1. Biogen Portfolio Update
Biogen US Medical
May 2015
MU-US-0036a

2. Guidance for Use
This slide deck is intended to be used in response to an unsolicited request for information when received from a payer customer. This slide deck contains hyperlinks to enable the US Medical colleague (E.g., MSL) to navigate the slide deck with the intent of delivering a narrowly tailored response to a question. It is for reactive use only, and is not intended to be distributed in any format.
Medical Guidance:
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Please ask why the question is being asked
Please ask what specific data is being requested
Utilize hyperlinks within the slide deck to tailor a response to the specific question.
Please do not show the “Table of Contents” hyperlink slide to the customer.
Ensure that the response is clear regarding approved vs investigational products/indications
Please note that the information contained within this slide deck was developed from referenced materials.

3. Biogen
About Biogen
Daclizumab HYP
Overview of Development
SELECT
DECIDE
Anti-LINGO-1
Tysabri SPMS
Tysabri Acute Ischemic Stroke
Anti-TWEAK Neublastin ISIS-SMNRx BIIB037 BAN2401 BG00011

4. Biogen Biogen is the world's oldest independent biotechnology company
Established 1978
Biogen has >7,500 employees worldwide and >$9.7 billion USD in annual revenues (2014)
Through cutting-edge science and medicine, we discover, develop and deliver to patients worldwide innovative therapies for serious neurodegenerative, hematologic and autoimmune diseases
Founded in 1978, we are the world’s oldest independent biotechnology company that today has a rapidly-expanding global footprint and employs approximately 7,000 people worldwide
Today, Biogen Idec is one of the oldest independent biotechnology companies in the world.
Biogen Idec is a Fortune 500 company and global technology leader that generates more than $6.9 billion in annual revenues. Our mission is to discover, develop, and deliver innovative therapies for the treatment of neurodegenerative diseases, hemophilia, and autoimmune disorders to patients worldwide through cutting-edge science and medicine. Our robust pipeline is supported by one of the industry’s leading capacities for biologics manufacturing, featuring nearly 200,000 liters of bioreactor capacity.
In 2012, Research & Development is expected to be approximately 24% to 25% of total revenue.
We have more than 7000 employees worldwide, a direct commercial presence in more than 29 markets, and a network of distribution partners in more than 70 additional markets, including emerging markets such as Central and Eastern Europe, Brazil, China, and India.
To our patients, we are the trusted source of vital therapies for multiple sclerosis, such as AVONEX®, TYSABRI®, TECFIDERA®, PLEGRIDY®, and FAMPYRA®. We also discovered RITUXAN®, the world's most prescribed treatment for non-Hodgkin's lymphoma and an effective treatment for rheumatoid arthritis.
To our employees, we are an exciting and invigorating place to work, an ambitious and nimble company where courageous innovation is encouraged and expected—not just of scientists but of every employee.
To our partners and investors, we are a profitable company with a rich and diverse pipeline. We have the resources, financial strength, and vision to successfully discover, develop, manufacture, and commercialize new products.
We now intend to continue our tradition in breakthrough therapies by delivering the next major innovation to the hemophilia community—long-lasting factors.
Reference
Biogen Idec. Available at
*Pharmaceutical Industry Profile 2012, Washington DC, PhARMA, April 2012.
Biogen. Available at

5. Approved Products
Multiple Sclerosis
Hemophilia

6. Biogen Pipeline* Late-Stage Early-Stage ALPROLIX* ELOCTATE* PLEGRIDY
Phase I
Phase II
Phase III
Filed
ALPROLIX*
Hemophilia B
FDA APPROVED
ELOCTATE*
Hemophilia A
FDA APPROVED
PLEGRIDY
Multiple Sclerosis
FDA APPROVED
Daclizumab HYP*
Multiple Sclerosis
TYSABRI
Secondary Progressive Multiple Sclerosis
ISIS-SMNRx*
Spinal Muscular Atrophy
Anti-LINGO
Acute Optic Neuritis
Anti-LINGO
Multiple Sclerosis
Anti-TWEAK
Lupus Nephritis
BAN2401*
Alzheimer's Disease
Early-Stage
Neublastin
Neuropathic Pain
BG00011
Idiopathic Pulmonary Fibrosis
TYSABRI
Acute Ischemic Stroke
E2609*
Alzheimer’s Disease
BIIB037*
Alzheimer's Disease
BIIB061
Multiple Sclerosis
ISIS-DMPKRx*
Myotonic Dystrophy
Anti-CD40 Ligand (CDP7657)
Systematic Lupus Erthematosus
* Partnered program
*Status as of May 2015

7. Daclizumab HYP* Multiple Sclerosis
Daclizumab HYP is a SQ form of daclizumab that is being developed for once-monthly administration and is produced using a high-yield manufacturing process. DAC-HYP is the only form of daclizumab that has been developed for LT use in MS. Two registry trials SELECT and DECIDE to evaluate it in people with RRMS.
Zenapax was another form of daclisumab that was indicated by the FDA for IV use for prophylaxis of acute organ rejection in pts receiving renal transplants. And was never studied in pts with MS.
*Daclizumab HYP is an investigational candidate

8. Daclizumab HYP
Daclizumab HYP is a humanized monoclonal antibody that binds to CD25, the alpha subunit of the high affinity IL-2 receptor that is expressed at high level on the T-cells thought to become abnormally activated in autoimmune conditions, such as MS1
High-affinity IL-2 receptor
Intermediate affinity IL-2 receptor
IL-2 Signaling by Blocking the High-Affinity Receptor (CD25) Pathway
IL-2 signaling is maintained via the intermediate - affinity IL-2 receptor in the presence of daclizumab
Figure: Sheridan JP, et. al. (Poster P430) Presented at the 25th Congress of European Committee for Treatment and Research in Multiple Sclerosis; Düsseldorf, Germany, September 9-12, 2009
1. Rose JW et al. Amer Acad Neurology. 2007: 69;

9. Intermediate-affinity
The IL-2 Receptor
High-affinity
IL-2R
Intermediate-affinity
IL-2R
The high-affinity IL-2R is composed of IL-2Rα, IL-2Rβ, and γC
IL-2Rα (CD25) has no known signaling function
IL-2Rβ and γC harbor all signaling capability
The intermediate-affinity IL-2R is composed of IL-2Rβ and γC but lacks the IL-2Rα1
IL-2Rα
(CD25) α
IL-2
IL-2 γ γ
IL-2 signaling is mediated via 2 IL-2 receptors:
The high-affinity IL-2 receptor is composed of the IL-2R  chain, the common  chain and an  chain also known as CD25.1
CD25 has no known signaling function whereas the  and  chains harbor all signaling capability.
The / chains are shared with IL-15R, whereas the  chain is shared with IL-4R, IL-7R, IL-9R, and IL-21R.2
The intermediate-affinity IL-2 receptor (IL-2R) is composed of the IL-2R chain and the common  chain.
The intermediate-affinity IL-2 receptor is present on resting and activated T cells1 whereas the high-affinity IL-2R is expressed when a T cell is activated.
DAC HYP is a high-affinity monoclonal antibody that binds the  subunit (CD25) of the IL-2 receptor and blocks its interaction with IL-2.
References
1. Wiendl H, Gross CC. Nat Rev Neurol. 2013;9:
2. Malek TR. Annu Rev Immunol. 2008;26:
Wiendl and Gross 2013: p3/col1/para1-2 β γC
(CD132)
IL-2Rβ
(CD122) β γC
(CD132)
Malek TR. Annu Rev Immunol. 2008: p457/col1/para2.
IL-2Rβ
(CD122)
DAC HYP=daclizumab high-yield process; IL=interleukin; R=receptor; γC=common gamma chain
1. Wiendl H, Gross CC. Nat Rev Neurol. 2013;9:
Wiendl and Gross 2013: abstract

10. Daclizumab HYP Proposed Mechanism of Action
High-affinity
IL-2R β γ
Intermediate-affinity
IL-2R
IL-2Rβ
(CD122) γC
(CD132)
IL-2Rα
(CD25)
DAC HYP binds the  subunit (CD25) of the high-affinity IL-2R and blocks its interaction with IL-2
DAC HYP does not block interaction between IL-2 and intermediate-affinity IL-2R α
By blocking the high-affinity IL-2R, DAC HYP modulates IL-2R signaling.
This slide depicts the high-affinity and intermediate-affinity IL-2 receptors (IL-2R) and their role in DAC HYP’s mechanism of action.1
DAC HYP selectively blocks the IL‑2 binding site of the high-affinity IL‑2 receptor by binding to CD25, thereby inhibiting assembly and signaling of the high-affinity IL‑2R. This results in:
DAC HYP only blocking IL-2 interaction with the high-affinity IL-2 receptor AND NOT blocking interaction between IL-2 and the intermediate-affinity receptor
This further results in increase of available IL-2 levels which can then interact with intermediate-affinity receptors on many cell types including CD56 bright NK cells, and expanding their numbers. NK cells are thought to control autoimmune T cells. Thus, DAC HYP modulates but does not completely block all IL-2 biology.
Key aspects of the DAC HYP’s mechanism of action:
Impairs CD25-dependent IL-2 signaling
Reduces CD25-dependent T-cell survival, proliferation, and effector function
Leads to proliferation of immunomodulatory CD56bright NK cells
Inhibits LTi cell development.
LTi=lymphoid tissue inducer; NK=natural killer
Reference
1. Wiendl H, Gross CC. Nat Rev Neurol. 2013;9: γ
IL-2Rβ
(CD122) β
Wiendl and Gross 2013: p1/col1/para2
And p2 key points γC
(CD132)
DAC HYP=daclizumbab high-yield process; IL=interleukin; R=receptor; γC=γcommon.
Wiendl H, Gross CC. Nat Rev Neurol. 2013;9:
Wiendl and Gross 2013: p6/col2/para2 and figure 3
Wiendl and Gross 2013: p2 key points

11. Daclizumab HYP Overview of Development1
2006
2007
2008
2009
2010
2011
2012
2013
2014
2015
2016
CHOICE (phase 2)
DAC* add-on with IFNβ
SELECT (phase 2)
DAC HYP vs placebo
SELECTION (phase 2)
DAC HYP blinded extension of SELECT
SELECTED (phase 2)
DAC HYP open-label extension of SELECTION
DECIDE (phase 3)
DAC HYP vs IM IFNβ-1a
EXTEND (phase 3)
DAC HYP open-label extension of DECIDE
N=230
N=621
N=517
N=420
N=1841
N=1204
*CHOICE used an investigational form of aclizumab different from daclizumab HYP
1Status as of May 2015
DAC=daclizumab; HYP=high-yield process; IFN=interferon; IM=intramuscular; RRMS=relapsing-remitting multiple sclerosis.

12. SELECT: Design Overview 52-Week Treatment Period
SELECT: MRI Substudy Design Overview
SELECT: Design Overview
SELECT: MRI Substudy Design Overview
52-Week Treatment Period
Placebo
Randomization
307 patients
Randomization
n=621 patients
DAC HYP 150 mg SC q4w
DAC HYP 300 mg SC every q4w 4 8 12 16 20 24 28 32 36 40 44 48 52
Primary endpoint
Annualized Relapse Rate
Secondary endpoints
New Gd+ lesions at weeks 8–24 (MRI substudy n=307)
Tertiary endpoint
EDSS disability progression at week 52
New T2 lesions at week 52
Proportion of subjects relapsing
Change in MSIS-29 physical score (quality of life measure)
Gold R, et al; SELECT study investigators. Lancet. 2013;381: .

13. SELECT Results: Annualized Relapse Rate (Primary Endpoint)
Adjusted ARR at end of trial (week 52)
50% relative
reduction
vs placebo
P=0.0002*
54% relative
reduction
vs placebo
P<0.0001*
Gold et al Lancet 2013: Results p4/col2/para1 and table 2
Gold et al Lancet 2013: Methods
p2/col2/para4 and p3/col1/p1
DAC HYP treatment resulted in 50-54% reduction of ARR relative to placebo in 1 year.
Results for the SELECT primary endpoint are presented in this slide.
ARR at 52 weeks was lower for patients in the DAC HYP 150-mg (54% reduction; 95% CI, 33-68) or 300-mg groups (50% reduction; 95% CI, 28-65%) than for those given placebo.
Reference
Gold R, et al; SELECT study investigators. Lancet. 2013;381:
Gold et al Lancet 2013: Results p4/col2/para1
Placebo (n=196)
DAC HYP 150 mg (n=201)
DAC HYP 300 mg (n=203)
*Estimated from a negative binomial regression model adjusted for number of relapses in 1-year period before trial entry, baseline EDSS score (≤2.5 vs >2.5), and age (≤35 vs >35 years)
ARR=annualized relapse rate; DAC HYP=daclizumab high-yield process; EDSS=Expanded Disability Status Scale. Gold R, et al; SELECT study investigators. Lancet. 2013;381:

14. SELECT Results: MRI Outcomes
Mean number of new Gd+ lesions at week 52
Adjusted mean number of new/ newly enlarging T2 lesions at week 52
70% relative reduction vs placebo P<0.0001*
79% relative reduction vs placebo P<0.0001*
86% relative reduction vs placebo P<0.0001*
79% relative reduction vs placebo P<0.0001*
DAC HYP treatment was associated with a significant reduction in the accumulation of new Gd+ lesions and new/newly enlarging T2 lesions.
MRI outcomes at week 52 are presented in this slide.
DAC HYP treatment reduced new MS lesion activity vs placebo.
Mean (SD) numbers of new Gd+ at week 52 were:
Placebo: 1.4 (2.3)
DAC HYP 150 mg: 0.3 (0.9); 79 % relative reduction vs placebo (P<0.0001)
DAC HYP 300 mg: 0.2 (0.7); 86 % relative reduction vs placebo (P<0.0001).
[Note: percent reduction not reported in paper, these data from slide deck]
Adjusted mean (95% CI) number of new/newly enlarging T2 hyperintense lesions at week 52 were:
Placebo: 8.1 ( )
DAC HYP 150 mg: 2.4 ( ); 70% relative reduction vs placebo (P<0.0001)
DAC HYP 300 mg: 1.7 ( ); 79% relative reduction vs placebo (P<0.0001).
In addition, in a subset of patients who had monthly MRI scans between weeks 8 and 24 (secondary endpoint), DAC HYP reduced mean (95% CI) number of new Gd+ lesions at weeks 8-24:
Placebo (n=104): 4.8 ( )
DAC HYP 150 mg (n=101): 1.5 ( ); P<0.0001
DAC HYP 300 mg (n=102): 1.0 ( ); P<
Longitudinal analysis showed that Gd+ lesion activity was greater in the 150-mg group than in the 300-mg group during weeks 4-24, but was similar at week 52.
Reference
Gold R, et al; SELECT study investigators. Lancet. 2013;381:
Gold et al Lancet 2013:results p. 5/col1/para2-3 and table 2
Placebo (n=195)
DAC HYP 150 mg (n=199)
DAC HYP 300 mg (n=200)
Placebo (n=195)
DAC HYP 150 mg (n=199)
DAC HYP 300 mg (n=200)
*Estimated from a proportional odds model adjusted for the baseline number of Gd+ lesions
*Estimated from a negative binomial regression model adjusted for the baseline number of T2 lesions
DAC HYP=daclizumab high-yield process; Gd+=gadolinium-enhancing.
Gold R, et al; SELECT study investigators. Lancet. 2013;381:
Gold et al Lancet 2013:results p. 5/col1/para3

15. Confirmed Disability Progression at End of SELECT
0.00
0.05
0.10
0.15 12 24 36 48 52
Time on study (weeks)
Proportion of patients with 12-week confirmed disability progression
43%
Reduction
P=0.091*
57%
P=0.021*
DAC HYP 150mg
DAC HYP 300mg
Placebo
Placebo
DAC HYP 150mg
DAC HYP 300mg
Proportion with 3-month confirmed disability progression
13.3%
5.9%
7.8%
*Estimated from Cox-proportional hazards model adjusting for baseline EDSS (≤2.5 vs. >2.5), and age (≤35 vs. >35),
Gold R, et al; SELECT study investigators. Lancet. 2013;381: .

16. SELECT: Adverse Events That Occurred in >5% of Patients During the Treatment PeriodAE
Placebo
(n=204)
DAC HYP 150 mg
(n=208)
DAC HYP 300 mg
(n=209)
MS relapse
38%
23%
20%
Nasopharyngitis
15%
14%
Upper respiratory tract infection 7% 9%
11%
Headache
10%
Pharyngitis 3% 6% 5%
Gold R, et al; SELECT study investigators. Lancet. 2013;381:

17. SELECT: Adverse Events of InterestAE
Placebo
(n=204)
DAC HYP
150 mg (n=208)
300 mg (n=209)
Infections
44%
50%
54%
Serious infections 0% 3% 1%
Cutaneous events*
13%
18%
22%
Injection site reaction, erythema, induration 2%
Serious cutaneous events
<1%
Malignancy
Death†
1 (<1%)
*Death: Patient recovering from serious cutaneous event died due to a complication of psoas abscess and ischemic colitis.
*Cutaneous events are those treatment-emergent AEs whose preferred term contains the word dermatitis, rash, or erythema, or whose preferred term is one of the following: drug eruption, drug hypersensitivity, dyshidrosis, eczema, granuloma annulare, pityriasis rosea, psoriasis, skin exfoliation, toxic skin eruption, urticaria. †Patient recovering from serious cutaneous event died due to a complication of psoas abscess and ischemic colitis Gold R, et al; SELECT study investigators. Lancet. 2013;381:

18. SELECT: Incidence of ALT/AST Abnormalities
Placebo
n=204
DAC HYP
150 mg
n=208
300 mg
n=209
1–3× ULN, n (%)
64 (31)
54 (26)
62 (30)
3–5× ULN, n (%)
6 (3)
7 (3)
>5× ULN, n (%)
1 (<1)
9 (4)
8 (4)
Abnormalities of ALT/AST >5× ULN
Typically occurred late in the treatment period (median onset day = 308)
Median recovery time = 62 days
7 patients resumed or continued therapy. None of these patients had a recurrence in the liver function test or abnormality in the next 5 months (the minimum period for which follow-up was available)
ALT=alanine aminotransferase; AST=aspartate aminotransferase; ULN=upper limit of normal. Gold R, et al; SELECT study investigators. Lancet. 2013;381:

19. SELECT and SELECTION: Design Overview
Double-Blind Treatment
DAC HYP 300 mg SC every 4 weeks (n=209)
DAC HYP 150 mg SC every 4 weeks (n=208)
Placebo (n=204) 4 8 12 16 20 24 28 32 36 40 44 48 52
SELECT: N=621
SELECTION: N=517
DAC HYP 150 mg (n=86)
DAC HYP 300 mg (n=84)
24-week washout (n=86)
DAC HYP 150 mg
DAC HYP 150 mg (n=86)
24-week washout (n=88)
DAC HYP 300 mg
DAC HYP 300 mg (n=87) 4 8 12 16 20 24 28 32 36 40 44 48 52
Primary endpoint
Annualised relapse rate
Primary endpoint
Safety and immunogenicity
Gold R et al. Lancet. 2013;381: ; Giovannoni G et al. Lancet Neurol. 2014;13:

20. SELECTION: Annualized Relapse Rate
Year 1
Placebo (n=163)
Year 1
DAC HYP (n=129)
Year 2
DAC HYP (n=129)
DAC HYP results are combined data for patients on continuous treatment with 150 mg or 300 mg.
Giovannoni G et al. Lancet Neurol. 2014;13:

21. Confirmed Disability Progression Proportion of Patients with 3-Month
SELECTION: Confirmed Disability Progression over 2 Years of DAC HYP Treatment
Placebo year 1
DAC HYP year 1
DAC HYP continuous
DAC HYP after placebo
0.3
0.2
0.1
0.0
Placebo patients
start DAC HYP
16%
Confirmed Disability Progression
Proportion of Patients with 3-Month
DAC HYP
13%
12%
K-M plot of time to sustained progression of disability for 3 months measured by an increase in EDSS score from baseline of SELECT over 2 years – ITT population.
Sustained progression is defined as at least a 1.0 point increase on the EDSS from a SELECT baseline EDSS score >= 1.0 sustained for 3 months or at least a 1.5 point increase on the EDSS from a SELECT baseline EDSS score of 0 sustained for 3 months. A cutoff of 74 days was used to determine sustained progression for 3 months.
Placebo
DAC HYP 7%
DAC HYP
(Year 2)
n=163
DAC HYP
Time on Study (months)
DAC HYP results are combined data for patients on continuous treatment with 150 mg or 300 mg.
Giovannoni G et al. Lancet Neurol. 2014;13:

22. SELECTION: MRI Assessments After 2 Years
New or Newly Enlarging T2 Lesions
Mean Number of New/Enlarging T2-Hyperintense Lesions
Year 1
Placebo (n=163)
Year 1
DAC HYP (n=129)
Year 2
DAC HYP (n=129)
DAC HYP results are combined data for patients on continuous treatment with 150 mg or 300 mg.
Giovannoni G et al. Lancet Neurol. 2014;13:

23. SELECTION: After 24-Week Washout from DAC HYP, Gd+ Lesions were Below Pre-treatment Baseline
End of 24 week washout
Number New Gd+ Lesions (mean)
End of 24 week washout
DAC HYP 150 mg
DAC HYP 300 mg
Year 1
Year 2
Year 1
Year 2
DAC HYP results are combined data for patients on continuous treatment with 150 mg or 300 mg.
Giovannoni G et al. Lancet Neurol. 2014;13:

24. SELECTION: Adverse Events of Interest
DAC HYP Starters
Year 1 of DAC HYP
DAC HYP Continuous
Year 2 of DAC HYP
DAC HYP Washout / Reinitiation
DAC HYP 150 mg
(n=86)
DAC HYP 300 mg
(n=84)
DAC HYP 150 mg
(n=87)
(n=88)
Serious Infections, n (%)
3 (3)
1 (1)
2 (2)
Serious Cutaneous Events, n (%)
ALT/AST > 5x ULN, n (%)
4 (5)
Malignancy, n
Death*
*One patient in the washout and re-initiation group died because of autoimmune hepatitis after re-initiation of 300 mg daclizumab HYP. Alanine aminotransferase was increased to 195 U/L about 8 weeks after re-initiation of daclizumab HYP and continued to rise in the following 3 months to 638 U/L in conjunction with an increase in serum bilirubin concentration to 1・5–2-times greater than the upper limit of normal before clinical symptoms of liver failure developed. The diagnosis of autoimmune hepatitis was made late in the disease course on the basis of an increased serum concentration of IgG and was confirmed with liver histology findings at autopsy. A contributory role of daclizumab HYP could not be excluded.
ALT, alanine aminotransferase; AST, aspartate aminotransferase; ULN, upper limit of normal
*One patient in the washout and re-initiation group died because of autoimmune hepatitis after re-initiation of 300 mg daclizumab HYP
DAC HYP results are combined data for patients on continuous treatment with 150 mg or 300 mg.
Giovannoni G et al. Lancet Neurol. 2014;13:

25. DECIDE: Study Design Overview
24-week follow-up
week treatment period
IM IFNβ-1a 30 μg every 1 week (n=922)
Randomization
(n=1841)
Follow-up
SC DAC HYP 150 mg every 4 weeks (n=919) 4 8 12 16 20 24 28 32 36 40 44 48
96-144 CD 56
CD56bright NK cell count* CD 56 CD 56 CD 56 CD 56 CD 56 CD 56 CD 56
EDSS and MSFC-3
assessments*
EDSS
Randomized double-blind, active-controlled study conducted to evaluate once-monthly DAC HYP as monotherapy as compared to INF-beta. Enrollement ended April (FYI US had 220 pts).
DECIDE is one of the only trials in MS designed to show reduction in annualized relapse rate and disease progression over 2 yrs versus an active comparator.
Avonex was selected as active comparator because it is an established trt for MS.
Primary Endpoint: ARR with objective of testing the superiority of DAC HYP sc over IFN-beta-1a IM in preventing relapse in pts with RRMS.
Secondary are disability progression and MRI efficacy measures (Gd+, T2)
EXTEND study- designed to provide up to 3 additional yrs of efficacy and safety data from DECIDE and started to enroll in Feb EXTEND will include a 6 month AUTOinjector sub-study (N<100 pts) and will include sites from US and other countries. Pts will be eligible to participate in EXTEND AUTO-injector sub-study after 9 months (week 36) roll-over into EXTEND.
EDSS
EDSS
EDSS
EDSS
EDSS
EDSS
Brain MRI
All subjects had a minimum of 2-years and maximum of 3-years of treatment Trial ended when last subject randomized completed 2-years
* Also assessed at weeks 60, 72, 84, 108, 120, 132, 144
EDSS, Expanded Disability Status Scale; DAC HYP=daclizumab high-yield process; IFN=interferon; IM=intramuscular; MSFC-3=Multiple Sclerosis Functional Composite; NK=natural killer; SC=subcutaneous;
Kappos L, Selmaj K, Arnold D, et al. Primary results of DECIDE: a randomized, double-blind, double-dummy, active-controlled trial of daclizumab HYP vs. interferon β-1a in RRMS patients. Presented at: Joint ACTRIMS-ECTRIMS Meeting. September 10-13, Boston, MA

26. DECIDE: Primary Endpoint Annualized Relapse Rate
45% Reduction (95% CI: 35.5%, 53.1%) p<0.0001
ARR
Kappos L, Selmaj K, Arnold D, et al. Primary results of DECIDE: a randomized, double-blind, double-dummy, active-controlled trial of daclizumab HYP vs. interferon β-1a in RRMS patients. Presented at: Joint ACTRIMS-ECTRIMS Meeting. September 10-13, Boston, MA

27. DECIDE: MRI Results 9.4 4.4 1.0 Mean number of lesions 4.3 2.1 0.4
*New/Newly Enlarging T2 Lesions
54% Reduction
P<0.0001
1.0
0.4
†New Gd+ Lesions
65% Reduction
P<0.0001
4.4
2.1
†New T1 Hypointense Lesions
‘blackholes’
52% Reduction
P<0.0001
Mean number of lesions
Key secondary endpoints:
DAC 150 mg: 54% reduction in new and newly enlarging T2 lesions at week 96 (P<0.0001)
DAC 150 mg: 16% reduction in 3-month confirmed disability progression confirmed disability progression (P=0.16)
Assuming disability confirmation based on observed rate in trial, DAC reduced 3-month confirmed disability by 21% (P=0.047)
n=841
n=864
n=909
n=900
n=908
n=899
IFN beta-1a 30 mcg
DAC HYP 150 mg
*2-year endpoint
† Tertiary Endpoints
Kappos L, Selmaj K, Arnold D, et al. Primary results of DECIDE: a randomized, double-blind, double-dummy, active-controlled trial of daclizumab HYP vs. interferon β-1a in RRMS patients. Presented at: Joint ACTRIMS-ECTRIMS Meeting. September 10-13, Boston, MA

28. DECIDE: Results Confirmed Disability Progression
DAC 150 mg: 16% reduction in 3-month confirmed disability progression confirmed disability progression (P=0.16)
Assuming disability confirmation based on observed rate in trial, DAC reduced 3-month confirmed disability by 21% (P=0.047)
*3-month confirmed: Patients censored after tentative progression (n-67) analyzed per primary method in the statistical analysis plan; secondary endpoint; all imputed as non-progressors;
†6-month confirmed: Patients censored after tentative progression (n=108) imputed per observed rate in trial; tertiary endpoint. Estimated proportions are the average over imputed datasets. For both endpoints risk reduction based on Cox proportional hazards model adjusted for baseline EDSS, history of prior IFN use, and age.
Kappos L, Selmaj K, Arnold D, et al. Primary results of DECIDE: a randomized, double-blind, double-dummy, active-controlled trial of daclizumab HYP vs. interferon β-1a in RRMS patients. Presented at: Joint ACTRIMS-ECTRIMS Meeting. September 10-13, Boston, MA

29. DECIDE: Overview of Safety
Deaths: 4 in AVONEX group, 1 in DAC; all considered not related to drug
Similar safety results for risk of infections and cutaneous events as in SELECT
Serious infections: DAC 4% AVONEX 2%
Serious cutaneous reactions: DAC 2% AVONEX <1%
Transaminases > 5 x ULN: DAC 6% AVONEX 3%
* All deaths were considered unrelated to treatment. The death in the DAC HYP group was due to aspiration pneumonia in a patient who had a MS relapse involving the brain stem and after withdrawing from the study. Deaths in the IFN beta-1a group were due to myocardial infarction, completed suicide, metastatic pancreatic cancer and peritonitis. AE, adverse event; SAE, serious adverse event
Kappos L, Selmaj K, Arnold D, et al. Primary results of DECIDE: a randomized, double-blind, double-dummy, active-controlled trial of daclizumab HYP vs. interferon β-1a in RRMS patients. Presented at: Joint ACTRIMS-ECTRIMS Meeting. September 10-13, Boston, MA

30. DECIDE: Common Adverse Events ≥10% of patients in any treatment group
Deaths: 4 in AVONEX group, 1 in DAC; all considered not related to drug
Similar safety results for risk of infections and cutaneous events as in SELECT
Serious infections: DAC 4% AVONEX 2%
Serious cutaneous reactions: DAC 2% AVONEX <1%
Transaminases > 5 x ULN: DAC 6% AVONEX 3%
Selmaj K, et al. Safety and tolerability of daclizumab HYP treatment in relapsing-remitting multiple scleorosis: Results of the DECIDE study. Presented at: Joint ACTRIMS-ECTRIMS Meeting. September 10-13, Boston, MA

31. DECIDE: Adverse Events of Interest
Deaths: 4 in AVONEX group, 1 in DAC; all considered not related to drug
Similar safety results for risk of infections and cutaneous events as in SELECT
Serious infections: DAC 4% AVONEX 2%
Serious cutaneous reactions: DAC 2% AVONEX <1%
Transaminases > 5 x ULN: DAC 6% AVONEX 3%
*Clinical assessment of causality based on structured approach (Rockey et al Hepatology 51:2117). One case in each group with causality score of “probable” or higher. ALT, alanine aminotransaminase; AST, aspartate aminotransaminase; ULN, upper limit of normal.
Kappos L, Selmaj K, Arnold D, et al. Primary results of DECIDE: a randomized, double-blind, double-dummy, active-controlled trial of daclizumab HYP vs. interferon β-1a in RRMS patients. Presented at: Joint ACTRIMS-ECTRIMS Meeting. September 10-13, Boston, MA

32. Anti-LINGO-1* Multiple Sclerosis (MS) & Acute Optic Neuritis (AON)
LINGO - “Leucine-rich repeat and Ig domain containing Nogo Receptor-interacting protein1
LINGO-1
Transmembrane protein that is selectively expressed in the brain and spinal cord1, 2
Expressed in neurons and oligodendrocyte precursor cells1, 2
Appears to inhibit oligodendrocyte precursor cell1, 2 differentiation
Antagonism of LINGO-1 leads to enhanced oligodendrocyte maturation and myelin production3
1Mi S, et al. Nature Neurosci. 2004;7:1-8, 2Mi S, et al. Int J Biochem Cell Biol. 2008;40: , 3Mi S, et al. Nature Neurosci. 2005;8:
*Anti-LINGO is an investigational candidate

33. Anti-LINGO-1 Multiple Sclerosis (MS) and Acute Optic Neuritis (AON)
Current treatments focus on targeting the immunological response
Anti-LINGO-1 (BIIB033) is the first drug candidate that targets CNS repair in MS through remyelination1
LINGO-1 is a CNS-specific, leucine-rich repeat (LRR) and lg-domain, membrane-associated glycoprotein2
Hypothesized that blocking the action of LINGO-1 may allow neuronal repair and remyelination following CNS injury1
Data on File. Biogen.
1. Rudick R et al. Expert Opin. Biol. Ther. 2008; 8(10):
2. Mi S, et al. Nature. 2004: 7;

34. Anti-LINGO-1 Mature oligodendrocyte
Lingo-1 protein prevents oligodendrocyte maturation
LINGO-1, allrly
Anti-LINGO-1 antibody binds LINGO-1, allowing oligodendrocytes to mature and function properly
LINGO-1, allrly
LINGO-1, allrly
Oligodendrocytes are brain cells that provide support and protection to neurons by myelinating their axons
In MS, oligodendrocytes are damaged and do not fully mature and, therefore, do not function properly
LINGO-1 a protein found in oligodendrocytes that suppresses their differentiation
ANTI-LINGO-1 is a monoclonal antibody that inhibits LINGO-1, allowing the oligodendrocytes to mature and provide myelination to neuronal axons
Myelinating
oligodentrocytes
Immature oligodentrocytes
Ndubaku U, deBellard ME. Acta Histochem. 2008;100:
Adapted from Jackman N et al. Physiology. 2009;24: ; Zhang SC. Nat Rev Neurosci. 2001;2:

35. LINGO-1 Blockade Resulted in Oligodendrocyte Differentiation
P<0.001 5 10 15 20 25
Control RNAi
Mature Oligodendrocytes
(% Total)
Lentivirus carry LINGO-1 specific RNAi infected oligodendrocytes shows that reduction of LINGO-
1 resulted in more highly differentiated, mature (MBP+) oligodendrocytes compared to control infected cells as
evident by increases in the length of cell processes and the presence of abundant myelin sheet-like structures, white arrow.
In LINGO-1 RNAi expressing cells there were 3 times as many mature oligodendrocytes as in control cultures (bar graph).
LINGO-1 expression was reduced by infection with LINGO-1 RNAi
lentivirus, and confirmed by RT-PCR (agarose gel).
LINGO-1 RNAi
No RNAi
Control RNAi
LINGO-1 RNAi
RNAi=ribonucleic acid interference.
Mi S et al. Nat Neurosci. 2005;8:

36. Anti-LINGO-1 Antibody Resulted in Remyelination in Animal Models of Demyelination
Control
Anti-LINGO-1
Cuprizone model
(1 µg/local)
Lysolecithin model
(1 mg/kg/IP)
Experimental autoimmune encephalitis (EAE)
(3 mg/kg/IP) *
Anti-LINGO-1 dose originally given but not confirmed from paper
Curizone model: 1 µg/local
Lysolecithin model: 1 mg/kg/IP
EAE model: 3 mg/kg/IP * * * *
Adapted from Mi S et al. Ann Neurol. 2009;65: ; Mi S et al. Presented at ECTRIMS; October 13–16, 2010; Gothenburg, Sweden. P731. * *
Demyelinated Axons
Remyelinated Axons

37. Anti-LINGO-1 Phase 1 Studies: Safety in Humans
Completed Single Ascending Dose (IV And SC) Study in Healthy Volunteers and a Multiple Ascending Dose (2 IV Doses 2 Weeks Apart) in MS Subjects (RRMS and SPMS)
In the multiple ascending dose study, common adverse events for anti-LINGO-1 at doses ranging from 0.3 mg/kg–100 mg/kg (combined) vs placebo were
Urinary tract infection (16% vs 13%)
Headache (16% vs 13%)
Upper respiratory tract infection (9% vs 20%)
PK was linear with a T1/2 typical of a mAb (≈2–3 weeks)
CSF penetration was low (≈0.1% of serum levels), but concentrations reached levels ≥EC90* values at 10 mg/kg dose
Findings supported advancing into phase 2 studies
*90% effective concentration. SC=subcutaneous; RRMS=relapsing-remitting MS; SPMS=secondary progressive MS; PK=pharmacokinetics; T1/2=half life.
Tran J et al, Neurology Neuroimmunology (N2 Journal) 2014; 1 (18)

38. Anti-LINGO-1 Phase 2 Studies
RENEW
Acute Optic Neuritis
Placebo-controlled proof of biology
Subjects with recent first episode of acute optic neuritis
Dose: 100 mg/kg q4wks×6
Endpoints:
Visual evoked potential (VEP)/multifocal VEP (latency delay)
Optical coherence tomography (retinal nerve fiber and ganglion cell layer loss)
Visual function (low contrast letter acuity, visual quality of life)
SYNERGY
Relapsing Forms of MS
Placebo-controlled proof of concept and dose ranging
Subjects with RRMS and relapsing SPMS receiving IM IFNβ-1a
Dose: 3, 10, 30, 100 mg/kg q4wks×18
Physical and cognitive endpoints:
EDSS/T25FW/9HPT/PASAT composite
Primary=improvement
Key secondary=delayed progression
MS-COG (information processing and learning and memory)
MRI (MTR, DTI, black holes, atrophy)
IM=intramuscular; IFNβ=interferon beta; EDSS=Expanded Disability Status Scale; T25FW=Timed 25-Foot Walking Test; 9HPT=9-Hole Peg Test; PASAT=Paced Auditory Serial Addition Test; DTI=diffusion tensor imaging.
Cadavid D et al. Presented at AAN; April 26–May 3, 2014; Philadelphia, PA USA. RENEW: P2.262; SYNERGY: P3.154.

39. Anti-LINGO-1 Phase 2 AON Study (RENEW) Completed
Subjects with first episode of acute optic neuritis
N=82 subjects randomized, 2 arms, 33 sites
Evaluating efficacy after onset of inflammatory CNS demyelination in a clinically eloquent area (the optic nerve)
The visual system affords an opportunity to study the functional consequences of CNS remyelination
Neurophysiology (VEP/mfVEP)
Survival of retinal ganglion cells (OCT)
Clinical benefit (contrast acuity)
Top line results revealed evidence of proof of biology for remyelination
34% improvement in average FF-VEP latency recovery at 24wks (p )
VEP=visual evoked potential; mfVEP=multifocal VEP; OCT=optical coherence tomography.

40. Anti-LINGO-1 Phase 2 MS Study (SYNERGY) Fully-enrolled and ongoing*
Active relapsing forms of MS
418 patients enrolled, 5 arms, 72 sites, 12 countries
Active relapsing MS patients will receive IM IFN beta-1a plus anti-LINGO-1 (4 doses) or IM IFN beta-1a plus placebo
18-months treatment duration allows study of clinical benefit
Allows the study of efficacy in preventive mode (with drug on board before new lesions develop) but also on pre-existing lesions
Advanced MRI methodology to study the morphological features of CNS repair
*As of May 2015

41. TYSABRI® (natalizumab)* Secondary Progressive MS (SPMS)
*Though approved for some indications, TYSABRI is an investigational candidate for SPMS

42. Secondary Progressive MS (SPMS)
Prevalence
Majority of patients with relapse remitting multiple sclerosis (RRMS) eventually develop secondary progressive multiple sclerosis (SPMS)
50% at 10 years; 90% at 25 years
At any given time, 30-40% of MS patients suffer from progressive disease1
SPMS Pathology
Intrathecal chronic inflammation drives secondary neurodegeneration via soluble toxic mediators in the CSF2
41% of brain autopsy specimens have ectopic meningeal lymphoid tissues3
1. Protocol 101MS326 Biogen Idec. 2. UK MS Brain Tissue Bank Data. 3. Magliozzi R et al, 2007.

43. Natural History of MS: Clinical and MRI Measures
Relapses/Disability
MRI T2 lesion load
MRI Activity
Secondary Progressive MS
Brain Volume
Preclinical
Relapsing-Remitting MS
Disability
Given variability in how disability is expressed from patient to patient and over time, what is the preferable outcome measure in MS?
MOTOR
SENSORY
BALANCE COGNITION
VISUAL
Etc. etc.
Time
Data on File. Biogen

44. RRMS  SPMS: Moving from an Acute, Focal Inflammatory Process to Chronic, Compartmentalized Global Inflammation
Meningeal lymphoid germinal-like centers
Perivascular white matter infiltrates
Modified from Uccelli et al
Trends Immunol. 26:
RRMS Exacerbation
Major Inflammation
Very high chemokine levels
Early Progressive MS
Less Inflammation
Moderate-low chemokine levels
CIS, RRMS
Inflammation
Moderate chemokine levels
Late Progressive MS
Low, but significant chemokine levels
Acute Gd+ Lesions
(White Matter)
Meningeal Foci
(Grey Matter)
“Chronic lesions”
Cortical Pathology
Illustration by Diego Cadavid and Jeff Browning. Biogen

45. Clinical Features of Progressive MS Phenotypes
Motor impairment
Progressive spastic paraparesis (weakness in the legs)1
Presenting symptom in majority of patients with progressive forms of MS (80%)
Involves impaired mobility with weakness, stiffness, clumsiness, dragging of legs
Impacts ability to walk long distances without rest
Progressive ataxic syndrome with cerebellar and brainstem involvement
Second most common presentation (15%)1-3
Upper limb dysfunction and impairment in activities that require manual dexterity4
Bladder and bowel dysfunction
Urgency and incontinence1
Predominant spinal cord involvement5,6
Cognitive symptoms
Progressive cognitive deficits are infrequent
Less common in PPMS than SPMS7
MS, multiple sclerosis; PPMS, primary progressive MS; SPMS, secondary progressive MS.
1. Miller DM, Leary SM. Lancet Neurol. 2007;6: ; 2. Tremlett H et al. J Neurol. 2009;256: ; 3. Harding KE et al. J Neurol Neurosurg Psychiatry. 2014;Jun 4. [Epub ahead of print]; 4. Holper L et al. J Neurol. 2010;257: ; 5. Thompson AJ et al. Brain. 1997;120: ; 6. Comi G. Mult Scler. 2013;19: ; 7. Comi G et al. J Neurol Sci. 1995;132:

46. Rationale for Natalizumab Treatment in SPMS
It is believed to prevent trafficking of lymphocytes across blood vessels and into the brain and spinal cord
May also suppress inflammation within the CNS1
Possible reduction in CXCL13 levels in the CSF of patients with active and progressive MS
Possible reduction in intrethecal levels of osteopontin, another molecule that has been implicated in MS progression at the experimental level
Post-hoc analyses of relapsing and non-relapsing SPMS studies suggest that natalizumab may be beneficial (T25FW, 9HPT)2
Speculative MoA: Peripheral effects, known, relevant to RRMS
Central effects?
Inhibition of binding of α4-positive lymphocytes with osteopontin/fibronectin. Thus, natalizumab may act to suppress existing inflammatory activity present within CNS
Christensen JR et al. Neurology. 2014;82;
Sellebjerg et al. Multiple Sclerosis (S4):

47. Ongoing Development & Research
ASCEND Trial Overview
An investigation of whether TYSABRI treatment slows the accumulation of disability not related to relapses in patients with SPMS
Primary endpoint: the proportion of subjects experiencing confirmed progression of disability as measured by a composite endpoint
FDA special protocol assessment (SPA) obtained with accepted regulatory endpoint
Study fully enrolled in May 2013 (N=889)
Data readout expected 2015
SCR=screening; R=randomization; IV=intravenous; q4w=once every 4 weeks.
Data on File. Biogen.

48. TYSABRI® (natalizumab)* Acute Ischemic Stroke
*Though approved for some indications, TYSABRI is an investigational candidate for acute ischemic stroke

49. TYSABRI in Ischemic Stroke
Prevalence
There are nearly 800,000 strokes of all types per year in the US
Ischemic stroke accounts for approximately 80%
Treatment
Recombinant tissue plasminogen activator (rtPA) only approved pharmacological therapy for acute ischemic stroke. Must be used within 3 hours of stroke onset (US Guidelines)
TYSABRI could be used as an adjunctive therapy with TPA
Blocking the α4β1 integrin with natalizumab is expected to reduce peri-stroke inflammation and thereby reduce the expansion of the infarct due to inflammation
Potential to be the first disease-modifying, anti-inflammatory therapeutic for stroke, with better efficacy and safety than TPA
As a result of acute dosing, PML is not expected to be an observed AE in stroke.
Data On File. John Walsh
Roger 2011 (From Protocol 101SK201)
Data On File. Biogen.
Roger 2011 (From Protocol 101SK201)

50. Etiology of Acute Ischemic Stroke (AIS)
Obstructed blood flow in the brain leads to ischemia
Blockage
Ischemic tissue
Ischemic Penumbra
Core ischemic zone
Infarction
Penumbra
Thrombus
ADDITIONAL MATERIAL FOR INTERNAL USE ONLY
This slide shows the etiology of AIS. It should be noted in this slide that stroke can only grow to the size of tissue bed which is left unperfused. The penumbra of ischemic tissue will eventually infarct if left alone and it is this area of ischemic tissue which we are trying to target with natalizumab.
Formation of a blood clot1
When a blood vessel is injured, the body uses platelets and fibrin to form blood clots which prevents blood loss; even when a blood vessels is not injured, blood clots can form in the body under certain conditions. The formation of a blood clot inside a blood vessel obstructing the flow of blood is called thrombosis. A blood clot that forms in a vessel and remains there is called a thrombus.
Other causes of AIS1
Carotid artery dissection – caused by a tear in one of the carotid arteries of the neck, which allows blood under arterial pressure to enter the wall of the artery and split its layers, which results in either an intramural hematoma or an aneurysmal dilatation
Vasoconstriction – caused primarily by blood vessel spasm (vasospasm)
Atherosclerosis – caused by artery walls thickening as a result of the accumulation of calcium and fatty materials such as cholesterol and triglyceride which reduces their elasticity and allows less blood to travel through them
The Internet Stroke Center. Ischemic Stroke. Available at: Accessed: Feb 2014
Abbreviations
AIS=acute ischemic stroke
Clot within artery blocks normal flow to the brain
Loss of blood supply results in ischemia
Two major zones of injury:
● Core ischemic zone
● Ischemic penumbra
Ischemia = restriction in blood supply to tissues
Core ischemic zone = area of severe ischemia (blood flow <10–25%)
Ischemic penumbra = rim of mildly-to-moderately ischemic tissue
Saver JL. Stroke 2006;37:263–6

51. Etiology of Acute Ischemic Stroke (AIS)
Ischemia leads to infarction (neuronal death)
Minutes after blockage, an ischemic cascade is initiated, leading to neuronal death (infarct) at the core zone
Unless blood flow is promptly restored, the penumbra also infarcts, resulting in a larger total infarct volume1
Golden treatment window during which pharmacologic or mechanical interventions are most likely
to be effective
ADDITIONAL MATERIAL FOR INTERNAL USE ONLY
This slide shows the etiology of acute ischemic stroke.
Pathophysiology1
Ischemia is a condition in which there is insufficient blood flow to the brain to meet metabolic demand, which results in poor oxygen supply and thus death of brain tissue (infarction). During a typical untreated AIS, 32,000 neurons are lost every second. Within an hour 120 million neurons are lost. Within 10 hours 1.2 billion neurons are lost, which ages the brain by 35 years. Therefore, the longer a stroke goes without medical attention, the greater the chance of permanent neurologic damage. It follows that the earlier a treatment is administered – the greater the chance that the infarct volume will be reduced. It should be noted that the window for intervention in ischemic penumbra is poorly defined and is dependent on the location of the ischemia and the patient’s collateral blood flow. It is, therefore, difficult to define a “golden hour” of treatment.
Process of ischemia (ischemic cascade)2 The process of ischemia is started by a series of biochemical reactions (ischemic cascade) that are initiated in the brain seconds after ischemia. The ischemic cascade is not always linear, in some cases it can be circular as one event can cause or be caused by multiple events. Also, cells receiving different amounts of blood June go through different chemical processes. Generally the ischemic cascade is characterized by an initial lack of oxygen which causes the neurons normal process for making ATP for energy to fail. This in turn halts ion transport pumps which results in an excess of calcium with in the cell and causes the production of cytotoxic chemicals which eventually results in cell necrosis.
Saunders et al. study3
Saunders et al. studied the reproducibility and accuracy of measurements of infarct volume using MRI and correlated the measurements with the patients’ functional outcomes. Patients (n=23) with cortical MCA territory infarcts were studied up to 72 hours after of stroke onset in a study which lasted over 2 years. Infarct volume was measured on T2 weighted FLAIR MRI.
It was found that measurements of infarct volume were highly accurate and reproducible. The Scandinavian Stroke Scale was used to calculate a prognostic score, and clinical outcomes were assessed at 3 months.
Infarct volume was found to significantly predict outcome. Mean infarct volume in the independent patients was 35.7±29.7cm3 compared with 88.3±71.3cm3 in dependent patients and 166.5±65.9cm3 in dead patients (p<0.001). The study concluded that measuring the size of middle cerebral artery infarction with MRI is a useful tool in assessing the prognosis and has a valuable role is assessing new therapeutic agents.
1. Saver JL et al. Stroke 2006;37:263–6
2. Idadecola C et al. Nature Medicine 2011;17:796–808
3. Saunders DE et al. Stroke 1995;26:2272–6
Abbreviations
AIS=acute ischemic stroke
ATP=Adenosine triphosphate
FLAIR=Fluid attenuated inversion recovery
MCA=Middle cerebral artery stroke
MRI=Magnetic resonance imaging
The larger the infarct volume, the worse the
clinical outcomes for AIS patients2
1. The Internet Stroke Center. The Ischemic Penumbra. Available at: Accessed: Jan 2014; 2. Saunders DE et al. Stroke 1995;26:2272–6

52. Common long term outcomes
Acute and long-term functional outcomes in AIS Type and degree of long-term disability depend upon area of brain affected and extent of damage
ADDITIONAL MATERIAL FOR INTERNAL USE ONLY
This slide shows the acute and long-term functional outcomes of AIS patients using the mRS. The data on this slide come from a study by Petty et al.1 who studied all residents of Rochester, Minnesota, with a first ischemic stroke from 1985– mRS was used to assess functional outcome at the time of stroke, 3 months and 1 year later. A neurologist and a nurse abstractor abstracted the medical record of each patient and recorded on standardized forms information regarding stroke risk factors and functional status before or at the time of first cerebral infarction and diagnostic studies, treatment, and dates of last follow-up and death after the stroke before January 1, 1993.
Maximal deficit is defined as the maximal severity of neurological deficits within the first 7 day after stroke measured by the mRS.
Outcomes in the study focussed on functional outcomes, rather than specific deficits as it can be difficult to assess a stroke patient’s outcome solely by describing their disabilities post-stroke. For example, some patients with hemiplegia (paralysis on one side of the body) can function well in everyday tasks and even return to work despite having half their body paralysed, whereas other patients would require supervision 24 hours a day.
1) Petty GW et al. Stroke 2000;31:1062–8
Abbreviations:
AIS=acute ischemic stroke
mRS=modified Rankin Scale
Common long term outcomes
paralysis/problems controlling movement
problems using or understanding language
sensory disturbances
problems with thinking and memory
emotional disturbances
*p= AIS=acute ischemic stroke; mRS=modified Rankin Scale
Petty GW et al. Stroke 2000;31:1062–8
No significant or slight disability: Rankin score of I or II; Moderately severe or severe disability: Rankin score of IV, V or dead

53. Natalizumab as AIS Therapy Natalizumab is believed to block the migration of lymphocytes that are thought to mediate post-AIS inflammatory responses that increase infarct volume
1. Natalizumab, an a α4β1 integrin antibody ( ), binds to α4β1 integrin receptors on all human leukocytes (except polymorphonuclear leukocytes)1
α4β1
integrin
2. Natalizumab binding blocks CNS α4β1 integrin from interacting with its ligand, vascular cell adhesion molecule-1 (VCAM-1), on the endothelial wall1
VCAM-1
ADDITIONAL MATERIAL FOR INTERNAL USE ONLY
This slide shows the hypothesized mechanism of action of natalizumab. Adhesion molecules are involved in the inflammatory demyelination process in the CNS. Adhesion molecules and ligands expressed on endothelial cells and leukocytes mediate the entry of activated T- and B-lymphocytes and monocytes into the CNS. The glycoprotein α4β1 integrin is one of these adhesion molecules and is expressed on lymphocytes, monocytes, mast cells, macrophages, basophils and eosinophils but not neutrophils. The expression of the α4β1 integrin increases after T-cell activation.
Natalizumab’s mechanism of action1
Natalizumab binds to α4β1 integrin on the surface of activated T-cells and other mononuclear leukocytes, preventing cellular adhesion between the T-cell and the endothelial cell – this disruption of the cell adhesion molecule’s interactions results in the prevention of mononuclear leukocyte migration across the endothelium and into the parenchyma, with a subsequent reduction in proinflammatory cytokines. A further mechanism of natalizumab June be the suppression of ongoing inflammatory reactions in diseased tissues by inhibiting the binding of α4-positive leukocytes with osteopontin and fibronectin. There are three potential modes of action:
Blockade of migration by blocking adhesion to endothelial cells and interaction with extracellular matric proteins
Blockade of priming by interaction with osteopontin and VCAM expressed on microglial cells and monocytes in situ
Induction of apoptosis by blocking interaction of α4-integrin bearing leukocytes with extracellular matrix proteins
Therefore, natalizumab June have dual anti-inflammatory effects: inhibition of recruitment of immune cells into inflamed tissue and suppression of existing inflammatory activity at the disease site.
Rudick RA et al. NEJM 2006;354:911–23
Abbreviations:
CNS=central nervous system
VCAM=endothelial vascular adhesion molecule 1
3. Blocking entry of leukocytes into the brain suppresses the inflammatory activity thought to cause post-AIS increases in infarct volume2
CNS=central nervous system,
1. Rudick RA et al. NEJM 2006;354:911–23; 2. Protocol 101SK201. Data on file. Biogen, Jun 2013

54. ACTION Phase II Study Primary objective:
Effect of a single dose of natalizumab infarct volume in AIS patients who have either already received, or are ineligible for, IV rt-PA treatment
Primary objective:
To assess the effect of natalizumab on infarct volume over first 5 days after stroke
Secondary objectives – to assess:
The effect of natalizumab on infarct growth at multiple time points after ischemic stroke
The effect of natalizumab on disability and neurological function (BI, mRS, NIHSS etc)
The safety of natalizumab via physical and neurological examinations:
vital sign measurements
hematology and blood chemistry
anti-natalizumab antibodies
monitoring of AEs and SAEs
Baseline
5 days
ADDITIONAL MATERIAL FOR INTERNAL USE ONLY
Effect of Natalizumab on Infarct Volume in Acute Ischemic Stroke (ACTION)
MRI scans
This slide shows the phase II study objectives. At the baseline the infarct will be measured using DWI MRI which is the most sensitive MRI method which can be used to identify acute cerebral infarction within the first few hours. As time progresses and the infarct evolves and ischemia results in cell death and disintegration, the once bright DWI MRI image appears dark. Therefore at day 5, FLAIR MRI is used to image patients as it offers the most sensitive method of imaging lesions 24 hours after LKN (by depicting areas of tissue T2 prolongation while suppressing CSF signal)1.
Xavier AR et al. Southern medical journal 2003;96:367–79
Abbreviations:
CSF=cerebrospinal fluid
DWI=diffusion weighted imaging
FLAIR=fluid attenuated inversion recovery
LKN=last known normal
MRI=magnetic resonance imaging
Day 5
AIS=acute ischemic stroke; AE=adverse event; BI=Barthel index; mRS=modified Rankin Scale;
NIHSS=National Institute of Health Stroke Scale; SAE=serious adverse event
Protocol 101SK201. Data on file. Biogen, Jun 2013; Clinicaltrials.gov NCT , accessed April

55. Anti-TWEAK (BIIB023)* Lupus Nephritis
*Anti-TWEAK is an investigational candidate. Efficacy and safety have not been established.

56. Lupus Nephritis Prevalence Treatment
Lupus Nephritis (LN) is present in up to 60% of Systemic Lupus Erythematosus (SLE) patients.1 (SLE occurs in approximately 20 to 70 cases per 100,000)2
Treatment
No indicated therapies
Treatment regimens include combination Mycophenolate mofetil with prednisone or cyclophosphamide with methypredinisolone
Suppress the immune system to treat the acute inflammatory injury3
Limited efficacy with increasing toxicities over time4
ATK Anti Tweak Background and ATLAS Study Design Slides Nov 2013
Cameron J. J of Amer Society of Nephrology. 1999; 10(2):
Pons-Estel GJ et al. Seminars in Arthritis and Rheumatism. 2010; 39(4):
Ortega L et al. Lupus. 2010; 19:
Waldman M and Appel GB. Kidney International. 2006; 70:

57. Anti-TWEAK (BIIB023)
TWEAK is a proinflammatory cytokine expressed by WBCs and functions as a soluble cytokine through the fibroblast growth factor (FGF)-inducible molecule 14 (Fn14)
Fn14 is highly induced in disease target tissues and implicated in the pathogenesis of LN
Anti-TWEAK is thought to target Fn14 and is designed to inhibit glomerular and tubular pathologies1
Phase II study ongoing and expected to be completed in 20192
Sanz AB et al. Kidney International. 2011; 80:
NCT
Data on File. Biogen.

58. BIIB023 Study Design
Protocol 211LE201 Data on File. Biogen

59. Neublastin (BG00010)* Neuropathic Pain
*Neublastin is an investigational candidate. Efficacy and safety have not been established.

60. Neuropathic Pain Prevalence
Estimated 1-2% of population experiences neuropathic pain. Possibly underestimated due to undiagnosed chronic pain1
Associated with physical injury to a nerve, systemic diseases (e.g. diabetes), autoimmune disorders, infections, etc.2
Treatment
Current therapies: LYRICA® (pregabalin), NEURONTIN® (gabapentin), CYMBALTA® (duloxetine)
Poor control of pain with increased side effects3
LYRICA® and NEURONTIN® are a registered trademarks of Pfizer Inc.; CYMBALTA® is a registered trademark of Eli Lilly and Company
1. Smith BH and Torrance N. Curr Pain Headache Rep
2. NINDS.NIH.gov
3. Investigator Brochure V7; Biogen.

61. Neublastin (NBN)
NBN is a potent cell survival and growth factor which signals through receptor GFRα3 highly expressed on pain-sensing neurons1
Possible targeted alleviation of pain and minimal CNS side effects were shown in animal studies
NBN is being investigated as a first-in-class, potentially restorative treatment for neuropathic pain and neuropathy associated with nerve damage2
Phase 2 study expected to be completed 20153
GFRα3 = GDNF family receptor alpha-3
GDNF = Glial cell-derived neurotrophic factor
Gardell L et al. Nature. 2003; 9:
Data on File. Biogen.
NCT

62. Neublastin – Program Development
Phase 1 SAD and MAD studies complete
Phase 2 POC Study in lumbar radiculopathy on-going
Multi-center, double-blinded, placebo‑controlled study, multi-dose study (~ 168 patients)
Neublastin (50, 150, 400, 800, and 1200 µg/kg) vs placebo IV three times a week for approximately 13 weeks
Primary endpoint: Change from baseline in the mean 24-h average general pain intensity score (AGPI) at the end of the treatment week using an 11‑point Numeric Rating Scale (NRS)
Protocol 103NS201 v6

63. ISIS-SMNRX* Spinal Muscular Atrophy
*ISIS-SMNRX is an investigational candidate. Efficacy and safety have not been established.

64. Spinal Muscular Atrophy (SMA)
SMA is an autosomal recessive neuromuscular disease. It results in the degeneration of alpha motor neurons in the spinal cord leading to proximal muscle weakness and paralysis.
Prevalence
Approximate incidence is 1 in 6,000 to 1 in 10,000 live births1
Though classified into three major types, the disorder demonstrates a continuous range of severity and overlap2
Type
Other Names
Age at Onset
Life Span
Highest Function Achieved
SMA I
Acute spinal muscular atrophy; Werdnig Hoffmann disease
0-6 months
<2 years
Never sit independently
SMA II
Chronic spinal muscular atrophy; Dubowitz disease
7-18 months
Varies from 2 years to the third decade of life
Sit independently, never stand
SMA III
Juvenile spinal muscular atrophy; Kugelberg-Welander disease
>18 months
Normal
Stand and walk alone
1. D’Amico A et al. Orphanet Journal of Rare Diseases. 2011; 6 (71);
2. Mitchell LR et al, Lancet. 2008; ;

65. Spinal Muscular Atrophy (SMA)
Current Treatments:
No indicated therapies for SMA. Treatment centers around the management of symptoms and preventing complications of SMA
SMA caused by genetic defects in the SMN1 gene that result in the lack of functional SMN protein
Intervention: Antisense oligonucleotide (ASO) to insert missing exon in “backup” gene
ISIS-SMNRX is believed to increase production of fully functional SMN protein in model systems
Uniformly 2’-0-methoxyethyl modified (MOE) antisense drug1
Chiriboga, C et al. Results of an Open-Label, Escalating Dose Study to Assess the Safety, Tolerability, and Dose Range Finding of a Single Intrathecal Dose of ISIS-SMNRX in Patients with Spinal Muscular Atrophy. Presented at AAN 2013

66. ISIS-SMNRX
ISIS-SMNRX is currently in Phase 3 trials; estimated to be completed in 20172
Granted Orphan Drug Status in US & EU and Fast Track in the US1
ISIS-SMNRX is a joint collaboration with ISIS Pharmaceuticals
1. Darras, B et al. Interim Results of a Phase 2 Study of ISIS-SMNRx in Children with Spinal Muscular Atrophy. Presented at AAN 2014
2. NCT
Data on File. Biogen.

67. Phase 2 Multiple-Ascending Dose, Open-Label Study in Medically Stable SMA Patients 2-15 Years of Age Study Complete
Objectives
Evaluate the safety and tolerability of multiple intrathecal doses of ISIS-SMNRx
Evaluate CSF, plasma PK, and clinical outcomes related to SMA (including HMFSE)
Darras, B et al. Interim Results of a Phase 2 Study of ISIS-SMNRx in Children with Spinal Muscular Atrophy. Presented at AAN 2014

68. Dose and Time Dependent Increases in HFMSE Scores after Multiple Doses of ISIS-SMNR*
In multi-dose study, SMN protein increase of 115% (p=0.004,
n=9) observed at 3 months
 In single-dose study, SMN protein increase of 160% (p=0.09,
n=6) observed at ~ 1 year
Darras, B et al. Interim Results of a Phase 2 Study of ISIS-SMNRx in Children with Spinal Muscular Atrophy. Presented at AAN 2014
*Study is now complete; data presented above is for first 3 cohorts, 12 mg data cohort not yet available (as of May 2015)

69. ISIS-SMNRx Phase 3 Study (ENDEAR)*
A Phase 3, randomized, double-blind, sham-procedure controlled study in infants with SMA
Global study in ~110 SMA infants ≤ 7 months old with 2 copies of SMN2
13 month study duration
Evaluate the efficacy and safety of ISIS-SMNRx
Primary efficacy endpoint is time to death/permanent ventilation
Additional efficacy endpoints include CHOP INTEND and motor milestones
Initiated - August 2014
Darras, B et al. Interim Results of a Phase 2 Study of ISIS-SMNRx in Children with Spinal Muscular Atrophy. Presented at AAN 2014
*Link to study details at

70. ISIS-SMNRx Phase 3 Study (CHERISH)*
A Phase 3, Randomized, Double-blind, Sham-Procedure Controlled Study in Children with SMA
Global study in ~120 SMA children with SMA
15 month study duration
Determine the efficacy and safety of ISIS-SMNRx
Primary endpoint is change in Hammersmith motor function score
Initiated
Darras, B et al. Interim Results of a Phase 2 Study of ISIS-SMNRx in Children with Spinal Muscular Atrophy. Presented at AAN 2014
*Link to study details at

71. Aducanumab (BIIB037)* Alzheimer’s Disease
*BIIB037 is an investigational candidate. Efficacy and safety have not been established.

72. Alzheimer’s Disease (AD)
Prevalence
Alzheimer’s disease (AD) is the most common cause of dementia, accounting for 60% to 80% of all cases1
Estimated that 5.2 million Americans suffer from dementia caused by AD in the US1 and million people living with dementia worldwide2
Estimated to increase to million worldwide by 20502
Current Approved Treatments*
Mild to Moderate AD - ARICEPT® (Donepezil), EXELON® (Rivastigmine), RAZADYNE® (Galantamine)
Moderate to Severe AD - ARICEPT ® (Donepezil), NAMENDA® (Memantine)
Current treatments regulate neurotransmitters in the brain which may help to improve thinking, memory, and speaking skills.
However, current therapies do not modify the underlying disease process and may not be effective for all patients affected by AD2
2014 Alzheimer’s Disease Facts and Figures. 2. Alzheimer’s Disease International
*All trademarks for drugs mentioned are the property of their respective owners

73. Aducanumab (BIIB037)
AD is defined by the presence of extracellular neuritic plaques (NPs) containing amyloid beta (Aβ) peptide and intraneuronal neurofibrillary tangles (NFTs) composed of tau protein in the brain1
BIIB037 is a human monoclonal antibody that targets aggregated forms of beta amyloid
Therapeutic rationale: Clearance of aggregated Aβ in the brain will attenuate the neurodegenerative process and slow the clinical progression of AD2
1. Hardy and Selkoe. Science. 2002; 197(5580): , 2 Data on File. Biogen.

74. Aducanumab (BIIB037)*
Recently completed a pre-specified interim analysis of Phase 1b
Phase 1b study is a randomized blinded placebo controlled ascending dose study in prodromal and mild AD patients who are also amyloid positive in the brain at baseline
Interim analysis indicated that BIIB037 reduced amyloid levels in a dose and time dependent fashion. Other preliminary findings:
Statistically significant effect on cognition at 54 weeks
Most significant safety findings have been amyloid-related imaging abnormalities (ARIAs). These events appear to be both dose and ApoE4 dependent, largely mild to moderate and self-resolving
Continuing the current Phase 1b study in a blinded fashion
Preparing to implement Phase 3 program
*As of May 2015
Data on File. Biogen

75. Aducanumab (BIIB037) Interim Phase 1B Analysis Effect on Mini Mental State Examination (MMSE)
Sevigny J, et al. Randomized, Double-blind, Placebo-controlled, Phase 1b Study of Aducanumab (BIIB037), an Anti-Aβ Monoclonal Antibody, in Patients With Prodromal or Mild Alzheimer’s Disease: Interim Results by Disease Stage and ApoE ε4 Status. Presented at 2015 AAN Congress, Washington, DC.

76. Aducanumab (BIIB037) Interim Phase 1B Analysis Safety Results Summary
Sevigny J, et al. Randomized, Double-blind, Placebo-controlled, Phase 1b Study of Aducanumab (BIIB037), an Anti-Aβ Monoclonal Antibody, in Patients With Prodromal or Mild Alzheimer’s Disease: Interim Results by Disease Stage and ApoE ε4 Status. Presented at 2015 AAN Congress, Washington, DC.

77. BAN2401* Alzheimer’s Disease
*BAN2401 is an investigational candidate. Efficacy and safety have not been established.

78. BAN2401
Suggested that amyloid beta (Aβ) protofibril, an intermediate in the aggregation process of the amyloid-β peptide, initiates and drives the neurodegenerative process in Alzheimer’s disease
BAN2401 is a humanized monoclonal antibody that specifically targets the protofibrillar form of Aβ1
Currently in phase 2 expected to be completed by 20162
Collaboration with Eisai Co.
NCT
Data on File. Biogen

79. BG00011* Idiopathic Pulmonary Fibrosis (IPF)
*BG00011 is an investigational candidate. Efficacy and safety have not been established.

80. Idiopathic Pulmonary Fibrosis (IPF)
Prevalence
Approximately 100,000 people in the United States have IPF
Most people diagnosed with IPF only live 3 to 5 years after diagnosis. Most common cause of death is respiratory failure1
United States National Library of Medicine website. “Idiopathic Pulmonary Fibrosis” Accessed October 7, 2014med-cor b.htm
Figure: National Heart, Lung, and Blood Institute website. “How the Lungs Work”
1. United States National Library of Medicine website. “Idiopathic Pulmonary Fibrosis”

81. Idiopathic Pulmonary Fibrosis (IPF)
Two therapies recently approved for the treatment of IPF
ESBRIET® (pirfenidone) was approved in the US on October 15, 2014
The mechanism of action is unknown1
OFEV® (nintedanib) was approved in the US on October 16th, 2014
Nintedanib is a tyrosine kinase inhibitor (TKI) that targets growth factor receptors involved in the mechanisms by which pulmonary fibrosis occurs. It inhibits the platelet-derived growth factor (PDGFR), fibroblast growth factor receptor (FGFR), and vascular endothelial growth factor receptor (VEGFR)2
Sequential therapy might represent the best use of current therapies but it does not provide a long-term solution to the problem; pirfenidone and nintedanib are not miracle drugs. Idiopathic pulmonary disease continues to progress, albeit more slowly, and whether either drug is efficacious as a second-line drug is not yet known. The search for better outcomes now faces an essential divide between so called personalised medicine and combination therapies.
United States National Library of Medicine website. “Idiopathic Pulmonary Fibrosis” Accessed October 7, 2014med-cor b.htm
ESBRIET® is a registered trademark of Intermune. OFEV® is a registered trademark of Boehringer ingelheim 1. 2.

82. BG00011 (anti-αvβ6 mAb)
αvβ6 integrin is expressed in low levels on alveolar epithelial cells in normal healthy adults and is tightly regulated by transforming growth factor-β (TGF-β); αvβ6 is upregulated with tissue injury
αvβ6 blockade provides a mechanism for injury- specific attenuation of TGF-β activation, inhibiting fibrogenesis
αvβ6 blockade provides a mechanism for injury- specific attenuation of TGF-β activity1
BG00011 is a humanized monoclonal antibody targeting integrin αvβ6.
BG00011, preclinically, exhibits anti-fibrotic activity in models of lung, kidney and liver disease. 2
Phase 2 studying patients with IPF; estimated completion 20153 1.
2. BI1IB Press Release
3. wwwl.clinicaltrials.gov NCT

83. Questions?