What have we learned from ?

Samantha Budd Haeberlein, PhD

Biogen, Cambridge, MA, USA

October 25, 2018

1 Disclaimer

• Aducanumab, is an investigational medicine and the benefit/risk profile has not been fully established. It has not received any marketing authorization and there is no guarantee that it will obtain such authorization in the future • The information and any data presented is early interim data from ongoing clinical trials and it is made available for scientific discussion only, in consideration of the general interest of the scientific community with respect to any progress in the research and development of possible treatments for Alzheimer disease • The information and any data presented are developed from scientific research and are not intended to predict the availability of any particular drug or therapy

Biogen licensed the worldwide rights to aducanumab from Neurimmune Holding AG in 2007 and is responsible for its development and the commercialization. As of October 22, 2017, Biogen and Eisai are collaborating on the development and commercialization of aducanumab globally. 2 Accumulation of Aβ is a core pathology in Alzheimer’s disease (AD)

Aβ, ; APP, amyloid precursor protein. 2017 Alzheimer’s Disease Facts and Figures. http://www.alz.org/documents_custom/2017-facts-and-figures.pdf. Accessed June 4, 2018; Dubois B, et al. Alzheimer’s & Dementia. 2016;12:292–323; Jack CR, et al. Brain. 2009;132:1355-1364. 3 Our understanding of the amyloid pathway today

Soluble Insoluble

Aggregated

Monomer Oligomer Fibril Amyloid plaque

Altered neuronal and synaptic morphology1,2 Structural and functional disruption of neuronal networks2-5 Postulated as causative of Alzheimer’s disease6,7

• The relevant pathological form of Aβ remains elusive • Soluble oligomers &/or insoluble fibrils may play important roles in disease

1. Koffie RM, et al. PNAS. 2009;106:4012–4017; 2. Spires-Jones TL, et al. Neurobiol Dis. 2009;33:213–220; 3. Kuchibhotla KV, et al. Neuron. 2008 July 31; 59(2): 214–225; 4. Meyer-Luehmann M, et al. Nature. 2008;451:720–724; 5. Haass C & Selkoe DJ. Nat Rev Mol Cell Biol. 2007;8:101–112; 6. Selkoe DJ & Hardy J. EMBO Mol Med. 2016;8:595–608; 7. Wang ZX, et al. Mol Neurobiol. 2016;53:1905–24. 4 Profiles of amyloid-targeted immunotherapies

Aducanumab1,2 BAN24013 Gantenerumab4 Crenezumab5,6 MEDI-18147 LY30028138 Bapineuzumab9 Solanezumab10

Current Phase 2 Phase 3 Phase 2 Phase 3 Phase 3 Phase 1 Discontinued Partially halted Status (Combo with BACEi)

Human Human (Phage display (Phage display Origin Humanized Humanized Humanized Humanized Humanized (RTM) library + affinity library + affinity maturation) maturation)

All forms of Aβ: All forms of Aβ: Fibrillar and Fibrillar and Fibrillar and Soluble monomeric Soluble monomeric Target Oligomeric> N3pG Fibrillar, Oligomeric, Oligomeric Aβ Oligomeric Aβ Oligomeric Aβ Aβ(1-42) Aβ Fibrillar, Monomeric Monomeric

N-terminus N-terminus Nt (3-11) + mid (18- C-terminus Aβp3-x N-terminus Mid-domain (13-24) Mid-domain (16-26) (3-7) (1-16) 27) (X-42) (1-5)

Effector Yes Yes Yes Reduced Reduced Yes Yes Yes Function

Plaque/CA Yes Yes Yes Low ? Yes Yes No A binding

ARIA Yes Yes Yes No No Yes Yes No

RTM, reverse translational medicine; BACEi, β-site APP-cleaving enzyme inhibitor; N3pG, pyroglutamate amyloid beta. 1. Sevigny et al, Nature. 2016;537:50-56; 2. Arndt J, et al. Sci Rep. 2018;8:6412; 3. Lord et al. Neurobiol Dis. 2009;36:425-34; 4. Bohrmann et al. J Alzheimers Dis. 2012;28:49-69; 5. Adolfsson et al. J Neurosci. 2012;32:9677-9689; 6. Atwal et al, Neurodegener Dis. 2017;17:591-1890. P828. 7. Bogstedt et al., J Alzheimers Dis. 2015;46:1091-1101; 8. DeMattos et al. Neuron. 2012 Dec 6;76:908-20; 9. Bard et al. Nat Med. 2000;6:916-919; 10. DeMattos et al. Proc Natl 5 Acad Sci U S A. 2001;98:8850-8855. What we have learned about the molecular characteristics of aducanumab

6 Aducanumab is a human IgG1 anti-Aβ developed in partnership with Neurimmune

Selected donor cohorts Immune response

B-cell CMC TOX screening Reverse Translational Medicine™ Technology

In vivo Antibody

validation cloning

Y

Y In vitro Recombinant Y validation production

CMC, chemistry and manufacturing controls; IgG, immunoglobulin G; Tox, toxicology. Neurimmune. Reverse Translational Medicine™ Technology Platform, 2016. http://www.neurimmune.com/-technology/rtm-technology-platform-.html. Accessed June 4, 2018; Sevigny J et al. Nature. 2016;537:50–56. 7 Aducanumab targets the N-terminus of Aβ

Aβ binding Specificity Aducanumab • All forms of Aβ Biogen/Eisai/ BAN2401 • Aggregated Aβ Neuroimmune Eisai/Biogen • Soluble Aβ 3-7 1-16 * Roche Eli Lilly * 3-11/18-27 16-26 J&J/ Genentech 1-5 13-24 * Pfizer 30-40

1DAEFRHDSGYEVHHQKLVFFAEDVGSNKGAIIGLMVGGVVIA42 Aβ sequence

*Denotes development that has been discontinued or partially halted. Arndt J, et al. Sci Rep. 2018;8:6412. 8 Structure of aducanumab Fab with Aβ1-11 shows minimal conformational change in Fab upon binding

(2.1 Å) of aducanumab Fab with A1-11

• Residues 2-7 adopt an extended conformation • Key interactions with CDRs H2, H3, L3

CDRs, complementary-determining regions. Arndt J, et al. Sci Rep. 2018;8:6412; Sevigny, J. et al. Nature. 2016;537:50–56. 9 Aducanumab is highly selective for Aβ aggregates

Negative Stain Electron Microscopy1 Dot Blot2

Aβ1-42 fibrils Antibody associated with fibrils

Binding of immunogold-labeled aducanumab Binding to insoluble Binding of immunogold- fibrillar and soluble labeled aducanumab oligomeric Aβ1-40

Right image reprinted with permission from Macmillan Publishers Ltd. 1. Arndt J, et al. Sci Rep. 2018;8:6412; 2. Sevigny J, et al. Nature. 2016;537(7618):50–56, copyright 2016. 10 Aducanumab does not bind to soluble monomeric Aβ

1.6 3 3D6 (Bapinuzumab) 3D6 (Bapinuzumab) chAducanumab chAducanumab 1.2 2

0.8 Aggregated 1 Soluble 0.4 Aβ42 peptide

Absorbance (450 nm) Aβ40 peptide Absorbance (450 nm)

(EC50 ≈ 0.2 nM) o (EC50 > 1000 nM) 0 0 0.0001 0.001 0.01 0.1 1 10 100 0.001 0.01 0.1 1 1 0 100 1000 [Antibody] (nM) [Biotin-Aβ (1–40)] (nM)

• Biochemical assays demonstrate:

o High affinity binding of BIIB037 for aggregated Aβ (EC50 ≈ 0.2nM) o No binding of BIIB037 to soluble monomeric Aβ (EC50 > 1000nM)

EC50, half maximal effective concentration. Figures reprinted with permission from Macmillan Publishers Ltd: Sevigny J, et al. Nature. 2016;537(7618):50–56, copyright 2016. 11 Aducanumab binding epitope may determine selective binding to Aβ aggregates

aducanumab bapineuzumab H6 H2 D7 R5 A2 L3 E3 F4 H3 H6 L1 D1

Buried Surface Area Contacts (Å2) aducanumab 506 12 Aducanumab Fab BAN2401 610 18 complexed with Aβ(1-11) peptide (2.1Å) PFA1 670 20 bapineuzumab 565 23 Adu binds to Aβ 3-7 gantenerumab 903 24

• A shallow and compact epitope may contribute to the selectivity for high molecular weight Aβ forms, without targeting Aβ monomers

BSA, buried surface area; CDRs, complementary-determining regions. Arndt J, et al. Sci Rep. 2018;8:6412. Protein data bank (PDB): http://www.rcsb.org/pdb/home/home.do. Accessed October 24, 2018. Bapineuzumab structure: PDB ID 4HIX; Gantenerumab structure: PDB ID 5CSZ; PFA1 structure: PDB ID 2IPU. 12 Aducanumab achieves sufficient brain exposure to bind amyloid deposits in APP transgenic mice (Tg2576)

Aducanumab Aβ

In vivo binding of aducanumab to Pattern of amyloid deposition amyloid deposits Serial section visualized with Visualized with anti-human IHC pan-Aβ IHC

APP, amyloid precursor protein; IHC, immunohistochemistry. Images reprinted with permission from Macmillan Publishers Ltd: Sevigny J, et al. Nature. 2016;537(7618):50–56, copyright 2016. 13 6-month aducanumab dosing reduces amyloid plaque in a dose-dependent manner in transgenic mice (Tg2576)

Guanidine Fraction DEA Fraction

120 120 Aβ40 Aβ 100 * 100 42 80 *** * 80 *** *

60 60 -50% 40 40 %of control % of control 20 20

0 0 PBS 0.3 1 3 10 30 PBS 0.3 1 3 10 30

Cortex Hippocampus 120 120 6E10 ThioS 100 100 80 ***** 80 60 60 ** ** -50% % control % %control 40 40

20 20

0 0 PBS 0.3 1 3 10 30 PBS 0.3 1 3 10 30 Dose (mg/kg) Dose (mg/kg)

DEA, diethylamine; ThioS, thioflavin S. *P<0.05 versus control. Sevigny J, et al. Nature 2016;537:50–56. 14 Aducanumab restores neurite calcium levels in transgenic mice with

Multiphoton live Control imaging in antibody Tg2576 mouse brain

35 Aducanumab

YFP, yellow fluorescent protein; CFP, cyan fluorescent protein. Kastenaka, KV. et al. Neurobiol. Dis. 2016;536:12549–12558. 15 Aducanumab recruits microglial cells and induces phagocytosis-mediated clearance of amyloid plaques in Tg2576 mice

PBS Aducanumab- treated

Aβ Iba-1

PBS, phosphate buffered saline; Iba-1, ionizing calcium-binding adaptor molecule 1. Sevigny J, et al. Nature 2016;537:50–56. 16 Clinical learnings from the Phase 1b PRIME study

17 Aducanumab Phase 1b study (PRIME) design

• PRIME is an ongoing Phase 1b study assessing the safety, tolerability, PK and PD of aducanumab in patients with prodromal or mild Alzheimer’s disease dementia • 197 subjects randomized, 196 dosed; 12-month placebo-controlled period, ongoing LTE

Population Treatment Arms Endpoints

Placebo* (n=48) • Primary endpoint: safety & tolerability • Prodromal/MCI due to AD 1 mg/kg (n=31) • Secondary endpoints: mild AD dementia serum PK, immunogenicity, 3 mg/kg (n=31) change in amyloid PET • MMSE ≥20 (Week 26) 6 mg/kg (n=30) • Stable concomitant • Exploratory endpoints 10 mg/kg (n=32) included CDR–SB, MMSE, change in amyloid PET • Positive amyloid PET Titration ApoE ε4 carriers; (Week 54); in the LTE all 1→10 mg/kg (n=23) endpoints except safety were exploratory

• Randomization: 3:1 active: placebo within cohorts, fixed-dose cohorts stratified by ApoE ε4 status • Patients randomized to placebo in the placebo-controlled period were switched to aducanumab 3 mg/kg or a titration regimen in the LTE (“placebo switchers”). Patients randomized to aducanumab 3, 6, or 10 mg/kg or titration in the placebo-controlled period continued in the same dose group in the LTE (“continuers”)

PK, pharmacokinetics; PD, pharmacodynamics; LTE, long-term extension; MCI, mild cognitive impairment; MMSE, Mini–Mental State Examination; PET, positron-emission tomography; CDR-SB, Clinical Dementia Rating-Sum of Boxes. *Pooled placebo group. ClinicalTrials.gov: https://clinicaltrials.gov/ct2/show/NCT03718819. Accessed October 24, 2018. 18 Target engagement

19 Amyloid plaque reduction as a measure of target engagement

• Amyloid PET when the PRIME study started was a 1 Bapineuzumab very new technology for multicenter clinical trials • Two pioneering studies bapineuzumab (11C-PiB PET) and gantenerumab moved the fields understanding on • Sample sizes • Placebo response Gantenerumab2 • Analysis methodologies • Aducanumab PRIME study • Screened all subjects for baseline levels of amyloid • >20 clinical sites • 18F-AV-45 (Amyvid) • Larger sample sizes per arm

11C-PiB PET, Pittsburgh compound B positron-emission tomography. *Difference between patients in the placebo group and those in the bapineuzumab group at week 78= -0.24 (p=0.003). 1. Rinne et al. Lancet. 2010;9:363-372; 2. Ostrowitzki et al Arch . 2012;69:198-207. 20 Aducanumab target engagement: dose- and time-dependent reduction in amyloid plaque as measured by PET

Dose and time dependent reduction in Amyloid-β (Aβ) plaque reduction: composite SUVR (PET)1 example amyloid PET images2

Baseline One year

Placebo

3 mg/kg

6 mg/kg

10 mg/kg

• Statistically significant reduction in amyloid plaque seen as early as 6 months • No increase in placebo arms

ANCOVA, analysis of covariance; PET, positron-emission tomography; SE, standard error; SUVR, standard uptake value ratio. Nominal p values: * P<0.05; **P<0.01; ***P<0.001 vs placebo. 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 patients who received at least 1 dose of study and had at least 1 post-baseline assessment of the parameter. 1. Viglietta et al. Aducanumab titration dosing regimen: 12-month interim analysis from PRIME, a randomized, double-blind, placebo-controlled Phase 1b study in patients with prodromal or mild Alzheimer’s disease. Presented at the 9th edition of Clinical Trials on Alzheimer’s Disease 21 (CTAD), December 8‒10, 2016, San Diego, CA, USA; 2. Sevigny J, et al. Nature. 2016;537:50–56. Aducanumab target engagement: dose- and time-dependent reduction in amyloid plaque in SUVR and centiloid

Change in SUVR1 Change in centiloid2 10 3.97 SE)

 0

-10 -10.18*

-20 **

-30 *** -28.25 ***

Centiloid Scale -40 -36.37 *** *** Weeks 0 26 54 -45.60 *** -50 Placebo n=42 42 38 1 mg/kg n=26 26 21 3 mg/kg n=29 27 26 -60 6 mg/kg n=24 23 23 -57.31 *** Adjustedfrom mean change baseline ( 10 mg/kg n=28 27 21 -70 Aducanumab Titration n=18 17 16 02654 Analysis visit (weeks)

Standardization: • Centiloid facilitates cross ligand / cross trial comparison

ANCOVA, analysis of covariance; SE, standard error; SUVR, standard uptake value ratio. Nominal p values: * P<0.05; **P<0.01; ***P<0.001 vs placebo. 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 patients who received at least 1 dose of study medication and had at least 1 post-baseline assessment of the parameter. 1. Viglietta et al. Aducanumab titration dosing regimen: 12-month interim analysis from PRIME, a randomized, double-blind, placebo-controlled Phase 1b study in patients with 22 prodromal or mild Alzheimer’s disease. Presented at the 9th edition of Clinical Trials on Alzheimer’s Disease (CTAD), December 8‒10, 2016, San Diego, CA, USA Viglietta et al. Data presented at CTAD 2016; 2. Data on file. Dose- and time-dependent reductions in SUVR observed with aducanumab regardless of reference/target regions

Aducanumab reduces amyloid plaque in regions Effect size for each brain target region in 10 mg/kg anticipated to have amyloid aducanumab group by reference region at week 54

SUVR, standard uptake value ratio. P<0.05; **P<0.01; ***P<0.001 vs placebo. 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 patients who received at least 1 dose of study medication and had at least 1 post-baseline assessment of the parameter. 23 Chiao P et al. J Nucl Med. 2018;pii: jnumed.118.209130. [Epub ahead of print]; Sevigny J et al. Nature. 2016;537:50-56. Aducanumab reduction in amyloid plaque is equivalent across prodromal/MCI due to AD and Mild AD dementia

Prodromal AD Mild AD dementia 0.05 0.05

0.00 0.00

-0.05 -0.05

-0.10 -0.10

-0.15 -0.15 Weeks 54 Weeks 54 Placebo 18 -0.20 -0.20 Placebo 20 1 mg kg 8 1 mg kg 13 3 mg/kg 12 -0.25 -0.25 3 mg/kg 14 6 mg/kg 10 6 mg/kg 13 10 mg/kg 12 10 mg/kg 9 -0.30 Titration 10 -0.30 Titration 6 Adjusted mean change ±change mean Adjusted SE -0.35 -0.35 0265402654 Week Week

MCI, mild cognitive impairment; ANCOVA, analysis of covariance; SE, standard error. Analysis based on ANCOVA model with factors of treatment, ApoE ε4 status (carrier/non-carrier) and baseline. Data on file. 24 Aducanumab reduction in amyloid plaque is equivalent in ApoE ε4 carriers and non-carriers

0.05 Carrier 0.05 Non-carrier

0.00 0.00

-0.05 -0.05

-0.10 -0.10

-0.15 -0.15 Weeks 54 Weeks 54 -0.20 Placebo 27 -0.20 Placebo 11 1 mg kg 12 1 mg kg 9 -0.25 3 mg/kg 17 -0.25 3 mg/kg 9 6 mg/kg 17 6 mg/kg 6 10 mg/kg 14 -0.30 -0.30 10 mg/kg 7 Titration 16 Titration - Adjusted mean change ±change mean Adjusted SE -0.35 -0.35 0265402654 Week Week

ANCOVA, analysis of covariance; SE, standard error. Analysis based on ANCOVA model with factors of treatment and baseline. Data on file. 25 Aducanumab continues to reduce amyloid plaque levels over 48 Months – by up to 75 centiloid units

Placebo-controlled LTE period period (all patients received aducanumab) 5 -5 -15 ** Placebo switchers -25 *** Change from *** baseline at Week -35 222 (SUVR units) -45 *** *** -51.20 -55 *** -57.26 ** -57.63 -65 *** -71.53 -75 -75.01 -85 Weeks 0 26 54 110 166 222 Placebo n=34 34 30 PBO switchers 18 15 12 1 mg kg n=26 26 21 3 mg/kg 13 6 7 Continuers -95 3 mg/kgn=292726 181213 6 mg/kgn=242323 181510 Adjusted mean change baseline from (±SE)

-105 Aducanumab 10 mg/kg n=28 27 21 13 7 7 0 26 54 110 166 222 Analysis visit (weeks)

LTE, long-term extension; MMRM, mixed model for repeated measures; PBO, placebo; SE, standard error, SUVR, standard uptake value ratio. * P<0.05; ** P<0.01; *** P<0.001 vs PBO in the placebo-controlled period and vs PBO switchers in the LTE period. Results based on MMRM, fitted with change from baseline as a dependent variable, and included fixed effects for categorical treatment, categorical visit and treatment-by-visit interaction, continuous baseline value, and laboratory ApoE ε4 status 26 (carrier and non-carrier). Data on file. Aducanumab reduction in amyloid plaque falls below a purported SUVR cut point for positive pathology

Placebo-controlled LTE period period (all patients received aducanumab) 1.50 Weeks 0 26 54 110 166 222 Placebo n=34 34 30 PBO switchers 18 15 12 1 mg kg n=26 26 21 3 mg/kg 13 6 7 3 mg/kg n=29 27 26 18 12 13 1.40 6 mg/kg n=24 23 23 18 15 10

Aducanumab 10 mg/kgn=282721 1377

1.30 Placebo switchers

a 1.20 The value of 1.10 is a purported quantitative cut-point 1.10 (a) that discriminates between positive Mean SUVR (±SE) and negative scans.1 1.00 Continuers

0.90 0 26 54 110 166 222 Analysis visit (weeks)

LTE, long-term extension; SUVR, standardized uptake value ratio; SE, standard error. 1. Joshi AD, et al. J Nucl Med. 2015;56:1736-1741. Data on file. 27 Clinical endpoints (Exploratory endpoints in Phase 1b study)

28 Clinical proof of concept: effect of aducanumab on clinical decline as measured by CDR-SB & MMSE

Change in CDR-SB Change in MMSE

CDR-SB is an exploratory endpoint. Analyses based on observed data. ANCOVA for 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 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 non-carrier), and baseline MMSE. Efficacy analysis population is defined as all randomized subjects who received at least 1 dose of study medication and had at least randomized patients who received at least 1 dose of study medication and had at least 1 1 post-baseline questionnaire assessment post-baseline questionnaire assessment.

MMRM, mixed model for repeated measures. CDR-SB, Clinical Dementia Rating–Sum of Boxes; LTE, long-term extension; PBO, placebo; SE, standard error. Viglietta et al. Aducanumab titration dosing regimen: 12-month interim analysis from PRIME, a randomized, double-blind, placebo-controlled Phase 1b study in patients with prodromal or mild Alzheimer’s disease. Presented at the 9th edition of Clinical Trials on Alzheimer’s Disease (CTAD), December 8‒10, 2016, San Diego, CA, USA. 29 Clinical stage impacts disease progression in the placebo arms but does not impact treatment effect of aducanumab

Prodromal AD Mild AD Dementia Weeks 54 Weeks 54 3.0 3.0 Placebo 18 Placebo 21 1 mg kg 15 2.5 1 mg kg 8 2.5 3 mg/kg 12 3 mg/kg 15 2.0 6 mg/kg 10 2.0 6 mg/kg 16 CDR-SB 10 mg/kg 10 10 mg/kg 13 1.5 Titration 12 1.5 Titration 9 1.0 1.0 change ±change SE Adjusted mean Adjusted 0.5 0.5 0.0 0.0 02654 02654 1.0 1.0 Weeks 54 0.5 Weeks 52 0.5 Placebo 19 Placebo 21 0.0 0.0 1 mg kg 9 1 mg kg 16 -0.5 3 mg/kg 12 -0.5 3 mg/kg 14 -1.0 6 mg/kg 10 -1.0 6 mg/kg 16 -1.5 10 mg/kg 12 -1.5 10 mg/kg 13 Titration 9 MMSE -2.0 Titration 12 -2.0 -2.5 -2.5 change ±change SE Adjusted mean Adjusted -3.0 -3.0 -3.5 -3.5 -4.0 -4.0 02452 02654 Week Week

MMSE, Mini–Mental State Examination; CDR-SB, Clinical Dementia Rating-Sum of Boxes; SE, standard error; ANCOVA, analysis of covariance. Analysis based on ANCOVA model with factors of treatment, ApoE ε4 status (carrier/non-carrier) and baseline. Data on file. 30 ApoE ε4 status does not impact disease progression or treatment effect with Aducanumab on CDR-SB and MMSE

3.0 Carrier Weeks 54 3.0 Non-carrier Weeks 54 2.5 Placebo 28 2.5 Placebo 11 1 mg kg 13 1 mg kg 10 2.0 3 mg/kg 18 2.0 3 mg/kg 9 6 mg/kg 19 6 mg/kg 7 1.5 1.5 CDR-SB 10 mg/kg 16 10 mg/kg 7 1.0 Titration 21 1.0 Titration -

change ±change SE 0.5 0.5 Adjusted mean Adjusted 0.0 0.0 -0.5 -0.5 02654 02654 Weeks 52 Weeks 52 1.0 Placebo 28 1.0 Placebo 12 0.5 1 mg kg 15 0.5 1 mg kg 10 0.0 3 mg/kg 17 3 mg/kg 9 6 mg/kg 19 0.0 6 mg/kg 7 -0.5 10 mg/kg 16 -0.5 10 mg/kg 9 -1.0 Titration 21 -1.0 Titration - MMSE -1.5 -1.5 -2.0 -2.0

change ±change SE -2.5 -2.5 Adjusted mean Adjusted -3.0 -3.0 -3.5 -3.5 -4.0 -4.0 02452 02452 Week Week

MMSE, Mini–Mental State Examination; CDR-SB, Clinical Dementia Rating-Sum of Boxes; SE, standard error; ANCOVA, analysis of covariance Analysis based on ANCOVA model with factors of treatment, ApoE E4 status (carrier/non-carrier) and baseline. Data on file. 31 PRIME: Treatment up to 48 months CDR–SB & MMSE data suggests clinical benefit in patients continuing aducanumab

Change in CDR-SB Change in MMSE

Placebo- Placebo- LTE period LTE period controlled controlled (all patients received aducanumab) (all patients received aducanumab) period period

Weeks 0 26 54 78 110 134 166 190 222

Placebo n=36 36 31 3 or 3→6 mg/kg 23 21 18 17 15 13 Difference 1 Difference from placebo from placebo 1 mg kg n=28 28 23 3 mg/kg 15 14 9 10 9 8 0 10 switchers at * switchers at 3 mg/kg n=30 30 27 21 16 14 14 14 14 Week 222 -1 * Week 220 9 6 mg/kg n=27 27 26 24 23 18 16 14 12 -2 * *

Aducanumab 10 mg/kg n=28 28 23 14 15 12 10 9 9 8 1.49 -3 0.79 -4 7 -5 5.42 6 -6 -1.38 -7 5 -8 2.02 -9 4 -3.09 0.75 -10 Weeks 0 24 52 76 108 132 164 188 220 3 -11 Placebo n=37 36 32 3 or 3→6 mg/kg 24 21 18 17 16 14 2 -12 1 mg kg n=26 26 25 3 mg/kg 15 15 10 10 9 8 -13 3 mg/kg n=29 29 26 21 17 15 14 14 14 -2.39 1 -14 6 mg/kg n=28 28 26 24 23 18 17 14 11

Aducanumab 10 mg/kg n=30 29 25 14 15 13 12 8 9 Adjustedfrom mean change baseline (±SE) Adjustedfrom mean change baseline (±SE) 0 -15 0 26 54 78 110 134 166 190 222 0 24 52 76 108 132 164 188 220 Analysis visit (weeks) Analysis visit (weeks)

*P<0.05 (vs placebo [Week 52] or placebo switchers [Weeks 76,108,132,164,188 and 220]). MMSE is an CDR-SB is an exploratory endpoint. Results based on MMRM, fitted with change from baseline as a dependent exploratory endpoint. Results based on MMRM, fitted with change from baseline as a dependent variable, and variable, and included fixed effects for categorical treatment, categorical visit and treatment-by-visit interaction, included fixed effects for categorical treatment, categorical visit and treatment-by-visit interaction, continuous continuous baseline value, and laboratory ApoE ε4 status (carrier and non-carrier). baseline value, and laboratory ApoE ε4 status (carrier and non-carrier).

MMRM, mixed model for repeated measures. CDR-SB, Clinical Dementia Rating–Sum of Boxes; LTE, long-term extension; PBO, placebo; SE, standard error. Analysis based on ANCOVA model with factors of treatment, ApoE E4 status (carrier/non-carrier) and baseline. Data on file. 33 PRIME: Reduction in brain amyloid correlates with slowing of cognitive decline at the individual and group levels

At the Individual-subject Level At the Group (Dose) Level Reduction in brain amyloid is significantly correlated Treatment-induced reduction in brain amyloid is with slowing of cognitive decline as measured by correlated with treatment-induced slowing of cognitive CDR-SB in the 10 mg/kg group at Week 54 decline as measured by CDR-SB at Week 54

Correlation between changes in PET SUVR and CDR-SB at Week 54 adjusting for baseline PET SUVR (a) Pearson P-value N correlation Improving Placebo 37 -0.03 0.8854 1 mg/kg 21 0.03 0.9163 3 mg/kg 26 0.49 0.0119 6 mg/kg 23 0.24 0.2861

Titration 16 0.39 0.1485 Improving CDR-SB: Adjusted CDR-SB: Adjusted mean difference from

10 mg/kg 19 0.64 0.0034 PBO in change from baseline at Week 54 (c) Amyloid PET SUVR: Adjusted mean difference from placebo in change from baseline at Week 54 (b)

Data on file. Analyses based on subjects who had changes from baseline at Week 54 in both amyloid PET SUVR and CDR-SB. Amyloid PET SUVR is calculated using whole cerebellum. a. The partial correlations that adjusted for the baseline amyloid PET SUVR were presented. b. Based on ANCOVA for change from baseline in PET SUVR, with factors of treatment, laboratory ApoE ε4 status (carrier and non-carrier) and baseline PET. 34 c. Based on ANCOVA for change from baseline in CDR-SB, with factors of treatment, laboratory ApoE ε4 status (carrier and non-carrier), baseline CDR-SB, and baseline PET. What about the 6 mg/kg cohort? Amyloid plaque reduction by SUVR Week 26 Week 54 • PET performs as expected in the 6mg/kg cohort Aducanumab, mg/kg (n) Aducanumab, mg/kg (n)

• But 6 mg/kg does not perform as expected on the Placebo 1 3 6 10 Titration Placebo 1 3 6 10 Titration (42) (26) (27) (23) (27) (17) (38) (21) (26) (23) (21) (16) clinical endpoints – particularly MMSE 0 • We have done an extensive review of the data

• No detectable differences in baseline characteristics -0.1 * ** • Baseline MMSE and CDR-SB scores not different than *** other cohorts -0.2 *** Composite SUVR, *** • Placebo decline of 6mg/kg cohort is consistent with other *** *** -0.3 cohorts *** • No detectable enrollment, site/rater differences baseline (±SE) from mean change adjusted MMSE 0.5 Difference from placebo at Week 52 • Majority of data was collected prior to 0 announcement of first results in 1, 3, and 10 mg/kg -0.5 * 1.91 cohorts. -1 1.70 SE)

േ 1.46 • These sample sizes are very small for clinical endpoints; -1.5 PRIME was not powered to detect clinical effects -2 0.47 baseline baseline ( -2.5 • The inconsistency is either due to chance alone, resulting from 0.25 -3 the small sample sizes, or caused by unknown or unobserved fromchange mean Adjusted -3.5 factors. 02452 • In the phase 3 study, parallel group design and larger sample Analysis visit (weeks) Placebo n= 45, 44, 40 1mg/kg adu n= 26, 26, 25 3mg/kg adu n= 29, 29, 26 size should address similar inconsistencies 6 mg/kg adu n= 28, 28, 26 10 mg/kg adu n= 30, 29, 25 Titration n= 21, 20, 21

ANCOVA, analysis of covariance; ARIA-E, amyloid-related imaging abnormalities - vasogenic edema; CDR-SB, Clinical Dementia Rating–Sum of Boxes; MMSE, Mini-Mental State Examination; SE, standard error; SUVR, standard uptake value ratio. Nominal p values: * P<0.05; **P<0.01; ***P<0.001 vs placebo. 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. PD analysis population is defined as all randomized patients who received at least 1 dose of study medication and had at least 1 post-baseline assessment of the parameter. Viglietta et al. Aducanumab titration dosing 35 regimen: 12-month interim analysis from PRIME, a randomized, double-blind, placebo-controlled Phase 1b study in patients with prodromal or mild Alzheimer’s disease. Presented at the 9th edition of Clinical Trials on Alzheimer’s Disease (CTAD), December 8‒10, 2016, San Diego, CA, USA. Safety

36 ARIA (amyloid related imaging abnormalities)

• The term ARIA refers to a spectrum of MRI signal abnormalities observed in the clinical trials of amyloid lowering agents. • Image presentation as vasogenic edema (ARIA-E) or deposition of heme products (ARIA-H) • Spontaneous ARIA-like events can occur in untreated AD and CAA • The mechanism leading to ARIA are not fully elucidated o Putative pathophysiological basis thought to be increased vascular permeability triggered by removal of parenchymal/ vascular amyloid

ARIA-E ARIA-H

ARIA, amyloid related imaging abnormalities; CAA, Cerebral Amyloid Angiopathy. Sperling R et al. Alzheimers Dement. 2011;7:367-385. 37 ARIA characteristics in PRIME

• Since the start of the PRIME study, ARIA-E has been observed in 46 of the 185 patients doses with aducanumab, with a cumulative incidence of 25% over the course of the study • Of the 46 patients with ARIA-E (± ARIA-H), 28 (61%) were asymptomatic and 18 (39%) had associated symptoms, which were typically mild • ARIA-E resolved on MRI in 44 of 46 patients and was ongoing in 2 patients at the time of withdrawal. In most cases resolving as assessed by MRI 4-12 weeks after onset • 8 patients experienced more than one event of ARIA-E (recurrent ARIA-E) which was similar to initial events • The incidence of ARIA-E in fixed dose cohorts was dose-dependent and occurred more frequently in ApoE ε4 carriers • The incidence of ARIA-E during the placebo-controlled period was lower in ApoE ε4 carriers receiving aducanumab titrated to 10mg/kg (35%) than in ApoE e4 carriers receiving fixed doses of 6mg/kg (43%) or 10mg/kg (55%) of aducanumab • The incidence of ARIA-H not accompanied by ARIA-E in the placebo-controlled period was low and similar across dose groups

ARIA-E, amyloid-related imaging abnormalities - vasogenic edema; ARIA-H, amyloid-related imaging abnormalities – haemosiderin. Data on file. 38 ARIA-E tends to occur early in the course of treatment with aducanumab

Patients switching from 1mg/kg after 14 infusions to 3mg/kg

ARIA-E, amyloid-related imaging abnormalities - vasogenic edema. Data on file. 39 What we will learn (Phase 3)

40 Aducanumab Phase 3 studies ENGAGE & EMERGE

Studies Two 18‐month, randomized, double‐blind, placebo‐controlled, Phase 3 studies Geography ~360 sites in 20 countries . MCI due to AD + mild AD dementia Population • MMSE 24‐30, CDR‐G 0.5, RBANS ≤ 85, enriched using Amyloid PET Doses . Two dose levels (low & high) and placebo, randomized 1:1:1 Duration . 18 months; followed by long‐term extension Primary endpoint . CDR sum of boxes . Secondary: MMSE, ADAS‐Cog 13, ADCS‐ADL‐MCI Other endpoints . Biomarkers: Aβ PET, tf‐MRI, ASL‐MRI, PBMC, blood‐based biomarkers . Sub‐studies: Amyloid PET, Tau PET, CSF disease‐related markers Sample size . ~1605 per study

Strong engagement and high interest of clinical sites/community in aducanumab • ~12,500 patients screened • Enrollment has completed July 2018

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; MMSE, Mini-Mental State Examination; PBMC, peripheral blood mononuclear cells; PET, positron-emission tomography; RBANS, Repeatable Battery for Assessment of Neuropsychological Status. 41 ClinicalTrials.gov: https://clinicaltrials.gov/ct2/show/NCT02477800. Accessed October 24, 2018; ClinicalTrials.gov: https://clinicaltrials.gov/ct2/show/NCT02484547. Accessed October 24, 2018; Data on file. With thanks! Patients, their caregivers, our Investigators and staff at the clinical trial sites

Aducanumab Data Safety Monitoring Committee Katie Harrison Blanche Tavernier Aducanumab Ph3 Steering Committee Lindsey Simov Kerry Lovelace Katherine Ortiz Dawn Fenton Al Sandrock Dakshaben Patel Brett Everhart Philipp von Rosenstiel Shannon Hohengasser Fabienne Emery Salbert Carmen Castrillo-Viguera Edwin Cuthbert Giovanni Facciponte Ping He Tianle Chen Helle Seem Jan Grimm Christian von Hehn Shuang Wu Jaime Torrington Marcel Maier LeAnne Skordos Huijuan Xu Katharina Bruppacher Christoph Hock Ying Tian Linda Maher Elizabeth Thelander Roger Nitsch Liz Miller Lily Huang Michelle Barrington Angela Neufeld Linda D’Amore Paola Marcon Kumar Kandadi Muralidharan Min Yee Pedro Allende Echevarrieta Spyros Chalkias Matt Stagray Peter Kracht Martin Bush Claudia Prada Gersham Dent Przemyslaw Setny Thomas Walz Laura Nisenbaum Karl Evans Bea Vanzieleghem Tina Olsson Prashant Bansal Kayoko Sakayori John O’Gorman Raj Rajagovindan Nori Hidaka Kim Umans Maggie Ying Tetsuhiro Shiota Helen Lockett krunal Shah Satoshi Tamura Ksenia Kastanenka Thierry Bussiere Daisy Nieto Naohiro Honda Brian Bacskai Paul Weinreb Julie Ranuio Emi Yamaoka Fang Qian Shane McLoughlin Yosuke Tachibana Joe Arndt Poorvi Chablani Narinder Chopra Ben Smith Tim Mullen Kate Wilson Chao Quan Ken Loveday Charity Roddy Krishna Praneeth Kilambi Jennifer Clark Marianne Bach Blake Pepinsky Sharon Allin Shobha Purushothama

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