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Biogen: A multi-faceted approach to Alzheimer's

disease

Samantha Budd Haeberlein, PhD VP, Alzheimer’s Disease

Discovery and Development

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Forward-looking statements

These presentations contain forward-looking statements, including statements relating to: clinical trials; potential safety

and clinical effects of research and development programs; and pipeline potential and progress. These forward-looking

statements may be accompanied by such words as “anticipate,” “believe,” “could,” “estimate,” “expect,” “forecast,”

“intend,” “may,” “plan,” “potential,” “project,” “target,” “will” and other words and terms of similar meaning. You should not

place undue reliance on these statements.

These statements involve risks and uncertainties that could cause actual results to differ materially from those reflected

in such statements, including: risks associated with clinical trials, including our ability to adequately manage clinical

activities, unexpected concerns that may arise from additional data or analysis obtained during clinical trials, regulatory

authorities may require additional information or further studies or may fail to approve or may delay approval of our drug

candidates; the risk that positive results in a clinical trial may not be replicated in subsequent or confirmatory trials or

success in early stage clinical trials may not be predictive of results in later stage or large scale clinical trials or trials in

other potential indications; the occurrence of adverse safety events, restrictions on use with our products or product

liability claims; our dependence on collaborators and other third parties for the development and commercialization of

products and other aspects of our business, which are outside of our control; and the other risks and uncertainties that

are described in the Risk Factors section of our most recent annual or quarterly report and in other reports we have

filed with the SEC. These statements are based on our current beliefs and expectations and speak only as of the date

of these presentations. We do not undertake any obligation to publicly update any forward-looking statements.

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Organize for Long-term Success

• Multiple Sclerosis

• Inflammatory Bowel

Disease (IBD)

• Alzheimer’s Disease

• Parkinson’s

• ALS

• Neuroimmunology

• Hemophilia

• Spinal Muscular

Atrophy (SMA)

• Neuropathic Pain

Specialty medicines Neurodegeneration Rare diseases

Focus areas

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Neurology Disease Area Focus

Unmet Need Core

Competency

MS

AD

PD

ALS

Adjacencies

• Ophthalmology

• Neuropathic pain

Validated

Targets

Development

Feasibility

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Drug Development:

How to Increase Probability of Success

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Alzheimer’s: An Opportunity to Change the

Disease

# Alzheimer’s Association Facts & Figures 2016, * Prince et al (2013) The Global Impact of Dementia 2013–2050.

• Terrible disease with modest

treatment options

• ~7 year lifespan after diagnosis

• 6th leading cause of death (US)

• ~5.4M patients diagnosed (US);

expected 13.8M by 2050#

• ~200k pts under age 65 (US)#

• Estimated $200B+ cost (US)#

• ~44M people affected worldwide*

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Vision: A global leader, establishing aducanumab as a foundational therapy

and building a portfolio of differentiated complementary therapies

Continue to evaluate external opportunities

Establish foundation Advance our programs Broaden impact

• Advance aducanumab

• Enable more patients to

access treatment

– Prevention

– Diagnosis

• Support BAN2401 and

E2609

• Implement biomarkers to

enable clinical decisions

• Advance Tau programs

• Investigate new MOAs

Biogen Alzheimer’s Disease R&D Strategy

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Discovery Phase 1 Phase 2 Phase 3 Filing

Aducanumab* (Anti-amyloid β mAb)

BAN2401† (Anti-amyloid β mAb)

E2609† (BACE inhibitor)

BIIB076* (Anti-Tau mAb)

BIIB080‡ (Tau ASO)

Additional MOAs

Alzheimer’s Disease Development Efforts

* Collaboration programs with Neurimmune

† Collaboration programs with Eisai

‡Collaboration program with IONIS

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Dominantly inherited (APP,

PS1, PS2) involved in

processing of amyloid

Human Genetics Pathology Proof of Concept

Key Evidence that β-amyloid

Dysregulation is Central to Disease

Pathological hallmarks

Amyloid-β (Aβ) plaques

Emerging clinical signals

(aducanumab, solanezumab,

crenezumab)

APP: amyloid precursor protein; PS1/PS2: presenilin-1/presenilin-2

Source:Goate et al Nature1991, Sherrington et al Nature 1995, Levy-Lahad et al Science 1995, Braak & Braak Neuroscience Lett 1987 & Neurobiology 1989;,

Brody & Holtzman Ann Rev Neurosci. 2008,

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Potential to Disrupt the Disease Cascade

Ab42

Soluble Ab40

Ab

APP

g-secretase

b-secretase

Ab peptide

oligomers

fibrils

E2609* BAN2401*

Aducanumab*

Synaptic

impairment

Tau Tangles

Cytotoxicity

Dementia

Tau Agents*

* Collaboration program

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Alzheimer’s Starts Many Years Prior to Onset of

Symptoms

Severe Moderate Mild

MCI due to AD /

Prodromal At risk Population

Jack, et al. Lancet Neurol (2013)

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Use of biomarkers in Alzheimer’s:

• In early clinical studies, to demonstrate target engagement

• To select the right patients

• To demonstrate effect on disease pathophysiology

Biomarkers – Enabling our Pipeline

Fluid Based Measures

Preclinical and clinical imaging

Human physiology and devices

Fluid-based

measures

Preclinical and

clinical imaging

Human physiology

and devices

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Aducanumab Drug Development

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Phase Ib Interim Results: Primary endpoint,

safety

• ARIA-E was the main safety and tolerability finding

• Dose and ApoE ε4 carriage dependent

• Majority of events are asymptomatic. Symptoms, when present

• Mostly rated as mild to moderate

• Generally transient and self-resolving

• Include headache, confusion, visual disturbances

• Monitorable and Manageable

• 56% of subjects who develop ARIA-E able to resume dosing without ARIA-E

recurrence

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Phase Ib Interim Results: Secondary endpoint,

amyloid PET Imaging

-0.30

-0.25

-0.20

-0.15

-0.10

-0.05

0.00

0.05

Week 26 Week 54

***

***

Placebo

(n=30)

1

(n=21)

3

(n=26)

10

(n=21)

Aducanumab (mg/kg)

6

(n=23)

*** **P<0.01; ***P<0.001 vs placebo

***

**

***

Placebo

(n=34)

1

(n=26)

Aducanumab (mg/kg)

3

(n=27)

6

(n=23)

10

(n=27)

Co

mp

osite

SU

VR

1

Ad

juste

d m

ea

n c

ha

ng

e fro

m b

ase

line

(±S

E)

Analyses based on observed data. ANCOVA for change from baseline with factors of treatment, laboratory ApoE ε4 status (carrier and non-carrier),

and baseline composite SUVR. PD analysis population is defined as all randomized subjects who received at least 1 dose of study medication and

had at least 1 post-baseline assessment of the parameter. 1. Ostrowitzki et al. Arch Neurol 2012; 2. Clark et al. Lancet Neurol 2012

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Phase Ib Interim Results: Exploratory endpoint,

CDR-sb Placebo (n=36, 36, 31) Aducanumab 1 mg/kg (n=28, 28, 23)

Aducanumab 3 mg/kg (n=30, 30, 27) Aducanumab 6 mg/kg (n=27, 27, 26)

Aducanumab 10 mg/kg (n=28, 28, 23)

CDR-sb is an exploratory endpoint. Analyses based on observed data. ANCOVA for change from baseline with factors of treatment, laboratory

ApoE ε4 status (carrier and non-carrier), and baseline CDR-sb. Efficacy analysis population is defined as all randomized subjects who received at

least 1 dose of study medication and had at least 1 post-baseline questionnaire assessment.

*

*P<0.05 vs placebo

Difference from

placebo at

Week 54

-0.15

-0.50

-1.24

-0.76

Analysis visit (weeks)

0.00

0.50

1.00

1.50

2.00

2.50

0 26 54

Ad

juste

d m

ea

n c

ha

ng

e fro

m

ba

se

line

(±S

E)

Test of linear trend of dose response p < 0.05

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Phase Ib Interim Results: Exploratory endpoint,

MMSE

* *

0.64

2.11 2.25

0.85

*P<0.05 vs placebo

Analysis visit (weeks)

Ad

juste

d m

ea

n c

ha

ng

e fro

m

ba

se

line

(±S

E)

MMSE is an exploratory endpoint. Analyses based on observed data. ANCOVA for change from baseline with factors of treatment, laboratory

ApoE ε4 status (carrier and non-carrier), and baseline MMSE. Efficacy analysis population is defined as all randomized subjects who received at

least one dose of study medication and had at least one post-baseline questionnaire assessment

Placebo (n=37, 36, 32) Aducanumab 1 mg/kg (n=26, 26, 25)

Aducanumab 3 mg/kg (n=29, 29, 26) Aducanumab 6 mg/kg (n=28, 28, 26)

Aducanumab 10 mg/kg (n=30, 29, 25)

0 24 52

Difference from

placebo at

Week 52

1.0

0.0

-1.0

-2.0

-3.0

Test of linear trend of dose response p < 0.05

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Aducanumab Ph1b Interim Results Indicate

• Statistically significant, dose- and time-dependent amyloid

plaque reduction at 6 months and 1 year

• Statistically significant, dose-dependent slowing of decline on

MMSE and CDR-SB at 1 year

• ARIA-E was the main safety/tolerability finding

ARIA-E, amyloid-related imaging abnormalities - vasogenic edema; CDR-SB, Clinical Dementia Rating-Sum of Boxes;

MMSE, Mini-Mental State Examination

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Of 165 patients randomized and dosed in PRIME, 92 met the Phase 3

criteria for Early AD: 26 with mild AD and 66 with prodromal AD

Selecting a Phase 3 Early AD Population based

on a Ph1b subpopulation

• We selected a subpopulation from PRIME for the Phase 3 study: Early AD

population

MCI, mild cognitive impairment; RBANS, Repeatable Battery for Assessment of Neuropsychological Status.

Phase 3 Early AD

Population PRIME Subpopulation

CDR Global Score 0.5

MMSE score ≥24

RBANS score ≤85

CDR memory domain score ≥0.5

Positive amyloid PET scan (visual read)

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Amyloid Plaque Reduction with Aducanumab in

the Early AD Subpopulation: Post-hoc Analysis

-0.35

-0.30

-0.25

-0.20

-0.15

-0.10

-0.05

0.00

0.05

Ad

jus

ted

me

an

ch

an

ge f

rom

ba

se

lin

e

(±S

E)

Analyses based on observed data. ANCOVA for change from baseline with factors of treatment, ApoE ε4 status (carrier and non-carrier), and

baseline composite SUVR. PD analysis population is defined as all randomized subjects who received at least 1 dose of study medication and had at

least 1 post-baseline assessment of the parameter

Placebo

(n=21)

1

(n=9)

3

(n=15)

10

(n=13)

Aducanumab (mg/kg)

6

(n=14)

Placebo

(n=23)

1

(n=12)

Aducanumab (mg/kg)

3

(n=14)

6

(n=15)

10

(n=15)

Week 26 Week 54

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Aducanumab Phase 3 Overview

ADAS-Cog 13, Alzheimer’s Disease Assessment Scale-Cognitive Subscale (13-item); ADCS-ADL-MCI, Alzheimer’s Disease Cooperative Study-

Activities of Daily Living Inventory (Mild Cognitive Impairment version); ASL-MRI, arterial spin labelling MRI; fMRI, functional MRI; MCI, mild

cognitive impairment; RBANS, Repeatable Battery for Assessment of Neuropsychological Status; vMRI, volumetric MRI

Phase 3 Design

Studies

Two 18-month, randomized, double-blind, placebo-controlled, Phase 3

studies with identical design:

- ENGAGE (NCT02477800)

- EMERGE (NCT02484547)

Population Early AD: MCI due to AD + mild AD

Enriched using Amyloid PET (visual reading)

ApoE ɛ4 genotype ɛ4-carriers and non-carriers

Dosing 3, 6 & 10mg/kg

Differential dosing based on ApoE ɛ4 genotype

Duration 18 months + 24 month long-term extension

Primary endpoint CDR-SB (change from baseline at week 78)

Other key endpoints Secondary: MMSE, ADAS-Cog 13, ADCS-ADL-MCI

Tertiary: amyloid PET (subset)

Sample size ~1350 per study (450/dose level; 1:1:1) across ~150 sites globally

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Alzheimer’s Disease is a Continuum Starting

Prior to Symptoms 10-15%ⱡ Conversion/year

MCI due to AD /

Prodromal At risk Population

~1.6M ~2.3M ~1.4M ~13M ~3.8M

27%* of over 65’s - US at

risk population

~8%# of over 65’s - US

amnestic MCI pop.

5.3 M - Diagnosed with

Alzheimer’s disease in the US

Amyloid positive,

cognition normal Cognitive and functional

decline fulfilling dementia Subjective memory

decline

Severe Moderate Mild

US Census Bureau 2014, * Jansen et al JAMA 2015, ⱡ Roberts et al Clin Geriatr Med 2013, Petersen et al Curr Alz Res 2009, Mitchell et al Acta Psych Scand 2009 # Petersen et al Neurol 2012, Whitwell et al Arch Neurol 2012, Plassman et al Ann Int Med 2008, Manly et al Arch Neurol 2005

Early AD

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Challenges for a Disease-modifying Therapy in

Early Alzheimer’s Disease

Social stigma Lack of early

disease

acceptance due to

perceived poor

outcomes and

caregiver burden

Payor concerns Large patient

population creates

new direct costs

and lack of

consensus on

determining value

Limited

capacity • Brain imaging

• Infusion

• AD-focused

HCPs

• Education of

PCPs

Few technology

solutions Need for

development and

standardization of

imaging tools or

biomarkers for

identification,

response or safety

Lack of

alignment on

measures Lack of consensus

on measures for

diagnosis, patient

population, clinical

response or

treatment goals

Screening

Diagnosis

Treatment Follow up

and

monitoring

Patient journey

Primary areas of concern that could limit access and

uptake if unaddressed

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Alzheimer’s Disease at Biogen

• Multi-pronged portfolio approach with amyloid and tau

• Aducanumab demonstrated proof of biology and concept in Ph1b &

has now begun enrolling subjects with early AD in two pivotal

Phase 3 studies (ENGAGE & EMERGE)

• Aducanumab has the potential to fundamentally change treatment

paradigm of AD by slowing the course of the disease

• We recognize the challenges of this disease area and are organizing

to address and prepare for them