多発性硬化症：経口薬の革命

Introduction

The launch of five novel orally administered disease-modifiers is set to revolutionize the multiple sclerosis (MS) market, which will more than double in value across the seven major markets from 2006 to reach $10.7 billion in 2016.

Scope

• Analysis of patient potential, unmet needs and clinical trial design in multiple sclerosis
• Overview of drugs in late- and early-stage clinical development; with analysis of key companies involved in the R&D pipeline
• Detailed profiles of key compounds in development for use in multiple sclerosis, with forecasts of drug revenues to 2016
• Discussion of Biogen Idec' s and Teva' s strategies and insight from key industry opinion leaders

Report Highlights

There is a significant need for a MS treatment with superior efficacy to current therapies with a less invasive and time-consuming route of administration. Novartis' s oral Fingolimod (FTY720) goes some way to meet these needs and represents the most highly anticipated pipeline drug since the initial launch of Tysabri in 2004.

Amid an increasingly competitive first-line therapy market, Datamonitor believes prospective players can gain competitive edge (and healthcare payer acceptance) by defining clear clinical differentiators in their trials. Head-to-head studies with a suitable comparator or showing benefit of add-on therapy represent two possible strategies.

Biogen Idec' s Rituxan (rituximab) and BioMS' s MBP-8298 are targeting the prevalent yet largely underserved primary progressive MS (PPMS) and secondary progressive MS (SPMS) indications. Datamonitor predicts that if Rituxan and MBP-8298 launch, then strong uptake can be expected.

Reasons to Purchase

• Understand unmet needs in the multiple sclerosis market based on key opinion leader comments
• Benchmark key late-stage disease-modifying multiple sclerosis compounds against current market leaders
• Assess the global (US, Japan, five major EU) sales forecasts of key late-stage pipeline drugs; and examine their clinical and commercial potential

Table of Contents

• 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