2007 Research & Development Day
Boston, MA May 17, 2007
Fair Disclosure: Under “Reg FD,” the SEC has set out a series of regulations regarding selective disclosure of material non-public information. In an effort to comply with these regulations, we believe it is important to state at the outset that our presentation todaytoday will not address, nor will we answer any questions relating to, material non-public information.
The information we plan to share with you today includes only information that is already in the public domain and/or information that is not material. Forward Looking Statements
This presentation includes forward-looking statements about: – the size and growth of the markets for our products, – estimates of sales for our products, – our expected filings with regulatory agencies, – the anticipated development and timing of programs in our clinical pipeline,and – Potential new applications for currently marketed products. Forward-looking statements are subject to risks and uncertainties that could cause actual results to differ materially from those that we expect. Important factors that could cause our actual results to differ include our continued dependence on our two principal products, AVONEX and RITUXAN, the uncertainty of success in commercializing other products including the launch of TYSABRI, the occurrence of adverse safety events with our products, the failure to execute our growth strategy successfully or to compete effectively in our markets, our dependence on collaborations over which we may not always have full control, possible adverse impact of government regulation and changes in the availability of reimbursement for our products, problems with our manufacturing processes and our reliance on third parties, fluctuations in our operating results, our ability to protect our intellectual property rights and the cost of doing so, and the risks of doing business internationally.
For a description of the risks and uncertainties that could cause our actual results to differ, please refer to the statements under “Risk Factors” in Item 1A in our Annual Report on Form 10-K and subsequent Quarterly Reports on Form 10-Q filed with the Securities and Exchange Commission.
These forward-looking statements speak only as of the date of this presentation, and we do not undertake any obligation to publicly update any forward-looking statements, whether as a result of new information, future events, or otherwise.
Page 2 May 17, 2007 2007 R&D Day Agenda
Introduction Jim Mullen, CEO 8:30 – 8:35
R&D Overview Cecil Pickett, President R&D 8:35 – 8:45
Neurology Al Sandrock, SVP Neurology R&D 8:45 – 9:45
Break 9:45 – 10:00
Immunology Evan Beckman, SVP Immunology R&D 10:00 – 10:50
Hemophilia Alan Bitonti, SVP Syntonix 10:50 – 11:05
Oncology David Parkinson, SVP Oncology R&D 11:05 – 12:00
Wrap Up / Q&A Cecil Pickett, President R&D 12:00 – 12:15
Page 3 May 17, 2007 Jim Mullen CEO
Introduction Pipeline Progression since the Merger
Pipeline Transitions
Research to Development 1st in Human Late Stage Development • Anti-TWEAK mAb • Anti-BR-3 mAb • Lumiliximab CLL • αvβ6 • BIIB14 • Galiximab NHL • BR-3 Fc • HSP90 inhib BIIB021 • BG-12 MS • Anti-BR-3 mAb • Hu anti-CD20 mAb • RITUXAN® Neurology • CD40L PEG-Fab • LTβR-Fc and Immunology • Anti-Cripto DM4 mAb • Anti TAG-72 mAb* • Anti-IGF-1R mAb • CBE-11* • HSP90 inhib 3647 • IFNβ GD* • Neublastin • FcG-FcE*
Filings / Approvals
• Approval of TYSABRI® for RRMS • Filing of TYSABRI in Crohn’s Disease • Approval of expanded RITUXAN oncology label • Approval of RITUXAN for RA in TNF-IR
* Denotes a discontinued program Page 5 May 17, 2007 Leveraging our Existing Assets
Oncology Neurology RITUXAN MS NHL Daclizumab MS Galiximab HSP90 Inhibitors MS NHL Solid Tumors BIIB14 Parkinson’s Lumiliximab BG-12 Parkinson’s CLL TYSABRI MS TYSABRI CDP323 Volociximab (M200) Oncology MS MS Solid Tumors
BR3-Fc LTβR-Ig Aviptadil RA TYSABRI PAH RA Crohn’s rFactor IX & VIII FUMADERM® Hemophilia Adentri 2nd Generation Psoriasis Heart Failure anti-CD20 BG-12 Immunology Psoriasis RA New Specialty Markets
Page 6 May 17, 2007 Select R&D Accomplishments since Merger
Pipeline advancements • 2 product launches (TYSABRI in MS and RITUXAN in RA and expanded oncology label) • 4 programs into late stage development • 8 programs into first in human trials • 10 programs from research into development
Corporate restructuring to enable external growth • 7 deals completed
Hiring of key talent
Creation of therapeutic areas to closely link discovery to development
Page 7 May 17, 2007 Cecil Pickett, Ph.D. President, Research and Development
Research and Development Overview Biogen Idec’s R&D Strengths
• Strong R&D fundamentals – World class biotherapeutic discovery and development organization
• Focused drug discovery efforts – Neurology – Immunology – Oncology
• Strong link between discovery research, clinical development, and strategic business units
• Proven track record of discovering and developing innovative molecules
• Extensive biologic manufacturing expertise
Page 9 May 17, 2007 R&D Strategy and Execution
• Focus on the discovery and development of novel therapeutics to address areas of high unmet medical needs – Internal discovery and external business development – Innovative first-in-class molecules as well as best-in-class molecules
• Conduct scientifically rigorous clinical proof of concept experiments to make quick go/no decisions
• Execute pivotal registration programs with a global clinical operations organization
Page 10 May 17, 2007 Opportunities to Improve R&D
Expanding our Capabilities Improving Productivity
• Broaden our core discovery and • Increase the number of development development capabilities candidate recommendations • Biologics and small molecules • Expand our small molecule capabilities • Internal discoveries and external • Focus on structure-based drug opportunities design • Enhance drug metabolism and • Improve the development process via formulation support for small a high through-put development molecules initiative • Accelerate first in human studies • Accelerate initiation of pivotal clinical studies • Reduce time between phase transitions • Develop a R&D sourcing strategy
Page 11 May 17, 2007 2007 R&D Day Agenda
Neurology Al Sandrock, M.D., Ph.D. 8:45 – 9:35 Q&A 9:35 – 9:45
Break 9:45 – 10:00
Immunology Evan Beckman, M.D. 10:00 – 10:40 Q&A 10:40 – 10:50
Hemophilia Alan Bitonti, Ph.D. 10:50 – 11:00 Q&A 11:00 – 11:05
Oncology David Parkinson, M.D. 11:05 – 11:50 Q&A 11:50 – 12:00
Wrap Up and Q&A Cecil Pickett, Ph.D. 12:00 – 12:15
Page 12 May 17, 2007 Al Sandrock, M.D., Ph.D. SVP, Neurology R&D
Neurology Pipeline Neurology R&D Pipeline
Multiple Sclerosis –BG-12 for MS –RITUXAN for MS –Daclizumab for MS –CDP323 (Oral VLA-4) for MS –LINGO for MS –PML Risk Mitigation
Other Neurologic Diseases –BIIB14 for Parkinson’s Disease –Neublastin for Neuropathic pain
Page 14 May 17, 2007 Stages of MS MS Lesion Types
Time since disease onset
Inflammation (interferon-sensitive) conduction block, demyelination, “bystander” axonal injury Degeneration (interferon-resistant) loss of neurons/axons
Relapsing- Secondary Remitting Progressive
Lesion 1. T cells + macrophages Types 2. Type 1 + Ab and complement 3. Distal oligodendrogliopathy 4. Oligodendrocyte apoptosis
Page 15 May 17, 2007 Pathophysiology of MS
Page 16 May 17, 2007 Neurology Strategy Overview
Continue to develop therapeutics to maintains Biogen Idec’s leadership position in the MS market – While MS market is large and competitive, significant unmet patient need still exists – Several mechanisms of action have a part to play in the pathology of MS thus creating the opportunity to develop multiple therapies – Biogen Idec goal is to leverage its significant expertise and KOL network to discover and develop multiple MS therapies
Expand beyond MS into other global specialty markets in neurology with significant unmet medical need
Page 17 May 17, 2007 BG-12 for Multiple Sclerosis
Page 18 May 17, 2007 BG-12 Activates the Nrf2 Pathway Protecting Cells Against Damage Caused by Oxidative Stress
Keap1 Nrf2 - Detox Enzymes - Antioxidant Enzymes Nrf2 - NADPH Generating Enzymes Maf - GSH Biosynthesis Enzymes X Jun - Chaperones ATF4 - Ubiquitination/Proteasome Nrf2 ARE
- Detoxification Nucleus - Normalization of energy metabolism - Repair/degradation of damaged proteins
Page 19 May 17, 2007 BG-12 Activates the Nrf2 Pathway Protecting Cells Against Damage Caused by Oxidative Stress
O
O O
O BG-12
- Detox Enzymes - Antioxidant Enzymes Keap1 Nrf2 - NADPH Generating Enzymes Maf - GSH Biosynthesis Enzymes Jun - Chaperones ATF4 - Ubiquitination/Proteasome Nrf2 ARE Keap1
- Detoxification Nucleus - Normalization of energy metabolism - Repair/degradation of damaged proteins
Page 20 May 17, 2007 BG-12 in RRMS Phase 2b Study Design
Blinded Placebo-Controlled Blinded Safety-Extension Treatment Phase Phase Screening Placebo BG-12 240 mg tid (720 mg/day) BG-12 120 mg qd (120 mg/day) Randomization BG-12 120 mg tid (360 mg/day) n=256
BG-12 240 mg tid (720 mg/day)*
4 8 12 16 20 24
24 weeks 24 weeks *Patients 120 mg tid during the first week to determine tolerability
Page 21 May 17, 2007 BG-12 in RRMS Phase 2b Trial Results
New Gd+ Lesions (Weeks 12 to 24) 6 Pre-Specified Primary End Point
5
4
3 69% P<0.001 2
1 n=54 n=59 n=56 n=54
Mean Number of New Gd+ Lesions Mean Number 0 Placebo 120 mg qd 120 mg tid 240 mg tid Treatment Group
Page 22 May 17, 2007 BG-12 in RRMS Phase 2b Trial Results
Relapse Efficacy
Treatment Group Placebo 120 mg qd 120 mg tid 240 mg tid n=65 n=64 n=64 n=63
Annualized relapse rate 0.66 0.42 0.78 0.44 (95% CI)* (0.43, 1.01) (0.24, 0.71) (0.52, 1.16) (0.26, 0.76)†
% relapse-free patients 69 78 64 71
CI=confidence interval; qd=once daily; tid=three times daily *ITT population, rate adjusted for number of relapses in 12 months prior to study †32% reduction vs placebo
Page 23 May 17, 2007 Safety Conclusions
• B-12 was generally safe and well tolerated. • Common AEs associated with BG-12 include headache, GI symptoms and flushing. • Similar proportion of patients with SAEs in placebo and BG-12 groups. • Similar incidence of infections between groups. • Reversible ≥3X ULN transaminases seen in 8 BG-12 treated patients.
Page 24 May 17, 2007 DEFINE Phase 3 Clinical Trial
Year 1 Year 2
BG-12 PO 240 mg tid (720 mg/day total, 2 capsules x 3 times a day)
Open Label AVONEX® (Interferon beta- 1a) Randomization 1:1:1 BG-12 PO 240 bid (480 mg/day total, 2 capsules x 2 times a day) ~1,000 patients
Placebo
EDSS √ √ √ √ √ √ √ √ √ MSFC √ √ √ √ √ √ √ √ √
0 12 24 36 48 60 72 84 96
48 weeks 48 weeks
Page 25 May 17, 2007 CONFIRM Phase 3 Clinical Trial
Year 1 Year 2
BG-12 PO 240 mg tid (720 mg/day total, 2 capsules x 3 times a day)
Open Label AVONEX® (Interferon beta- 1a)
BG-12 PO 240 bid (480 mg/day total, 2 capsules x 2 times a day) Randomization 1:1:1:1 ~1,200 patients Copaxone® 20 mg/day SC injection
Placebo
EDSS √ √ √ √ √ √ √ √ √ MSFC √ √ √ √ √ √ √ √ √
0 12 24 36 48 60 72 84 96
48 weeks 48 weeks
Page 26 May 17, 2007 BG-12 Summary
Molecule • Dimethyl Fumarate
Formulation • Enterically coated drug in capsule; oral administration
Molecular • Activates Nrf2 signaling pathway, essential for immune homeostasis and cellular defense Hypothesis • Inhibits NFkB and pro-inflammatory cytokine signaling
Therapeutic • Combination of cytoprotective and anti-inflammatory properties Hypothesis not provided by current or emerging MS therapeutics
Potential • MS, Psoriasis, RA, Psoriatic Arthritis, ALS, Alzheimer’s, Indications Parkinson’s
Stage/Status • MS: Two Ph. 3 trials initiating
Partnership / • Acquired partner Fumapharm AG June 2006 Alliances
Page 27 May 17, 2007 RITUXAN for Multiple Sclerosis
Page 28 May 17, 2007 RITUXAN Mechanism of Action
Rituximab ADCC Macrophage, monocyte, or natural killer cell
CD20 FcγRII, FcγRIII
Cell lysis
CDC Complement activation (C1qC1rC1s)
MAC B cell CD20
Cell lysis
Apoptosis
ADCC = antibody-dependent cellular cytotoxicity. CDC = complement-dependent cytotoxicity. Page 29 May 17, 2007 RITUXAN Phase 2 Study Design
Screen (4 wks) Treatment period (48 wks)
MRI
Primary Endpoint
Secondary Endpoint
Week -40 2 4 12 16 20 24 28 36 48
Wk 4 MRI to evaluate safety Rituximab Secondary Endpoint Infusion Primary Endpoint Total number of Gd-enhancing Proportion of patients relapsing Wks 0-24 New Gd-enhancing lesions lesions at Wks 12, 16, 20, and 24 T2 lesion volume changes B/L-Wk 24
2:1 Randomization and stratified by Site, EDSS ≤2.5, >5), and prior therapy (none or stopped ≥6 months or in past 6 months)
Page 30 May 17, 2007 RITUXAN Phase 2 Study Results
• In patients with RRMS, treatment with rituximab led to significantly (p<0.0001) fewer inflammatory brain lesions over 6 months compared with placebo — a 91% relative reduction
• The proportion of patients with relapses during 24 weeks was also significantly reduced in the rituximab-treated group compared with placebo (P=0.0238) — a 58% relative reduction
• A significant (P=0.0077) reduction from baseline to Week 24 in T2 lesion volume
• These benefits were achieved with no evidence of new safety signals
• These data provide proof of principle that B cells play a role in the pathophysiology of RRMS
Page 31 May 17, 2007 RITUXAN Development Status
• Phase 2/3 study in PPMS ongoing – Randomized, double-blind, placebo-controlled study – Patients randomized to receive: • Rituximab 1000 mg IV on days 1 and 15 (every 6 months) • Placebo on days 1 and 15 (every six months) – Primary endpoint: • Time to confirmed EDSS progression at week 96 – Completed enrollment in Q4 2005 – Data expected H1 2008 • Phase 2 or 3 in RRMS planned for Ocrelizumab late 2007/early 2008
Page 32 May 17, 2007 RITUXAN Summary
Molecule • Chimeric mouse/human antibody directed against the CD20 antigen expressed on human B-cells.
Formulation •IV
Molecular • Selectively depletes B cells Hypothesis
Therapeutic • Elimination of CD20 positive B-cells reduces or eliminates Hypothesis inflammatory cascades and interactions with T-cells
Potential • Current: RA • Potential: Lupus Nephritis, Systemic Lupus Erythematosus, Indications ANCA-Associated Vasculitis, PPMS, RRMS • Approved in combination in RA for TNF inadequate responders Stage/Status • RA DMARD-IR (Ph III), SLE (Ph II/III), LN (Ph III), PPMS (Ph II/III), AAV (Ph II/III)
Partnership / • Collaboration with Genentech Alliances
Page 33 May 17, 2007 Daclizumab for Multiple Sclerosis
Page 34 May 17, 2007 JL15 Daclizumab Mechanism of Action
• IL2R composed of 3 subunits (α = CD25, β = CD122, γ = CD132) • All three subunits required for high-affinity IL-2R signaling (1pM) • Daclizumab abrogates formation of high-affinity IL-2R • Cells that express β- and γ-chains are still capable of IL-2 signaling via the intermediate affinity IL-2 receptor (100pM – 1 nM)
Page 35 May 17, 2007 Slide 35
JL15 Recreate; show NK cell function Jillian Licata, 2/27/2007 Daclizumab CHOICE Add-on Trial Design Screening Randomize Follow-up Period (No Dac)
MRI:
Week 0 4 8 12 16 20 24 34 44 72
Patients 24 weeks 48 weeks on IFN-b 24 weeks 48 weeks
230 Subjects 1:1:1 2 mg/kg q 2 wks Primary Efficacy 1 mg/kg q 4 wks Placebo Endpoint
Trial met primary end point and results will presented at an upcoming medical meeting in H2 2007
Page 36 May 17, 2007 Daclizumab SELECT Monotherapy Trial Design
Screening Follow-up Period (No Dac) Randomize
MRI:
Week 0 4 8 12 16 20 24 48 72
24 weeks 24 weeks 24 weeks
297 subjects 300mg q 4 wks 1:1:1 150mg q 4 wks 300mg q 4 wks Placebo q 4 wks- 150mg q 4 wks If a relapse is confirmed Placebo q 4 wks then IFN is acceptable concomitant medication
Page 37 May 17, 2007 Daclizumab Summary
Molecule • Humanized antibody against IL2 receptor
Formulation • Injectable
Molecular • Binds to the alpha subunit of the IL-2 receptor Hypothesis
• Inactivation of pathogenic T cells will result in disease Therapeutic modifying activity in multiple immune related disorders. Hypothesis
Potential • MS, Asthma, Transplant and other immune disorders. Indications • Phase 2 in multiple sclerosis. SELECT monotherapy to start Stage H2 07. CHOICE combo data presentation H2 07. Partnership / Alliances • Collaboration with PDL Biopharma
Page 38 May 17, 2007 CDP323 (Oral VLA-4 Inhibitor) for Multiple Sclerosis
Page 39 May 17, 2007 CDP323 Program Summary
• Oral agent in validated pathway • To date, 3 Phase 1 studies done in 75 healthy volunteers – Preliminary safety and tolerability up to 1000mg bid for 7 consecutive days –PK –PD • Inhibition of VCAM binding to α4 integrins can be maintained throughout a 12 or 24 hour dose interval at dose levels well tolerated by human subjects • Short half life increases potential for additional indications • Phase 2 studies slated to start in Q2 2007 • Partnership with UCB
Page 40 May 17, 2007 LINGO
Page 41 May 17, 2007 Lesions of MS
Source: New England Journal of Medicine Page 42 May 17, 2007 LINGO is a Negative Regulator of Oligodendrocyte Myelination
25 P < 0.001 ** 20
15
10 (% of total) of (%
Control RNAi 5 Mature oligodendrocytes Mature
0 No RNAi Control RNAi LINGO-1RNAi LINGO-1 RNAi Control Control RNAi
LINGO-1 LINGO-1 RNAi
β-actin
Page 43 May 17, 2007 LINGO is Expressed by Oligodendrocyte Progenitor Cells in MS Lesions
Alain Chedotal Page 44 May 17, 2007 Inhibition of Oligodendrocyte Differentiation in MS
Neural Stem Cell Oligodendrocyte Premyelinating Myelinating Oligodendrocyte Progenitor Oligodendrocyte
bFGF/EGF PDGF/bFGF
Shh CNTF/T3 MS
Page 45 May 17, 2007 Anti-LINGO Promotes OPCs Differentiation (In vitro) and Myelin Repair in Rat MOG EAE Model (In Vivo) Control Anti-LINGO
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Page 46 May 17, 2007 An antibody to LINGO may promote myelin repair in MS
Neural Stem Cell Oligodendrocyte Premyelinating Myelinating Oligodendrocyte Progenitor Oligodendrocyte
bFGF/EGF PDGF/bFGF Shh CNTF/T3 Anti-LINGO-1 Mab
Page 47 May 17, 2007 Systemic Delivery of anti-LINGO Promotes Myelin Repair in Lysolecithin Demyelination Model
Control Hu-IgG2 Anti-LINGO
anti- Lysolecithin LINGO, i.p. IHC
day 0 day 1 day 7
Page 48 May 17, 2007 Anti-LINGO promotes OPC Differentiation in vitro
Control Antibody Anti-LINGO
Page 49 May 17, 2007 LINGO Summary
• LINGO, a protein on the cell membrane of neurons and oligodendrocytes, is a negative regulator of myelination
• Blocking LINGO could enhance remyelination in MS lesions
• IND expected H2 2008/2009
Page 50 May 17, 2007 Multiple Approaches to MS Therapeutics
Natalizumab/ Rituximab CDP 323 BG00012
Daclizumab
IFNβ-1a
Anti-LINGO-1 IFNβ-1a
Page 51 May 17, 2007 PML Risk Mitigation
Page 52 May 17, 2007 5 Key Initiatives
Determination of PML risk: 1. Assessment of potential risk factors for PML development in HIV+ population – Assess whether also applies to MS patients receiving TYSABRI 2. Investigation of markers of cellular immune status as predictors of an increased risk – Investigate effect of TYSABRI on immune system Management of PML: 3. Discovery of early diagnostic markers of PML in HIV+ population – Validation for MS TYSABRI patients 4. Rapid Removal of TYSABRI via plasmapheresis to allow immune reconstitution and arrest of PML progression 5. Finding of an effective anti-JCV therapy
Page 53 May 17, 2007 Discover PML risk factors and/or early diagnostic markers in HIV+ population
Retrospective analysis of longitudinal samples from HIV+ patients for two years prior to PML
JCV envelope VP1 pentameric structure and genetic polymorphism
Top view Side view
At least one mutation in 80% of PML samples(n=52); 0% in non-PML samples(n=253)
If confirmed, may help to identify persons at enhanced PML risk or be used as early diagnostic marker of PML
Page 54 May 17, 2007 Investigate markers of cellular immune status as predictors of an increased risk
1. Evaluate immune status using Cylex® assay in patients while receiving or after stopping immunosuppressive drugs
Cylex® assay status in transplant patients 2. Correlate the results to: – Specific immunosuppressant – Duration of that therapy – Time since discontinuation of therapy
3. If the results are compelling we will recommend it as a test for patients coming off immunosuppressive drugs prior to starting TYSABRI
Page 55 May 17, 2007 5HT2a Blockers as Potential anti-JCV Therapy
5HT2a blocker Inhibition of human glial cells infection by JC Virus
100 Mianserin 90 (IC50=0.01uM) 80
70
60
50
40
30
20
10
0 no drug 0.01 0.1 1 10 25 50 Drug Concentration (uM) Dr. Atwood, Brown University; unpublished O’Connor, K.A. & Roth, B.L. Nat. Rev. Drug Discov. (2005)
• Safe drugs, large number are on the market • Excellent biodistribution in the brain
Page 56 May 17, 2007 Therapeutic Potential of JCV Specific siRNA
• Demonstrated JC virus suppression by JCV specific siRNA in vitro • Demonstrated effective siRNA delivery to oligodendrocytes in vivo • Options for delivery of RNAi therapeutic • Direct intraparenchymal administration • Systemic with hyperosmotic blood brain barrier disruption
Cleavage
(A)n JCV mRNA
The siRNA would “save” Limit the damage to myelin “Save” the patient uninfected oligodendrocytes
Page 57 May 17, 2007 Example of an Emergency Treatment Protocol for PML in a TYSABRI patient
Scenario 1: No change in lesion size, Gd-, clinically stable → follow Scenario 2: No change in lesion size, Gd+, clinically stable → follow Scenario 3: +/- change in lesion size, Gd+, clinically worse → steroids Scenario 4: Increase in lesion size, Gd-, clinically worse → siRNA
Suspicious clinical event
Tysabri Plasma Exchange
MRI weekly 5HT2a receptor antagonist
Page 58 May 17, 2007 Long-term Expanding within the MS = Strategy = Marketplace and Beyond
Core MS Products • AVONEX • TYSABRI • JCV research
Expanded MS Portfolio • BG-12 Core MS Expanded MS Beyond MS Maximize share of Develop pipeline Develop pipeline • RITUXAN MS spend (internal/external) INTO “High Impact” • Daclizumab Neurology Areas • CDP323 Focus on effectiveness • LINGO
Beyond MS • Parkinson’s • Neuropathic Pain • Alzheimer’s • etc
Page 59 May 17, 2007 BIIB14 (Adenosine A2a Receptor Antagonist) for Parkinson’s Disease
Page 60 May 17, 2007 Parkinson’s Disease
• Disease Characteristics • Tremor, slow movement, rigidity, balance problems • Average 15 year progression from Stage I (mild) to V (severe) • Unmet Need • Current therapy is symptomatic; L-dopa and DA agonists are effective for a while but efficacy wanes over time • L-dopa and DA agonists are associated with nausea, orthostatic hypotension, and hallucinations; can cause drug-induced dyskinesia. •Market • ~1.9 million PD patients in US and EU • BIIB-targeted neurologists write 50-60% of all PD scripts
Page 61 May 17, 2007 The Therapeutic Window for Dopamine Replacement Therapies narrow over time
Efficacy
Side effects
0 5 10 15
Diagnosis Years Early Stage Late Stage
Page 62 May 17, 2007 Parkinson’sNormalParkinson’s Basal Disease Ganglia +Disease A2a Circuitry Antagonist
CerebralCerebral CortexCortex
StriatumStriatum (Putamen) (Putamen) D1 D2 Dopamine VA/VLVA/VL
GPeGPe STNSTN SNcSNc
GPi/SNrGPi/SNr Spinal cord
Page 63 May 17, 2007 BIIB14 Ph. 2a Early Stage PD Trial Design
Randomized, Double-Blind, Dose Escalation Study
BIIB14 10 mg Placebo
BIIB14 30 mg Placebo ***Safety Tolerability BIIB14 30-100 mg Placebo Activity
BIIB14 100 mg Placebo
8 weeks treatment
Page 64 May 17, 2007 BIIB14 Ph. 2a Late Stage PD Trial Design
PART A: Randomized, PART B: Parallel - Group Double-Blind Dose Escalation Dose Exploration
BIIB14 10 mg Placebo MTD
BIIB14 30 mg Placebo MTD - 1
BIIB14 100 mg Placebo Placebo
Max Tolerated Dose Safety, Tolerability, (MTD) Activity
2 weeks treatment 8 weeks treatment
Page 65 May 17, 2007 BIIB14 Summary
Molecule • Novel small molecule with high potency and specificity
Formulation • Once daily, oral administration
Molecular • Antagonizes A2a receptors in the striatum, which is Hypothesis clinically relevant in Parkinson’s Disease
Therapeutic • Synergistic with L-dopa, or as mono-therapy Hypothesis • Other A2a antagonists shown effective in Parkinson’s
Potential • Parkinson’s Disease Indications
Stage • Ph. 2 initiation Q2 2007
Partnership / • In-licensed from Vernalis 2004 Alliances
Page 66 May 17, 2007 Neublastin for Neuropathic Pain
Page 67 May 17, 2007 Post-Diabetic/Post-herpetic Pain Commercial Context
Disease Characteristics - Chronic pain associated with inability to work/sleep - Typically chronic, persisting for months to years - Significant impact on quality of life Unmet Need - Current therapies are symptomatic and results in significant pain relief in only ~40%-50% of patients, not disease modifying - Gabapentin associated with sedation, dizziness Market - ~440K post-diabetic/post herpetic pain target patient population - Two-thirds of target patients estimated to be treated at neurologist and pain specialists
Page 68 May 17, 2007 The GDNF Family and their Receptors
GDNF NTN NBN PSP
RET RET RET RET
GFR 2 GFRα3 GFRα 1 α GFRα 4 (RETL2) (RETL3) (RETL1) (RETL4) avian only
Page 69 May 17, 2007 Neublastin is Neurotrophic for Sensory Neurons
Plate dissociated sensory 7d IHC for βIII-tubulin; neurons into NBN count labeled neurons
Control 250
200
150
NBN 100
50
0 0 0.1 1 3 30 100 50 50 [NBN (ng/ml)] NGF GDNF
Page 70 May 17, 2007 Neublastin receptor is selectively localized to pain sensory neurons
Tissues Ret GFRα1 GFRα2 GFRα3 PNS Retina +++ +++ + Trigeminal ganglia +++ +++ ++ ++ Superior cervical ganglia +++ +++ ++ Dorsal root ganglia +++ ++ ++ ++ Spinal cord Dorsal ± + + Ventral +++ +++ + Brain Hypothalamus + +++ + Thalamus Reticular ++ +++ ++ Ventral medial + +++ ++ Substantial nigra +++ +++ Amygdala ++ ++ ++ Systemic administration of therapeutic doses of NBN has not been associated with weight loss in animals.
Page 71 May 17, 2007 Reversal of Neuropathic Pain is Maintained in Long-Term
(4 Week) SNL Study
15 21 * * * * * * * * * * 12 * * * 18 * * * SNL, NBN * * * 9 SNL, NBN * 15 6 *
12 3 SNL, vehicle Tactile Threshold (g) SNL, vehicle (s) Thermal Latency 0 9 4 8 12 16 20 24 28 4 8 12 16 20 24 28 Pre-SNL Days Post-SNL Pre-SNL Days Post-SNL
WT-rNBN113 * p<0.05 vs vehicle 1 mg/kg, s.c.
[Gardell et. al]
Page 72 May 17, 2007 Neublastin Summary
Molecule • Novel neurotrophic protein in GDNF family
Formulation • Formulated for systemic administration
Molecular • Interaction of Neublastin with its receptor on nociceptive sensory Hypothesis neurons activates downstream signaling, normalizing cellular changes resulting from damage or disease
Therapeutic • Neublastin will alleviate neuropathic pain by normalizing the Hypothesis altered cellular physiology of nociceptive sensory neurons
Potential • Peripheral neuropathy Indications • Neuropathic pain
Stage • Pre-IND
Partnership / • Licensed from NsGene for Peripheral Nervous System Alliances indications
Page 73 May 17, 2007 Questions & Answers Evan Beckman, M.D. SVP, Immunology R&D
Immunology Pipeline Immunology & Emerging Therapeutic Area Agenda
Immunology TA Pipeline Summary & Strategy Immunology TA Program Reviews – Rheumatoid Arthritis • RITUXAN / B Cell Therapies for RA •LTβR-Fc (Soluble Lymphotoxin Beta Receptor) for RA • Anti-TWEAK monoclonal antibody for RA – Lupus & Other Rheumatic Autoimmune Disorders • RITUXAN / B Cell Therapies for SLE / Lupus Nephritis • Anti-CD40L PEG-Fab for SLE – Crohn’s Disease • TYSABRI for Crohn’s Disease Emerging TA Pipeline Summary & Strategy Emerging TA Program Review – Long Acting rFactor IX & rFactor VIII for Hemophilia Q&A
Page 76 May 17, 2007 Immunology at Biogen Idec
• Experience – Veteran team of immunology discovery researchers with record of generating product development candidates •(LTβR-Fc, anti-CD40L PEG-Fab, BR3-Fc, anti-BR3 mAb, LFA3-Fc, anti-CD20 mAb, anti-CD23 mAb) – BIIB products approved worldwide in a wide range of indications including rheumatoid arthritis, psoriasis and MS – experienced development team • With additional development experience in Lupus, Crohn’s disease
• Diseases have predictive clinical endpoints
• Broad application across a range of diseases / markets – Lifecycle opportunities
Page 77 May 17, 2007 Opportunities for Life Cycle Management
AutoimmuneAutoimmune RA,RA, SLE,SLE, MS,MS, IBDIBD
InflammatoryInflammatory DiseasesDiseases OncologyOncology COPD,COPD, Asthma,Asthma, NHL,NHL, CLL,CLL, solidsolid tumortumor Atherosclerosis,Atherosclerosis, MetabolicMetabolic syndromesyndrome Immunology
InfectiousInfectious DiseaseDisease OrganOrgan ProtectionProtection HepatitisHepatitis Stroke,Stroke, MIMI
Page 78 May 17, 2007 Immunology Strategy
Neuro- Lupus Scleroderma RA Asthma IBD Transplant Psoriasis Disease degenerative Unmet Need + + + + + + +++ + + + + + + + + +
Immune Targets T Cells √ √ √ √ √ √ √ √ Adhesion/ √ √ √ √ √ √ √ √ Migration B Cells √ √ √ √ √ √ Monocytes/ √ √ √ √ √ √ Dendritic Cells Cytokines/ √ √ √ √ √ √ Chemokines Eosinophils/ √ Mast Cells
Page 79 May 17, 2007 Mechanisms of Interest
• We have chosen to focus on certain key areas of biology
B Cell Cell Cytokines Tolerance Modulation Trafficking Chemokines
RITUXAN TYSABRI AVONEX® Anti-CD40L hu Anti-CD20 BR3-Fc LTßR-Fc LTßR-Fc Anti-BR3 LTßR-Fc Anti-TWEAK Anti-CD40L
Page 80 May 17, 2007 Biogen Idec Immunology Pipeline
Pre-Clinical Phase 1Phase 2 Phase 3 Market Indication Stage
Rheumatoid TNF-IR – Marketed RITUXAN arthritis DMARD-IR – Ph3
FUMADERM Psoriasis Marketed – Germany
TYSABRI Crohn’s disease Filed in U.S. & E.U.
Lupus – SLE & RITUXAN SLE – Phase 2/3 Lupus Nephritis LN – Ph 3 Rheumatoid Ocrelizumab Phase 3 (2nd gen. CD20 MAb) arthritis Soluble LTβR Rheumatoid Phase 2 (LTβR-Fc) arthritis Inflammatory Soluble BAFF Phase 1 (BR3-Fc) disorders
Anti-CD40L Lupus Preclinical
Rheumatoid Anti-TWEAK Preclinical arthritis
Partnered Programs
Page 81 May 17, 2007 Rheumatoid Arthritis in the United States
• Chronic, progressive disease that results in disability and reduced quality and duration of life
• The RA biologics market is expected to reach $10B by 2015 2.8M RA Prevalence • Prevalence per 100,000: 0.9% • Incidence per 100,000: 32.7
2.1M RA Diagnosed 1,600 Growth in Treated RA Mod/Severe Patients • Standard of care evolving toward 1,400 2006-2015 1.5 M Mod/Severe using novel therapies earlier in 1,200
DMARD IR 1,000 disease for better outcomes 915K 800
Patients (,000's) Patients 600 320K TNF • The RA market place will 400 Treated
200 become increasingly competitive 210K TNF-IR 0 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 TNF IR DMARD IR 2006
Sources: Datamonitor, Decision Resources Page 82 May 17, 2007 Strategic Opportunities for RA
• Biologics • RITUXAN, LTβR-Fc, – TNF-IR / DMARD-IR Anti-TWEAK –Early RA – Combination therapy
• Oral small molecules • Preclinical candidates
• Personalized • Translational medicine approaches
Page 83 May 17, 2007 RITUXAN / B Cell Therapies for Rheumatoid Arthritis
Page 84 May 17, 2007 RITUXAN Mechanism of Action
RITUXAN ADCC Macrophage, monocyte, or natural killer cell
CD20 FcγRII, FcγRIII
Cell lysis
CDC Complement activation (C1qC1rC1s)
MAC B cell CD20
Cell lysis
Apoptosis
ADCC = antibody-dependent cellular cytotoxicity. CDC = complement-dependent cytotoxicity. Page 85 May 17, 2007 RITUXAN Clinical Development Rheumatoid Arthritis
• RITUXAN approved in RA for anti-TNF IR patients – Q1 2006 • Phase III trials ongoing in DMARD-IR
DMARD – IR RA Anti-TNF – IR RA Patients who Methotrexate Anti-TNF Anti-TNF Patient Methotrexate have had prior Inadequate Inadequate Inadequate Population Naive treatment with Responders Responders Responders Enbrel Phase III Phase III Phase III Phase II TAME Phase Phase III IMAGE SUNRISE REFLEX Combination Study SERENE Radiographic Controlled Study Study # of patients Study Re-treatment Study (n = 500) (n = 520) (n = 60) (n = 852) (n = 555)
Initiated Q4-05 Initiated Q1-06 1-year Status Initiated Q1-06 radiographic Initiated Q2-06 Completed Completed data filed with enrollment Q4-06 enrollment Q4-06 FDA
Data Readout Late 2007 / Late 2007 / June 2006 Early 2008 Early 2008 EULAR
Page 86 May 17, 2007 RITUXAN RA Next Steps
• RITUXAN X-Ray data filed Q1 2007 with FDA – First data in TNF-IR patients • RITUXAN TNF-IR retreatment trial ongoing – SUNRISE readout late 2007 / early 2008 • RITUXAN DMARD-IR trials ongoing – SERENE readout late 2007 / early 2008 •2nd generation anti-CD20 (ocrelizumab) in RA – Phase 3 program initiated
Page 87 May 17, 2007 LTβR-Fc (Soluble Lymphotoxin β Receptor) for Rheumatoid Arthritis
Page 88 May 17, 2007 LTβR-Fc (BG9924)
• Fusion protein – Human lymphotoxin beta receptor (LTβR) – Fc portion of human IgG1 • Disulfide-linked glycosylated, dimeric protein
Page 89 May 17, 2007 Surface LTα/β and LIGHT pathways
Lymphtoxin α/β Pathway is implicated in: LIGHT Pathway is implicated in: • Liver, spleen and lymph nodes • Mucosal and hepatic inflammation • Gut mucosa and Peyer’s patches LTα/β LIGHT (lymphotoxin) Activated lymphocytes and resting B cells
Stromal cells, myeloid lineage cells HVEM Receptor LTβ Receptor
Organization of lymphoid architecture, T-cell, dendritic cell activation cellular positioning, etc. Page 90 May 17, 2007 Surface LTα/β and LIGHT pathways
Lymphtoxin α/β Pathway is implicated in: LIGHT Pathway is implicated in: • Liver, spleen and lymph nodes • Mucosal and hepatic inflammation • Gut mucosa and Peyer’s patches LTα/β LIGHT (lymphotoxin) LTβR-Fc Activated lymphocytes and resting B cells
Dual Pathway Inhibitor
Stromal cells, myeloid lineage cells HVEM Receptor LTβ Receptor
Organization of lymphoid architecture, T-cell, dendritic cell activation cellular positioning, etc. Page 91 May 17, 2007 LTβR in Chronic Inflammation
New cells enter the region and Innate T Cells Alarms eff modify the microenvironment Mφ LTβR High Endothelial B Cells Venule (HEV) Neutrophils Naive T Resting Flat Endothelium Naive B
Activated Flat Organization Endothelium pDC Plasma Cells LTβR
Ectopic Lymphoid Structure
Chronic inflammation creates ectopic GC B lymphoid structures and lymphocyte Inflammation and migration into synovium Autoimmune Response
Page 92 May 17, 2007 Synovial Ectopic Lymphoid Structures in Chronic Inflammatory Diseases Like RA
Inhibition of the LT pathway can disrupt ectopic lymphoid Ectopic lymphoid organization and limit B- structures and T-cell activation.
LTβR-Fc can disrupt the formation of ectopic lymphoid structures in RA synovium
RA Synovium Normal Synovium Page 93 May 17, 2007 LTβR-Fc in Animal Models of Autoimmune Disease
Model Effect Arthritis Activity on established disease similar to TNF Inhibitors IBD Activity is equal to TNF inhibitors
MS Similar to anti-CD40L therapy, only at ~100x lower doses
Diabetes One of few agents shown to affect well-established disease in NOD
Transplant One of few agents known to block the CD8 rejection arm
Page 94 May 17, 2007 LTβR-Fc: Preclinical Evidence
Prophylactic & therapeutic in Collagen Induced Arthritis model
Prophylactic Therapeutic
1x weekly treatment initiated 8 Control IgG Saline 7 1 6 5 4 3 2 Arthritis Index LTβR-Fc LTβR-Fc 1 0 20 30 40 50 60 70 80 Days Post-Immunization Days Post-Immunization
Fava et al, 2003
Page 95 May 17, 2007 LTβR-Fc: Next Steps
• Phase 2a data – Abstracts submitted ACR 2007 Meeting (Boston, Nov 7-11) – Preliminary data drove initiation of robust Phase 2b program • Initiate Phase 2b RA trial in DMARD-IR mid-2007 – 380 patients, dose ranging trial – Primary endpoint ACR50 at 3 months • Initiate Phase 2b RA trial in TNF-IR mid-2007 – 120 patients – Primary endpoint ACR50 at 3 months
Page 96 May 17, 2007 LTβR-Fc (BG9924)
Molecule • Extracellular domain of the lymphotoxin β Receptor fused to Fc of human IgG
Formulation •SC
• Lymphotoxin system controls early events in the autoimmune Molecular cascade, regulating critical positioning of immune cells in Hypothesis lymphoid tissue, effector T cell maturation & chemokine expression •LTβR-Fc ameliorates autoimmune disease in multiple animal Therapeutic models. Targeting LT system with LTβR-Fc has potential to Hypothesis reduce aberrant immune activation in immune mediated inflammatory conditions
Potential •RA Indications • SLE; Crohn’s; Ulcerative Colitis; MS; Transplantation
• Phase IIa in RA encouraging, abstracts submitted ACR 2007 Stage • Phase IIb initiated Partnership / • Not partnered Alliances Page 97 May 17, 2007 Anti-TWEAK Monoclonal Antibody for Rheumatoid Arthritis
Page 98 May 17, 2007 TWEAK/Fn14 Pathway Scientific Overview
Compelling Features of the TWEAK/Fn14 Pathway TWEAK/Fn14 Pathway
• Member of the TNF/TNFR superfamily Tweak Fn14 • Highly conserved in evolution
• Disease/injury specific; receptor expression is highly regulated
CDR-L2 CDR-H1 • Activation drives pathological tissue remodeling CDR-H3
VH • Potential application in multiple diseases/TAs; Lead indication is RA VL • Not required for adaptive immunity; Likely favorable safety profile CDR-L1 CDR-L3 CDR-H2 Therapeutic composition: Humanized anti-TWEAK mAb
Page 99 May 17, 2007 Anti-TWEAK Inhibits Multiple Pathologies in CIA
Anti-TWEAK inhibits joint inflammation, loss of cartilage and bone 35 Anti-TWEAK inhibits synovial angiogenesis 30 P=0.004 P=0.04 25 * * 20 15 10 5 0 mIgG2a P5G9 P5G9 Full Overall Inflammation Inflammation Overall
* P=0.007 8 35 P=0.04 30 6 P=0.03 * * 25 20 4 15
2 10 5 Vessels/field 0 Bone Resorption 0 mIgG2a P5G9 P5G9 Full mIgG2a anti-TWEAK
8 Perper et al, 2006, J. Immunol 177:2660 6 P=0.05 P=0.03 * * 4
2 Cartilage Loss Cartilage 0 mIgG2a P5G9 P5G9 Full
Page 100 May 17, 2007 Activation of TWEAK/Fn14 Pathway in Human RA
TWEAK is elevated in RA synovial fluids TWEAK is produced in RA synovium P = 0.0152
1
0.1
0.01 TWEAK (ng/ml) TWEAK 0.001 RA(52 samples) OA(17 samples)
anti-TWEAK P3H8 staining
T. Smeets & P.P. Tak (AMC, Netherlands) TWEAK (ng/ml) TWEAK
SF mono counts
Page 101 May 17, 2007 Role of TWEAK in Joint Inflammation in RA
synovial macrophage ¾ Like TNF, TWEAK can stimulate synovial fibroblasts and induce the production of downstream cytokines/chemokines such TNF TWEAK as IL-6 and IL-1.
¾ TWEAK and TNF do not induce each synovial other, but can act additively or fibroblast synergistically.
¾ Synovial fibroblast responsiveness to TWEAK and TNF is donor-dependent. IL-1 IL-6 IL-8
The macrophage/fibroblast model of joint inflammation
Page 102 May 17, 2007 TWEAK is a Potent Inducer of Arthritogenic Mediators in Human Synoviocytes
TWEAK TNF Combo TWEAK TNF Combo TWEAK TNF Combo TWEAK TNF Combo 13.06 9.05 21.51 3.09 18.34 15.30 8.08 3.86 12.14 14.75 8.40 55.93
Ctl TWEAK TNF Combo Ctl TWEAK TNF Combo Ctl TWEAK TNF Combo Ctl TWEAK TNF Combo RANTES IL-1β IL-6 GRO1 GM-CSF IL-1α Fractalkine IL-8 IL-15Rα IL-15 ENA-78 TRAF-1 MMP1 MMP9 IL-6R
Donor #1 Donor #2 Donor #3 Donor #4
Expression level low high Page 103 May 17, 2007 Anti-TWEAK mAb
Molecule • Neutralizing humanized mAb directed against the cytokine Tumor Necrosis Factor-like Weak inducer of Apoptosis (TWEAK)
Formulation • IV infusion or subcutaneous injection
• TWEAK acts on key cell types (Fn14+) that drive pathological Molecular changes in disease target tissue • In RA, these include synoviocyte and chondrocyte activation Hypothesis (bone and cartilage damage); synovial angiogenesis (new blood vessels) • Efficacious in rodent models of arthritis • TWEAK and Fn14 expressed in human RA synovial fluid/tissue Therapeutic • Blocking TWEAK will be beneficial in degenerative, inflammatory Hypothesis diseases by inhibiting activation of key cell types that drive pathological changes in target tissue and by promoting tissue regeneration
Potential •RA Indications • Other neuroinflammatory/degenerative diseases
Stage • RA – IND targeted for 2008
Page 104 May 17, 2007 Systemic Lupus Erythematosus in the US
•Seizures • Malar rash • Psychosis Neurologic Dermatologic • Discoid rash • Photosensitivity
• Pericarditis Cardio- • Pleuritis pulmonary • Chronic autoimmune disorder • Nephritis - Minimal change - Mesangial which may affect virtually any Renal -FSGN -PGN part of the body and can range in - Membranous severity from mild to life- • Anti-DNA •Anti-Ro Immunologic threatening •Anti-Sm •Vasculitis •Anemia Hematologic • Thrombocytopenia • Leukopenia • An estimated 425,000 diagnosed •Arthritis Joint patients in US
630K Lupus Prevalence Growth in Treated ERL and LN Patients 2007-2015 • High unmet need due to limited 425K Diagnosed 500 efficacy of current therapies 450 400 350 300 • Long-term use of current drugs 300K Mod/Severe 250 SLE 50% 200 such as Cytoxan have poor
150K Patients (,000's) 150 100 safety profile Class II-V 50 190K 70% 30% LN 130K 0 2007 2007 2008 2009 2010 2011 2012 2013 2014 2015 Lupus Nephritis SLE Sources: Datamonitor, Decision Resources Page 105 May 17, 2007 RITUXAN / B Cell Therapies for Systemic Lupus Erythematosus / Lupus Nephritis
Page 106 May 17, 2007 RITUXAN Clinical Development SLE and Lupus Nephritis
• RITUXAN development ongoing in SLE and LN • Enrollment for both expected to complete in 2007
Lupus Program
Systemic Lupus Patient Lupus Nephritis Population Erythematosus
Phase Phase II/III Phase III Study EXPLORER LUNAR # of patients (n=250) (n=140)
Initiated Q2-05 Initiated Q1-06 Status Completed Complete enrollment Q1-07 enrollment H2-07
Data Readout Mid 2008
Page 107 May 17, 2007 RITUXAN Immunology
Molecule • Chimeric mouse/human antibody directed against the CD20 antigen expressed on human B-cells.
Formulation •IV
Molecular • Binds to the CD20 antigen present on the majority of B cells. Can lead to lysis of targeted cells through complement-dependent cytotoxicity, Hypothesis antibody–dependent cellular cytotoxicity and induction of apoptosis.
Therapeutic • Elimination of CD20 positive B-cells reduces or eliminates inflammatory Hypothesis cascades and interactions with T-cells
Potential • Approved: RA; Ongoing development: SLE, LN, ANCA-Associated Indications Vasculitis, Primary Progressive & Relapsing Remitting MS
• Approved for TNF-IR RA Stage • Ongoing: RA DMARD-IR (Ph III), SLE (Ph II/III), LN (Ph III), PPMS (Ph II/III), AAV (Ph II/III)
Partnership • Genentech (March 16, 1995) – Co-promote / Strategic input into Alliances Development
Page 108 May 17, 2007 Anti-CD40L PEG-Fab for Systemic Lupus Erythematosus
Page 109 May 17, 2007 CD40L is Essential for T Cell-Dependent Immunity Pathway Overview sIg
… and is proinflammatory B TCR Cell MHC-Ag activated platelets CD3 CD4 T Cell CD40 CD40L CD40L (CD154) (CD154) MHC-Ag CD40 CD40 CD40 induced by IFNγ dendritic MHC-Ag cell mφ and endothelial cells, microglia smooth muscle cells, fibroblasts, epithelial cells
Page 110 May 17, 2007 Open Label Study of Anti-CD40L mAb in Four Active SLE Patients
• Decreases observed in anti-dsDNA autoAbs, proteinuria and SLEDAI • Long-term remission seen in 2 of 4 patients
JCI 2003, 112:1506
Page 111 May 17, 2007 CD40L Program
• Anti-CD40L mAb demonstrated promising efficacy in preclinical and early clinical studies • Program halted due to thrombotic adverse events • Further work suggested thrombotic events may be Fc mediated • Partnership with UCB / Celltech to develop PEG-Fab fragment
Page 112 May 17, 2007 Anti-CD40L Fab-PEG Inhibits Mouse Lupus Nephritis
control Fab'-PEG 100
80
60
40
20 Hamster anti-CD40L mAb Murine anti-CD40L IgG1 mAb Murine anti-CD40L Fab'-PEG 0 18 20 22 24 26 28 30 32 34 36 38 40 42 % Scoring ProteinuriaMice % >300mg/dl
Weekly dosing
Age (weeks)
Page 113 May 17, 2007 Anti-CD40L PEG-Fab
Molecule • Anti-CD40L inhibitor (PEG-Fab)
Formulation • Possible administration route i.v. or s.c. • A mAb based anti-CD40L inhibitor can be both a safe and Molecular effective inhibitor of the CD40/CD40L pathway by removing or Hypothesis crippling Fc effector function, or by additionally eliminating crosslinking activity. Therapeutic • The above entity will be therapeutic for autoimmune and inflammatory diseases and allotransplantation alone or with Hypothesis adjunctive therapy Potential •SLE Indications • RA, MS, Transplant
Stage • Preclinical
Partnership / • UCB (partnered in Nov 2003) Alliances
Page 114 May 17, 2007 TYSABRI for Crohn’s Disease
Page 115 May 17, 2007 Crohn’s Disease Treatment Paradigm
Treatment Paradigm Product Attributes
Severity Induction Maintenance Safety* Efficacy Price*
1st Line 5-ASA Low Low Mild High 2nd Line + Oral Steroids
3rd Line + Immunosuppressants Moderate 4th Line + REMICADE / HUMIRA
5th Line IV Steroids High High Low Severe Surgery 6th Line
* This product attribute scoring does not pertain to IV steroids which are relatively safe and inexpensive.
Source: Ulcerative Colitis Practice Guidelines in Adults (Update): American College of Gastroenterology, Practice Parameters Committee (2004) Page 116 May 17, 2007 Crohn’s Disease Market Overview
A. Large # of Patients B. Treated by Specialists CD Suffers (000s) • Crohn’s patients are diagnosed and treated 400 Approximately regularly by gastroenterologists 300 800,000 Crohn’s • These doctors can be addressed with a 200 patients in the small sales force US & EU 100 • 11,000 practicing GIs in the US • Less than 1,000 focused specialists 0 US EU
C. Growing Market D. High Unmet Need
$3.0 US Sales ($Bs) • Better treatments are needed, especially for $2.5 moderate to severe Crohn’s patients $2.0 • Current therapies still have limitations $1.5 $1.0 $0.5 $0.0 2006 2008 2010 2012 2014
Source: Decision Resources, Pharma Prescriber, Remicade Label, AMA.org Page 117 May 17, 2007 Anticipated Changes in Treatment
Dynamic Market implication • One new anti-TNF in 2007 • Anti-TNF competition will grow – HUMIRA 2x/month S.C. biologic market in Crohn’s Disease
• Safety concerns are emerging from • Reduced immunosuppressive use use of biologics in combination with new entrants, particularly in combination with biologics
• Safety concerns over chronic steroid • Steroid sparing ability will be use are growing become more important
• Data using anti-TNF earlier in the • If positive data should help drive treatment algorithm will be available anti-TNFs to be used earlier in the in 2008–2009 algorithm
Source: Advisory Meetings & Market Research initiatives
Page 118 May 17, 2007 TYSABRI Induction Data is Comparable to Anti-TNFs
Placebo Clinical Response at 4 weeks Competing Therapy TYSABRI 100 P<0.01 REMICADE HUMIRA CIMZIA TYSABRI 82 80 P<0.002 P=0.01 P=0.007 64 P<0.05 P=0.003 P=0.003 p=0.01 59 59 P=0.001 60 54 54 54 50 51 42 37 37 Percent 40 31
20 16
0 Placebo 5 mg/kg 10 20 Placebo 40/20 80/40 160/80 Placebo 100 mg 200 mg 400 mg Placebo 300 mg N=25 N=27 mg/kg mg/kg N=74 mg mg mg N=73 N=74 N=72 N=72 N=250 N=259 N=28 N=28 N=74 N=75 N=76
Targan et al. N Engl J Med. 1997;337:1029-1035. Hanauer et al. Gastroenterol. 2006;130:323-333. Schreiber et al. Gastroenterol. 2005 Sep;129:807-18 Page 119 May 17, 2007 TYSABRI Maintenance Data Compares Favorably to Anti-TNFs
Remission at 1 year Placebo 80 Competing Therapy REMICADE HUMIRA TYSABRI TYSABRI
60 P=0.007 P<0.001 P<0.001 55
40 36
Percent 29 22 20 15 12
0 ACCENT 1 CHARM ENACT-2 (5 mg/kg q8w) (40 mg/eow) (300 mg/q4w)
Page 120 May 17, 2007 Concomitant Immunosuppressives are Not Needed to Maintain Remission Placebo 70 P ≤ 0.002 for all comparisons with placebo TYSABRI 60 60 58 55 55 54 53 50
40
30 31 30 30 Percent 23 22 21 20
10
(171) (168) (111) (106) (60) (62) (171) (168) (111) (106) (60) (62) 0 ITT -IMM+ IMMITT -IMM + IMM Month 6 Month 12 Note: Patient numbers are indicated in numbers in parentheses Page 121 May 17, 2007 TYSABRI CD Profile
• Phase 3 program: – ENACT-1, ENACT-2, ENCORE total of 1,754 patients • Induction data comparable to the anti-TNFs • Maintenance data is strong in relation to anti-TNFs – Durable maintenance of remission – Reduced need for Steroids – No need for concomitant immunosuppressives – Enhanced QoL • Immunogenicity and tolerability are comparable to anti-TNFs • Risk of Opportunistic Infections, including PML
Page 122 May 17, 2007 TYSABRI CD Next Steps
• Anticipated News / Events – DDW abstracts May 19-24 – CHMP opinion mid-2007 followed by EMEA decision – FDA panel expected Q3 – October FDA PDUFA date
Page 123 May 17, 2007 TYSABRI (natalizumab) Crohn’s Disease
Molecule • Humanized IgG4κ monoclonal antibody
Formulation • 300 mg IV infusion every four weeks
• TYSABRI binds to the alpha-4 subunit of integrin, molecules Molecular important to adhesion and migration of cells from the vasculature into inflamed tissue. TYSABRI blocks integrin Hypothesis association with vascular receptors, limiting adhesion and transmigration of leukocytes.
• Efficacy in specific disorders may be related to reduction in Therapeutic specific inflammatory cell populations in target tissues. Hypothesis • In Crohn’s Disease (CD) efficacy may be related to migration into gut via MAdCAM-1.
Stage/Status • Crohn’s disease: US and EU – submitted to regulatory authorities
Partnership / • Collaboration with Elan signed 2000 Alliances
Page 124 May 17, 2007 Immunology Development Summary
• Biogen Idec currently has important marketed products targeting key immunologic pathways
• Unmet need remains in many autoimmune diseases
• Leveraging our core expertise in immunology, next generation projects will bring further value in autoimmune disease
Page 125 May 17, 2007 Emerging Therapeutic Area Pipeline
Pre-Clinical Phase 1Phase 2 Phase 3 Market Indication Stage
ADENTRI Heart Failure Phase 2
Pulmonary arterial Aviptadil Phase 2 hypertension
Long Acting Hemophilia B rFactor IX Preclinical
Long Acting Hemophilia A rFactor VIII Preclinical
Partnered Programs
Page 126 May 17, 2007 Questions & Answers Alan Bitonti, Ph.D. SVP, Syntonix
Hemophilia Therapeutic Area Syntonix and Biogen Idec
• Biogen Idec acquired private Syntonix January 2007 – Functioning as wholly owned subsidiary in Waltham, MA – Manufacturing capability and expertise allows accelerated pathway to market
• Long acting Factor IX product for hemophilia B – Proprietary longer acting FIX:Fc fusion protein – Fundamental advance in Fc fusion technology – Biovitrum joint development and commercialization • Syntonix to market in North America – IND expected to be filed with regulatory agencies in 2007
• Other programs include long acting factor VIII for hemophilia A
Page 129 May 17, 2007 Hemophilia
• Disease characteristics – Inherited bleeding disorder: blood does not clot normally, patients bleed for a longer time following an injury
• Unmet need – Improvements in frequency of administration for acute use and prophylaxis
• Hemophilia market – Approximately 18,000 patients in the U.S • Hemophilia B (FIX) 3,800 • Hemophilia A (FVIII) 14,200 – Focused specialist physician audience • 145 CDC supported hemophilia treatment centers – Global FVIII and FIX sales of $4.2 billion in 2005 and growing • FIX Market ~$740M (Wyeth’s BeneFIX and plasma derived-products) • FVIII Market ~$3.5B (Baxter, Bayer, Wyeth and plasma derived-products)
Page 130 May 17, 2007 Long Acting rFactor IX (FIX) for Hemophilia B
Page 131 May 17, 2007 Long Acting rFIX Potential Advantages
• Low risk to proof of efficacy IX – Well understood etiology – therapy replaces r missing protein cto Fa – Relatively small clinical trials with clear endpoints • Less frequent administration potentially a major advantage H H – Fewer injections for more severe bleeders/active patients using on-demand therapy CH2 CH2 – Could grow prophylaxis market where patients currently use 2 or more injections per week CH CH • Physician demand for new source of rFIX 3 3 • Relatively little competitive activity SynFusion Monomer
Page 132 May 17, 2007 Long Acting rFIX Enhanced Pharmacokinetics
Half-life Species rFIX (BeneFIX) Syntonix rFIX Mouse, FIX-deficient 13 hours 50-55 hours Rat 6 hours 35-40 hours Dog, FIX-deficient 14-18 hours1,2 45-50 hours Cynomolgus monkey 12.7 hours 2 45-50 hours
References: 1. Brinkhous et al Blood 88:7:1996, 2. McCarthy, K et al Thromb Haemost 87:824:2002
Page 133 May 17, 2007 Long Acting rFIX Development Timeline
• Acquisition by Biogen Idec enables and accelerates pathway to market
• Next steps – IND expected to be filed with regulatory agencies in 2007 – Pilot study readout potentially H1 2008
• Pivotal study design parameters – 50 to 60 patients – One year of treatment – Potential initiation near YE 2008 – May qualify for fast track status
Page 134 May 17, 2007 Long Acting rFactor VIII (FVIII) for Hemophilia A
Page 135 May 17, 2007 Long Acting rFVIII Market, Advantages & Timeline
• Similar market dynamics for Hemophilia A – Unmet medical need for more convenient therapy – Targeting prophylaxis patients and severe bleeders/active patients – Relatively limited competitive activity
• Long acting rFVIII – Potential improved frequency of administration – Promising in vivo data • Significant increase in length of activity in Factor VIII deficient mice – Relatively small trials with defined endpoints
• Working toward IND – Potential IND / first in human study in 2009
Page 136 May 17, 2007 Questions & Answers David Parkinson, M.D. SVP, Oncology R&D
Oncology Pipeline Biogen Idec Oncology R&D
• Therapeutic area of strategic focus for the company • Creation of an integrated oncology R&D together with an Oncology Business Unit • Assembly of internal expertise and external network of advisors • Strategic partnerships: therapeutics and diagnostics • Building competitive, focused discovery and developmental efforts; creating areas of strength and therapeutic complementarities
Page 139 May 17, 2007 Biogen Idec Oncology Portfolio
• Antibodies against lymphocyte antigens: – RITUXAN, galiximab, lumiliximab • Antibodies against integrins: – Volociximab, natalizumab • Small molecule Hsp90 inhibitors: – BIIB021, follow on program • Small molecule signal transduction inhibitors: – Sunesis collaboration
Page 140 May 17, 2007 Oncology Pipeline
Pre-Clinical Phase 1Phase 2 Phase 3 Market Indication Stage NHL – Marketed RITUXAN NHL & CLL CLL – Ph3 ZEVALIN NHL Marketed Marketed
Anti-CD80 (galiximab) NHL Phase 3
Late Anti-CD23 Registrational Stage (lumiliximab) CLL Phase 2b
M200 / anti-α5β1 (volociximab) Solid tumors Phase 2 Hsp90 Inhibitor Start Phase 2 in Solid tumors (BIIB021) 2007 (BIIB021) Anti-Cripto-DM4 (BIIB015) Solid tumors File IND in 2007
MMK Inhibitors Solid tumors Preclinical Early Stage Early Anti-IGF-1R (BIIB022) Solid tumors Preclinical
natalizumab Oncology Preclinical
Partnered Programs
Page 141 May 17, 2007 Galiximab (anti-CD80 mAb) for Non-Hodgkin’s Lymphoma
Page 142 May 17, 2007 CD80 Expression on Lymphoma
• Follicular NHL – 100% (32/32) Dorfman et al., 1997 – 100% (6/6; weak) Munro et al., 1994 – 100% (6/6; weak) Dogan et al., 1998 – 100% (12/12) Younes et al., 2003 – 93% (27/29) unpublished; BIIB-IHC study
• Diffuse large B-cell NHL – 81% (56/71) Stopeck et al., 2000 – 100% (15/15; large cell and immunoblastic) Dorfman et al., 1997 – 75% (8/12) Vyth-Dreese et al., 1998
• Hodgkin’s lymphoma – 100% (47/47) Delabie et al., 1993 – 95% (19/20) Nozawa et al., 1998 – 100% (9/9) Munro et al., 1994
Page 143 May 17, 2007 Potential Mechanisms of Action of Galiximab
IL-10 Nega TGF-β R tive egul ation TregTreg ThTh CellCell l DC CD80 gna l si iva 40 rv -CD Su 40L s CD ine tok CD86 CD80 cy
CD80 ? Malignant n o t B cell ti c n Myeloid a e Myeloid r m t t suppressor cells t i a u o r c m e e Survival/ h R C & Angiogenic factors CD80 Galiximab can potentially IL-1,IL-6, IL8 alter CD80 dependent immunomodulation in Macrophage tumor microenvironment
Page 144 May 17, 2007 Galiximab + Rituximab Increase Survival Human B-Lymphoma Mouse Model (n=40)
100 galiximab (200 µg) + rituximab (200 µg) (N = 10) 80
60 galiximab (200 µg; N = 10)
40 Survival (%) rituximab (200 µg; N = 10) 20
Control (N = 10) 0 10 20 30 40 50 60 70 Days After Implant
Younes et al., Clinical Lymphoma, 2003 Mar;3(4):257-9
Page 145 May 17, 2007 Phase I/II Galiximab Monotherapy
• N=37, Dose-escalation study of galiximab (125, 250, 375, or 500 mg/m2/wk x 4) • Favorable safety profile – Most common related AEs were fatigue, nausea, and headache • Tumor burden reductions in 46% of patients • Overall response rate = 11% (4 of 37 patients) – 375 mg/m2 (N = 21): 2 CRs, 1 PR – 500 mg/m2 (N = 10): 1 PR • PFS for responders: 11.2, 24.3+, 26.5, and 31 months Czuczman et al., J Clin Oncology, 2005
Page 146 May 17, 2007 Galiximab Summary
• Preclinical data suggests multiple anti-tumor mechanisms of action • Combination of galiximab and RITUXAN preclinically is superior • Recent AACR abstract demonstrates galiximab/chemotherapy therapeutic enhancement • Randomized Phase III registration trial under SPA underway; RITUXAN +/- galiximab in 700 patients with refractory follicular lymphoma, endpoint DFS • Potential accelerated registration strategy in refractory Hodgkin’s Disease Czuczman et al., J Clin Oncology, 2005 • Other indications (e.g. front-line NHL) to be explored
Page 147 May 17, 2007 Galiximab (Anti-CD80, IDEC-114)
Molecule • A PRIMATIZED® monoclonal antibody directed against CD80 (B7.1) on the surface of normal and malignant B lymphocytes
Formulation • 50 mg/mL single use formulations for IV infusion
• Mediates antibody dependent cellular cytotoxicity (ADCC) on Molecular CD80+ non-Hodgkin’s & Hodgkin’s cell lines • In combination enhances anti-tumor activity of RITUXAN & Hypothesis chemotherapy • Immunomodulatory mechanisms may contribute to efficacy
Therapeutic • Increases progression free survival when used in combination with rituximab in relapsed non-Hodgkin’s lymphoma (NHL) Hypothesis • May improve ORR in relapsed or refractory Hodgkin’s lymphoma
Potential • Primary Indication: Relapsed follicular NHL Indications • Additional indications: Untreated follicular NHL, diffuse large B cell lymphoma, Hodgkin’s disease
Stage • Phase III ongoing
Page 148 May 17, 2007 Lumiliximab (anti-CD23 mAb) for Chronic Lymphocytic Leukemia
Page 149 May 17, 2007 CD23 and CLL
CD23 Lumiliximab Macaque variable regions Human constant regions Neoplastic (IgG1 kappa isotype) B-CLL
CD23 • Low affinity receptor for IgE • Functions to regulate IgE synthesis, sCD23 may have other IgE-independent functions • CD23a is constitutively expressed on CLL cells
Lumiliximab • IgG1 chimeric (macaque-human) anti-CD23 monoclonal antibody • Structurally indistinguishable from human antibodies • Binds CD23 with high affinity (Kd = 0.12nM)
Page 150 May 17, 2007 Lumiliximab Primary Mechanism of Action is Apoptotic Cell Death
Apoptosis in CLL B cells DNA Fragmentation SKW cells 70 60 50 40 30
Apoptosis (%) 20 10 0 Isotype Lumiliximab Control
• Lumiliximab induced apoptosis in B lymphoma cell lines correlates to CD23 expression
• Lumiliximab induced apoptosis in 14 of 16 CLL patients • Induction of apoptosis via the intrinsic pathway (Caspases 3,9,PARP with cytosolic cytochrome C induction)
Page 151 May 17, 2007 Lumiliximab + Fludarabine or Rituximab Prolongs Survival in Xenograft Models
Lumiliximab + Fludarabine Lumiliximab + Rituximab 100 100
Lumiliximab + Lumiliximab + 80 Fludarabine 80 Rituximab
60 60 Lumiliximab (200 µg) Rituximab 40 Fludarabine 40 (200 µg) Survival (%) Survival (%) (1 mg/kg) Lumiliximab 20 20 Control Control (200 µg) 0 0 10 20 30 40 50 60 20 40 60 80 Days Following Implant Days Following Implant Human B-lymphoma/SCID mouse model: – Lumiliximab alone ↑ S – Rituximab alone ↑ S – Lumiliximab/Rituximab ↑ S vs. single agent – Lumiliximab/Fludarabine ↑ S vs. single agent
Page 152 May 17, 2007 Ph I/II: Lumiliximab + FCR vs. Historical FCR Efficacy Comparison
152-30 (L + FCR)1 MDACC (FCR)2 n=31 n=177 Overall response 22 (72%) 130 (73%)
Complete response 16 (52%) 45 (25%)
Partial response 3 (10%) 85 (48%)
Unconfirmed partial 3 (10%) response*
Response criteria for CR and PR are the same for both studies *Unconfirmed partial responses are included in the overall response
MDACC: MD Anderson Cancer Center
1. Byrd et al. ASH 2006; Abstract 32; 2. Wierda et al. J Clin Oncol 2005;23:4070–4078
Page 153 May 17, 2007 Lumiliximab Summary
• Novel mechanism of action involves induction of apoptosis in B-CLL by anti-CD23 mAb • Preclinical data shows enhancement of fludarabine- and RITUXAN-mediated anti-CLL effect • Clinical data consistent with these observations – Doubling of CR rate in refractory CLL patients • Registration trial underway – 276 patients randomized to FCR +/- lumiliximab with CR endpoint for accelerated/conditional approval
Page 154 May 17, 2007 Lumiliximab (Anti-CD23, IDEC-152)
Molecule • A PRIMATIZED® monoclonal antibody directed against CD23 found on the surface of B-CLL cells Formulation • 50 mg/ml single use formulation for IV administration
• Induces apoptosis, antibody-dependent cell-mediated cytotoxicity, Molecular complement-dependent cytotoxicity Hypothesis • Works synergistically with rituximab and chemotherapy
Therapeutic • Improves response rates and progression free survival (PFS) in Hypothesis Chronic Lymphocytic Lymphoma (CLL) patients
Potential • Chronic Lymphocytic Leukemia, Small Lymphocytic Lymphoma Indications
Stage • Registration trial ongoing
Partnership / • Not partnered Alliances
Page 155 May 17, 2007 Volociximab (M200, anti-α5β1 integrin mAb) for Solid Tumors
Page 156 May 17, 2007 Volociximab Represents a Novel Anti-angiogenic Terapeutic Strategy
Integrin Family (Hynes, Cell, 2002) • Translate extracellular information into context- appropriate cellular responses (adhesion, migration, survival) • Endothelial cell integrins: α5β1, αv β 3, αvβ5
α5β1 Integrin • Binds to fibronectin in the extracellular matrix • Expressed on vascular endothelial cells (EC) and up-regulated on angiogenic tumor endothelium • Modulates EC adhesion, migration and survival • Variably over-expressed by malignant tumor cells • Expressed by monocytes / macrophages
Page 157 May 17, 2007 Volociximab Targets Multiple Cell Types within the Tumor Microenvironment
From Joyce, J.A. 2005. Cancer Cell 7: 513-520. endothelialendothelial macrophagemacrophage cellcell tumortumor cellcell
Page 158 May 17, 2007 Volociximab: Development Strategy
• Productive collaboration with PDL BioPharma • Recent development of a surrogate antibody targeting rodent alpha5beta1 integrin permits biological and therapeutic profiling: – Dissecting direct (anti-tumor cells) vs indirect (anti- angiogenesis, anti-stromal) mechanisms – Dose,schedule, pharmacodynamic characterization – Comparisons and contrast with anti-VEGF therapies • Application of findings to therapeutic development strategies: – Enabling studies for registration trials – Confirmation of Proof-of-Concept in early patient trials
Page 159 May 17, 2007 Volociximab: Clinical Trial Program
• Phase I completed: dose and schedule characterization • Phase II single arm trials completing in pancreatic and renal carcinomas, melanoma • Phase II trials in 2nd and 3rd line ovarian carcinoma starting H2 2007 • Chemo/combo trial in non-small cell lung carcinoma to start by year end 2007 • Further trials in renal carcinoma planned • Data expected in 2008
Page 160 May 17, 2007 Volociximab (M200)
Molecule • Chimeric IgG4 antibody to the α5β1 integrin heterodimer
Formulation • Liquid for intravenous delivery
Molecular • The α5β1 integrin plays a critical role in tumor angiogenesis by Molecular establishing endothelial cell (EC) interactions with the ECM. These Hypothesis interactions support EC survival, proliferation, and migration.
Therapeutic • Blocking the interaction between α5β1 and the ECM will inhibit tumor Hypothesis angiogenesis and thereby inhibit tumor progression.
Stage • Phase 2 single arm in RCC, pancreatic, melanoma • Initiating trials in ovarian, NSCLC, RCC Potential • Opportunity for broad application across solid tumors Indications
• Joint co-development / co-commercialization Partnerships collaboration: PDL BioPharma and Biogen Idec
Page 161 May 17, 2007 Natalizumab (anti-α4β1 integrin mAb) in Oncology
Page 162 May 17, 2007 Natalizumab in Oncology VLA-4 Biology
Integrin α4β1 (VLA-4) is best known as a leukocyte adhesion receptor mediating arrest and extravasation of lymphocytes via interaction with its receptor VCAM1 on activated endothelial cells.
Hematopoietic cells VCAM Lymphocytes, Monocytes, α4β1 Eosinophils, Neutrophils, Granulocytes Fibronectin (CS-1)
Activated endothelium
Page 163 May 17, 2007 Targeting VLA-4 in Oncology– Potential Mechanisms of Action
• Direct antitumor activity against VLA-4 expressing tumor cells (hematologic malignancies) • Reversal of cell adhesion mediated drug resistance (hematologic malignancies, solid tumors?) • Inhibition of tumor angiogenesis & lymphangiogenesis (solid tumors)
Page 164 May 17, 2007 Clinical Development of Natalizumab In Oncology
• Proof of concept trial in multiple myeloma planned to start H1 ‘08 • Preclinical studies for further characterization of proof of concept initiated • Solid tumor clinical studies to follow
Page 165 May 17, 2007 Natalizumab for Oncology
Molecule • Humanized IgG4κ monoclonal antibody
Formulation •IV infusion
Molecular • Natalizumab binds to the alpha-4 subunit of integrin molecules Hypothesis
• Potential role in oncology: Therapeutic • Direct antitumor activity against VLA-4+ tumor cells Hypothesis • Reversal of cell adhesion mediated drug resistance • Inhibition of tumor angiogenesis & lymphangiogenesis Stage • Proof of concept trial in multiple myeloma planned to start H1-08 • Solid tumor clinical studies to follow
Potential • Opportunity for broad application across hematologic and solid Indications tumors
Partnerships • Collaboration with Elan – August 2000
Page 166 May 17, 2007 Small Molecule Hsp90 Inhibitors in Oncology
Page 167 May 17, 2007 The Hsp90 Chaperone Cycle Hsp90 inhibition leads to proteasomal degradation of clients
Page 168 May 17, 2007 Hsp90 Regulates Multiple Signaling Pathways
Page 169 May 17, 2007 Hsp90 Client Proteins in Cancers Sensitivity to a Wide Range of Tumors
Client Drug Sensitivity Cancer Type
ErbB2/HER-2 high breast, ovarian, gastric, colon, NSCLC ZAP-70 high B-CLL Akt/p-AKT high breast, glioblastoma Raf-1/pRaf high melanoma ER, PR, AR, high breast, prostate HIF-1α high breast, renal Mutated B-Raf moderate melanoma EGFR moderate breast, ovarian, NSCLC, GBM IGF-R1 moderate multiple myeloma, cervical, sarcomas Bcr-Abl moderate CML c-Kit moderate fibrosarcomas, GIST Flt3 moderate AML Mutated JAK-2 moderate polycythemia vera, myeloproliferative diseases Page 170 May 17, 2007 Malignant Progression Drives Increased Hsp90 Activation
Page 171 May 17, 2007 Biogen Idec’s Inhibitors Selectively Bind Activated Hsp90
• Hsp90 represents 2-3% of total cytosolic protein • In normal cells, exists in inactive form • Hsp90 exists in complexed, active form in advanced cancer (Kamal et al., Nature 2004) •1st generation natural products (e.g. geldanamycin, 17-AAG) selectively bind activated form, with toxicity limitations • Biogen Idec synthetic Hsp90 inhibitors exhibit up to 100-fold selectivity for activated Hsp90
Page 172 May 17, 2007 Differences between BIIB021 and 17-AAG
Characteristic BIIB021 17-AAG Source Natural Synthetic Route Oral Intravenous Hepatotoxic ? No Yes (DLT) Formulation Easy, solid form Difficult MDR substrate ? No Yes
Application Broad Narrower (Not Rb-defective or Bcl-2++)
Page 173 May 17, 2007 BIIB021: Comparison with 17-AAG
100
80 IC50 (uM)
60 BIIB021 0.032 17-AAG 0.022 40 %Her-2 Degraded 20
0 0.001 0.010 0.100 1.000 10.000 100.000 Concentration (uM)
Page 174 May 17, 2007 BIIB021 Pharmacodynamics & Biomarkers
0 30 60 120 (mg/kg)
HER2 Circulating pHER2 HER-2 ectodomain
pAKT 1.2 Raf1 1.0 0.8 1X oral pRaf 0.6 BIIB021 0.4 cdk6 0.2 cerbB-2/c-neu (ng/ml) cerbB-2/c-neu 0.0 Cyclin D CTRL+BLK 30 60 125 Dose (mg/kg) Hsp70
PI3K p85 Spleen Hsp70 BT474 s.c.breast cancer xenograft
Page 175 May 17, 2007 Dose-Dependent Antitumor Activity of BIIB021
N87 Stomach Carcinoma Control PO QD M-F Xenograft BIIB021 31mg/kg PO QD M-F 450 BIIB021 62.5 mg/kg PO QD M-F 400 BIIB021 125mg/kg PO QD M-F 350
300 P values : 250 0.02 200 0.002 150 0.0001 100 50
Mean Tumor Volume (mm3) 0 30 40 50 60 70 Time (day)
Page 176 May 17, 2007 BIIB021 – Preclinical Status
• A novel synthetic Hsp90 inhibitor that induces client protein degradation and tumor cell death at low nanomolar concentrations • Selective for the activated form of Hsp90 and selectively kills malignant cells • Active against eight tumor types tested in vivo • Antitumor activity and tolerability are schedule-independent • Orally-bioavailable, independent of MDR and with metabolic and toxicology profiles distinct from 17-AAG • Serum and cellular biomarkers validated
Page 177 May 17, 2007 BIIB021 – Clinical Status
• Drugs and expertise obtained by May 2006 purchase of Conforma Therapeutics • First oral Hsp90 inhibitor to enter clinical development • Development stage drugs: – CNF1010 – lipid formulation of 17-AAG (ansamycin) • Phase I completed (development discontinued) – BIIB021 (CNF2024) – first synthetic Hsp90 inhibitor • Completing Phase I; Phase II trials soon to start in range of indications
Page 178 May 17, 2007 Hsp90 Inhibitor BIIB021 (CNF 2024)
Molecules • Synthetic Hsp90 inhibitor
Formulation • Oral capsule
• Hsp90 is a molecular chaperone required for the activity of Molecular specific “client” proteins that are involved in tumor cell signaling. Hypothesis Inhibition of Hsp90 causes client protein degradation leading to tumor cell stasis and/or death.
Therapeutic • Tumor cell dependence on Hsp90 function; Hsp90 inhibition results in degradation of proteins essential for cancer cell Hypothesis survival
Potential • HER-2 positive breast, non-small cell lung, gastric and other Indications solid tumors, GIST, MDS etc.
Stage • Phase I: solid tumors and CLL (ongoing), initiating Phase I/II
Partnership / • Acquired with Conforma 2006 Alliances
Page 179 May 17, 2007 Summary: Biogen Idec Oncology Portfolio
• Two monoclonal antibodies (galiximab, lumiliximab) in registration trials complement historical RITUXAN strength • Two anti-integrin monoclonal antibodies target novel anti-cancer mechanisms • Small molecule Hsp90 inhibitors are first and best-in- class • Earlier programs in signal transduction inhibition utilize both large and small molecule technologies • Productive development partnerships: PDL BioPharma, Elan, Sunesis
Page 180 May 17, 2007 Questions & Answers Cecil Pickett, Ph.D. President, Research and Development
Wrap Up and Q&A R&D Summary
• Biogen Idec’s pipeline continues to strengthen via organic as well as external growth
• Pipeline contains exciting programs in all phases of development across our target therapeutic areas
• 2007 is set to be a year of clinical execution…. • Develop the most promising late stage compounds • Move our earlier programs towards proof of concept
• …. and 2008 is poised to be a year of clinical data results
Page 183 May 17, 2007 Questions and Answers 2007: A Year of Execution
• Develop the most promising late stage compounds
Program Status Indication BG-12 Phase 3 MS Galiximab Phase 3 NHL Lumiliximab Registrational Ph 2b CLL
• Move earlier stage compounds towards Proof-of-Concept
Program Status Indication Daclizumab Phase 2 MS CDP323 Phase 2 in 2007 MS LTβR-Fc Phase 2 RA Voliciximab (M200) Phase 2 Solid tumors HSP90 inhibitor Phase 2 in 2007 Solid tumors Adentri Phase 2 Heart Failure Aviptadil Phase 2 PAH BIIB14 Phase 2a Parkinson’s
Page 185 May 17, 2007 2008: A Year of Results Select Upcoming Pipeline Events
2007 2008 2009 MS Franchise • AVONEX • TYSABRI CD Decisions (EU, US) • RITUXAN RRMS Ph 2 Ph 2/3 PPMS
CD-20 Franchise Ph 3 RA -IR Ph 2/3 Ph 3 Ph 2/3 LN • RITUXAN SLE CLL • Ocrelizumab Ph 3 RA
Emerging Pipeline Lumiliximab Ph 2b CLL
LTβR-Fc Ph 2a RA LTβR-Fc Ph 2b RA M200 Ph 2a Ovarian
Dac Ph 2 combo Factor IX Ph 1/2 HSP 90 Inhib Ph 2 Neublastin Neuro Pain Adentri Ph 2 CDP323 Ph 2b Ph 2a BIIB14 Ph 2a Dac Ph 2 mono
Page 186 May 17, 2007 Anticipated Pipeline Milestones/Events 2007
Event Timing
Clinical Data Availability 9 RITUXAN RRMS – Ph 2 AAN (5/07) RITUXAN CLL – Ph 3 (REACH - Interim Analysis) Q3 Galiximab NHL – Ph 2a CALGB arm Q4 Daclizumab CHOICE – Ph 2 (24 Week data) Q4 LTβR-Fc RA – Ph 2a ACR (11/07)
Regulatory Events 9 Submit RITUXAN RA X-ray data (US and EU) Q1 TYSABRI CD regulatory decision (EU) Q3 TYSABRI CD FDA panel meeting Q3 TYSABRI CD regulatory decision (US) Q4
Page 187 May 17, 2007 Anticipated Pipeline Milestones/Events 2008
Event Timing Clinical Data Availability Registrational Trials RITUXAN DMARD-IR RA H1 RITUXAN anti-TNF-IR RA H1 RITUXAN SLE – Ph. 2/3 H1 RITUXAN PPMS – Ph. 2/3 H1 RITUXAN CLL – Ph. 3 H2
Ph. 2 Adentri Heart Failure – Ph. 2 H1 Factor IX Hemophilia B – Ph. 1/2 H1 Volociximab (M200) Ovarian cancer – Ph. 2a Q2 LTβR-Fc RA – Ph. 2b H2 CDP323 MS – Ph. 2b H2 BIIB14 PD – Ph. 2a H2 HSP90 inhibitor – Ph 2 YE
Regulatory Events Submit sBLA for RITUXAN in DMARD-IR RA H1 Submit sBLA for RITUXAN in CLL* H2
*Assumes favorable result from REACH trial interim analysis
Page 188 May 17, 2007