactions reported with the use of Avonex
    - Avonex' s major competitors and key strengths and weaknesses
- Interferon pipeline overview
  - Pipeline summary
    - There are two interferon drugs in the late-stage R&D pipeline for MS in 2007
- Alferon N injection (interferon alfa-n3)
  - Drug overview
  - Clinical trial data
    - Alferon N under Hemispherx
    - Retrospective, uncontrolled study
  - Drug evaluation
- Tauferon
  - Drug overview
  - Clinical trial data
    - Pre-clinical and Phase I
    - Phase II trial initiated
  - Drug evaluation
- Interleukin antibodies pipeline overview
  - Pipeline summary
    - There are three interleukin antibodies in the late-stage R&D pipeline for MS in 2007
- Daclizumab
  - Drug overview
  - Clinical trial data
    - Phase II open-label clinical studies
    - Phase II CHOICE study assessing daclizumab added to ongoing interferon-beta treatment
    - CHOICE study meets primary endpoint
  - Drug evaluation
- CNTO-1275
  - Drug overview
  - Clinical trial data
    - Phase I data show subcutaneous injection of CNT0-1275 is well tolerated
    - Patient recruitment completed in safety and efficacy Phase II trial
  - Drug evaluation
- ABT-874
  - Drug overview
  - Clinical trial data
  - Drug evaluation
- Other cytokines pipeline overview
  - Pipeline summary
    - There are four other cytokine drugs in the late-stage R&D pipeline for multiple sclerosis in 2007
- Rituxan (rituximab)
  - Drug overview
    - Rituxan was first approved for non-Hodgkin' s lymphoma in 1997
    - Ongoing developments of Rituxan in multiple indications
  - Clinical trial data
    - Positive 24-week ' HERMES' Phase II RRMS data
    - Results from Phase II/III PPMS OLYMPUS trial expected in H1-2007
    - Additional PPMS study in four patients shows Rituxan suppresses B-cells
  - Patient potential
  - Marketing potential
  - Satisfaction of unmet needs
    - Unmet need 1: improved efficacy
    - Unmet need 2: improved side-effect profile
    - Unmet need 3: approval for a wider range of MS severities
    - Unmet need 4: improved delivery method
    - Unmet need 5: fewer drug interactions
  - Forecasts to 2016
- Campath (alemtuzumab)
  - Drug overview
  - Clinical trial data
    - Early pilot MS studies
    - Suspension of Phase II RRMS CAMPATH MS 223 trial due to safety concerns
  - Drug evaluation
- ATL-1102 (ISIS-107248)
  - Drug overview
  - Clinical trial data
    - ATL-1102 proved well-tolerated through Phase I studies
    - Phase II ATL-1102 study in RRMS patients restarts after one-year suspension
    - Recent animal study supports the use of ATL-1102 in MS
  - Drug evaluation
- MLN1202
  - Drug overview
  - Clinical trial data
    - Results from Phase II trial in 40 RRMS patients set for H1-2007
  - Drug evaluation
CHAPTER 6 IMMUNOMODULATOR LATE-STAGE DRUG ANALYSIS AND FORECASTS
- Comparative forecasts
- Comparative Datamonitor drug assessment summaries
- Overview
  - Pipeline summary
    - There are four key immunomodulator drugs in the late-stage R&D pipeline for multiple sclerosis in 2007
- BG-12
  - Drug overview
  - Clinical trial data
    - BG-12 achieves primary endpoint in a 257- patient Phase II RRMS study
    - Phase III BG-12 MS clinical program includes the DEFINE and CONFIRM international trials that plan to enroll more than 2,000 patients
  - Patient potential
  - Marketing potential
  - Satisfaction of unmet needs
    - Unmet need 1: improved efficacy
    - Unmet need 2: improved side-effect profile
    - Unmet need 3: approval for a wider range of MS severities
    - Unmet need 4: improved delivery method
    - Unmet need 5: fewer drug interactions
  - Forecasts to 2016
- Laquinimod (SAIK-MS)
  - Drug overview
  - Clinical trial data
    - Phase I dose escalation study meets primary endpoint and identifies 1.2mg as being the maximum-tolerated daily dose.
    - Phase II trial primary endpoint met with laquinimod 0.3mg/day
    - 77% of patients remained relapse-free during Phase II investigation trial of laquinimod at a higher dose
    - Teva discusses Phase III Laquinimod clinical program plan with regulatory authorities on back of positive Phase IIb safety and efficacy results
  - Patient potential
  - Marketing potential
  - Satisfaction of unmet needs
    - Unmet need 1: improved efficacy
    - Unmet need 2: improved side-effect profile
    - Unmet need 3: approval for a wider range of MS severities
    - Unmet need 4: improved delivery method
    - Unmet need 5: fewer drug interactions
  - Forecasts to 2016
- Cpn10 (XToll)
  - Drug overview
  - Clinical trial data
    - Phase I studies demonstrate tolerability of Cpn10 IV infusion and SC injection
    - Undisclosed Phase IIa trial results meet set objectives
  - Drug evaluation
- GEM-SP
  - Drug overview
  - Clinical trial data
  - Drug evaluation
- TV-5010
  - Drug overview
  - Drug evaluation
CHAPTER 7 MYELIN BASIC PROTEIN MODULATOR LATE-STAGE DRUG ANALYSIS AND FORECASTS
- Overview
  - Pipeline summary
    - There are two myelin basic protein modulator drugs in the late-stage R&D pipeline for MS in 2007
- MBP-8298
  - Drug overview
    - The design of MBP-8298 includes MBP residues 85-96 plus amino acid extension at both ends
    - MBP-8298 apparently induces immunological tolerance to autoimmune targeting of MBP
    - The University of Alberta has been granted 88 worldwide patents concerning MBP-8298
  - Clinical trial data
    - An in-depth development program of MBP-8298 sees it currently progressing through three MS clinical trials
    - MBP-8298 showed a reduction of MBP autoantibody in the CSF in chronic progressive MS sufferers during Phase I studies
    - Positive Phase II chronic progressive MS study results paved the way for Phase III SPMS trials
    - The MAESTRO-01 & MAESTRO-03 Phase II/III clinical trials in SPMS patients
    - Commencement of MINDSET-01 Phase II RRMS trial as BioMS aims to advance MBP-8298 into a second indication
  - Patient potential
  - Marketing potential
  - Satisfaction of unmet needs
    - Unmet need 1: improved efficacy
    - Unmet need 2: improved side-effect profile
    - Unmet need 3: approval for a wider range of MS severities
    - Unmet need 4: improved delivery method
    - Unmet need 5: fewer drug interactions
  - Forecasts to 2016
- BHT-3009
  - Drug overview
  - Clinical trial data
    - Phase I MS trial of BHT-3009 as monotherapy or in combination with atorvastatin
    - Phase II RRMS trial initiated in February 2006
  - Drug evaluation
CHAPTER 8 DEHYDROGENASE INHIBITOR LATE-STAGE DRUG ANALYSIS AND FORECASTS
- Overview
  - Pipeline summary
    - There are two dehydrogenase inhibitor drugs in the late-stage R&D pipeline for MS in 2007
- Teriflunomide (HMR-1726)
  - Drug overview
  - Clinical trial data
    - Phase II proof-of-concept study with 179 MS patients
    - Pivotal Phase III study EFC6049 continues to recruit two years after initiation
    - Sanofi-Aventis discloses long-term Teriflunomide development plans and look to initiate combination studies and studies in early MS
  - Patient potential
  - Marketing potential
  - Satisfaction of unmet needs
    - Unmet need 1: improved efficacy
    - Unmet need 2: improved side-effect profile
    - Unmet need 3: approval for a wider range of MS severities
    - Unmet need 4: improved delivery method
    - Unmet need 5: fewer drug interactions
  - Forecasts to 2016
- CellCept (mycophenolate mofetil)
  - Drug overview
  - Clinical trial data
    - Phase III RRMS trial of CellCept as monotherapy or in combination with Avonex
  - Drug evaluation
CHAPTER 9 HUMAN IMMUNOGLOBULIN LATE-STAGE DRUG ANALYSIS AND FORECASTS
- Overview
  - Pipeline summary
    - There are two human immunoglobulin drugs in the late-stage R&D pipeline for MS in 2007
- Venilon
  - Drug overview
  - Drug evaluation
- Gamunex (IGIV)
  - Drug overview
  - Clinical trial data
    - Phase II trial in RRMS patients was started in 2002 and is now complete
  - Drug evaluation
CHAPTER 10 THERAPEUTIC VACCINE LATE-STAGE DRUG ANALYSIS AND FORECASTS
- Overview
  - Pipeline summary
    - There are two therapeutic vaccine drugs in the late-stage R&D pipeline for MS in 2007
- NeuroVax
  - Drug overview
  - Clinical trial data
    - Phase I data presented in the late 1990s showed potential for the TCR peptide vaccine
    - NeuroVax remains in Phase II trials, six years after studies began
  - Drug evaluation
- Tovaxin
  - Drug overview
  - Clinical trial data
    - Positive interim results from two Phase I/II clinical trials released in 2005
    - TERMS 150 patient Phase IIb trial initiated in August 2006
  - Drug evaluation
CHAPTER 11 OTHER LATE-STAGE DRUG ANALYSIS AND FORECASTS
- Comparative forecasts
- Comparative Datamonitor drug assessment summaries
- Overview
  - Pipeline summary
    - There are six drugs classified as other in the late-stage R&D pipeline for MS in 2007
- Mylinax (oral cladribine)
  - Drug overview
    - Mylinax awarded Fast Track status by FDA for relapsing forms of MS
  - Clinical trial data
    - Previous studies of injectable cladribine support the use of the drug in MS
    - Achievement of therapeutic drug blood levels led the way for Mylinax Phase III studies
    - Phase III CLARITY study recruits over 1,300 RRMS patients
    - Initiation of ONWARD study of Mylinax & new formulation of Rebif add-on treatment
  - Patient potential
  - Marketing potential
  - Satisfaction of unmet needs
    - Unmet need 1: improved efficacy
    - Unmet need 2: improved side-effect profile
    - Unmet need 3: approval for a wider range of MS severities
    - Unmet need 4: improved delivery method
    - Unmet need 5: fewer drug interactions
  - Forecasts to 2016
- Fingolimod (FTY720)
  - Drug overview
  - Clinical trial data
    - Positive Phase II trial data reported by Novartis in January 2005
    - Six-month Phase II trial data presented in June 2005 at the 15th European Neurological Society meeting in Vienna, Austria
    - 12-month Phase II data show sustained benefits and good tolerability of fingolimod
    - Positive 18-month and two-year data presented
    - Phase III FREEDOMS program and FTY720D2309 trial evaluating the daily dosing of FTY720 have been initiated
    - TRANSFORMS study
  - Patient potential
  - Marketing potential
  - Satisfaction of unmet needs
    - Unmet need 1: improved efficacy
    - Unmet need 2: improved side-effect profile
    - Unmet need 3: approval for a wider range of MS severities
    - Unmet need 4: improved delivery method
    - Unmet need 5: fewer drug interactions
  - Forecasts to 2016
- MN-166 (ibudilast)
  - Drug overview
  - Clinical trial data
    - One year Phase II efficacy data expected in Q107
  - Drug evaluation
- Firategrast (SB-683699; T-0047)
  - Drug overview
  - Clinical trial data
    - Phase II trials of SB-683699 suspended because of safety concerns
    - Phase II MS trial resumed in January 2007
  - Drug evaluation
- Oral E3 (Trimesta)
  - Drug overview
  - Clinical trial data
  - Drug evaluation
- E2007
  - Drug overview
CHAPTER 12 INNOVATIVE EARLY-STAGE PROJECTS
- Key Phase I and preclinical compounds in multiple sclerosis
- BalanCell
- Nanocort
CHAPTER 13 SYMPTOMATIC MULTIPLE SCLEROSIS PIPELINE
- Overview
  - Pipeline summary
- Fampridine-SR
  - Drug overview
  - Clinical trial data
- MCT-125
  - Drug overview
- Erythropoietin
  - Drug overview
BIBLIOGRAPHY
- Journals
- Websites
- Posters
APPENDIX A
- Methodology
  - Definition of the MS market
    - Estimated 2006 sales revenue
    - Product forecasts
    - Definition of a standard unit
    - Estimation of launch dates
    - Patent expiry and generic assumptions
    - Japanese market data
  - Additional information
- Contributing experts
- Report methodology
APPENDIX B
- About the CNS analysis team
- Disclaimer
- List of Tables
  - Table 1: Forecast key pipeline products for multiple sclerosis in the seven major markets ($), 2006-2016
  - Table 2: Disease-modifying pipeline drugs in Phase III development for multiple sclerosis, 2007
  - Table 3: Disease-modifying pipeline drugs in Phase II development for multiple sclerosis, 2007
  - Table 4: Biogen Idec' s pipeline multiple sclerosis drugs, 2007
  - Table 5: Teva' s pipeline multiple sclerosis drugs, 2007
  - Table 6: Prevalence of multiple sclerosis in the seven major markets, 2006
  - Table 7: The average rating of the clinical unmet needs in multiple sclerosis
  - Table 8: Key facts for marketed disease-modifying drugs for multiple sclerosis in the seven major markets, 2007
  - Table 9: Percentage of patients diagnosed with each stage of MS who receive disease-modifying drug therapy, 2006
  - Table 10: Expanded Disability Status Scale (EDSS) for multiple sclerosis
  - Table 11: Key interferon drugs in late-stage R&D pipeline for MS, 2007
  - Table 12: Biogen Idec' s Avonex: key facts
  - Table 13: Comparisons of the four leading MS disease-modifiers
  - Table 14: Key interferon drugs in late-stage R&D pipeline for multiple sclerosis, 2007
  - Table 15: Key interleukin antibody drugs in late-stage R&D pipeline for multiple sclerosis, 2007
  - Table 16: Key other cytokine drugs in late-stage R&D pipeline for multiple sclerosis, 2007
  - Table 17: Key events, approval and launch dates impacting Rituxan revenue forecasts for multiple sclerosis in the seven major markets, 2007-2016
  - Table 18: Key immunomodulator drugs in late-stage R&D pipeline for multiple sclerosis, 2007
  - Table 19: Key events and launch dates impacting BG-12 revenue forecasts in the seven major markets, 2007-2016
  - Table 20: Key events and launch dates impacting Laquinimod revenue forecasts for multiple sclerosis in the seven major markets, 2007-2016
  - Table 21: Key myelin basic protein modulator drugs in late-stage R&D pipeline for MS, 2007
  - Table 22: Key events, approval and launch dates impacting MBP-8298 revenue forecast for multiple sclerosis in the seven major markets, 2007-2016
  - Table 23: Key dehydrogenase inhibitor drugs in late-stage R&D pipeline for multiple sclerosis, 2007
  - Table 24: Key events and launch dates impacting Teriflunomide revenue forecasts for multiple sclerosis in the seven major markets, 2007-2016
  - Table 25: Key human immunoglobulin drugs in late-stage R&D pipeline for multiple sclerosis, 2007
  - Table 26: Key therapeutic vaccine drugs in late-stage R&D pipeline for multiple sclerosis, 2007
  - Table 27: Key other drugs in late-stage R&D pipeline for multiple sclerosis, 2007
  - Table 28: Key events and launch dates impacting Mylinax revenue forecast for multiple sclerosis in the seven major markets, 2007-2016
  - Table 29: Key events and launch dates impacting Fingolimod revenue forecast for multiple sclerosis in the seven major markets, 2007-2016
  - Table 30: Drugs in Phase I development for multiple sclerosis, 2007
  - Table 31: Drugs in clinical and pre-clinical development for multiple sclerosis, 2007
  - Table 32: Key drugs in late-stage R&D pipeline for symptomatic treatment of multiple sclerosis, 2007
  - Table 33: Estimation of launch dates by phase of development
  - Table 34: Estimated generic discounts by country, 2006
  - Table 35: Estimation of brand erosion by following patent expiry by country
  - Table 36: pipeline drug assessment weighting scale
- List of Figures
  - Figure 1: multiple sclerosis drug assessment summary for the seven major markets ($m), 2007-2016
  - Figure 2: Breakdown of the late stage pipeline by form of multiple sclerosis, 2007
  - Figure 3: Delivery method of multiple sclerosis pipeline drugs, 2007
  - Figure 4: Injection method of the 15 injectable multiple sclerosis pipeline drugs, 2007
  - Figure 5: Segmentation of multiple sclerosis
  - Figure 6: World distribution of multiple sclerosis
  - Figure 7: Percentage of diagnosed MS patients who suffer from each type of MS, 2006
  - Figure 8: Clinical unmet needs in multiple sclerosis according to KOLs, 2007
  - Figure 9: Percentage of patients diagnosed with each stage of MS who receive disease-modifying drug therapy, 2006
  - Figure 10: Breakdown of the late-stage multiple sclerosis pipeline by class, 2007

Pipeline Insight: Multiple Sclerosis - The oral revolution

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