Evaluation of aducanumab efficacy in early Alzheimer’s disease

Samantha Budd Haeberlein,1 Stephen Salloway,2 Paul S. Aisen,3 Frederik Barkhof,4,5 Carmen Castrillo-Viguera,1 Tianle Chen,1 Sharon Cohen,6 Oskar Hansson,7,8 Ping He,1 Takeshi Iwatsubo,9 Craig Mallinkrodt,1 Catherine Jane Mummery,10 Kumar Kandadi Muralidharan,1 Laura Nisenbaum,1 Rajasimhan Rajagovindan,1 Bruno Vellas,11 Shuang Wu,1 Lili Yang,1 Ying Tian1

1. Biogen, Cambridge, MA, USA 2. Departments of Neurology and Psychiatry, Alpert Medical School of Brown University, Providence, RI 3. Alzheimer Therapeutic Research Institute, University of Southern California, San Diego, CA 4. Institute of Healthcare Engineering and Institute of Neurology, University College London, London, UK 5. Department of Radiology and Nuclear Medicine, VU University Medical Center, Amsterdam, Netherlands 6. Toronto Memory Program, North York, ON, Canada 7. Clinical Memory Research Unit, Department of Clinical Sciences, Lund University, Malmö, Sweden 8. Memory Clinic, Skåne University Hospital, Malmö, Sweden 9. Department of Neuropathology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan 10. Dementia Research Centre, Queen Square Institute of Neurology, University College London, London, UK 11. Toulouse Gerontopole University Hospital, Univeriste Paul Sabatier, INSERM U 1027, France

AD/PD 2021, Virtual Conference March 9-14, 2021 1 Disclosures

• SBH, CCV, TC, PH, CM, KKM, LN, RR, SW, LY, and YT are employees of Biogen and may be stockholders • SS was a site investigator and co-chair of the Investigator Steering Committee for the ENGAGE study and is a consultant to Biogen. He also receives research support and is a consultant to Eisai, Novartis, Genentech, Roche, Avid, and Lilly • PSA was Chair of the Steering Committee, has received research support from Lilly, Janssen, Eisai, the Alzheimer Association, NIH and FNIH, and has consulted for Merck, Roche and ImmunoBrain Checkpoint • FB was supported by NIHR Biomedical Research Centre at UCLH. He receives personal fees for consultancy from Bayer, Biogen, Roche, IXICO Ltd, Novartis and Combinostics • SC was an ENGAGE trial site investigator and an Aducanumab Steering Committee member. She is a consultant to Biogen, Cogstate, ProMIS Neuroscience, and RetiSpec and receives research support (paid to institution) from AgeneBio, Alector, Anavex, Biogen, CCHI, Eisai, Genentech, Green Valley, Eli Lilly, RetiSpec, Roche, and Vielight • OH has acquired research support (for the institution) from AVID Radiopharmaceuticals, Biogen, Eli Lilly, Eisai, GE Healthcare, Pfizer, and Roche. In the past 2 years, he has received consultancy/speaker fees from AC Immune, Alzpath, Biogen, Cerveau and Roche • TI is a consultant to Eisai and Roche • CJM was an ENGAGE trial site investigator and an Aducanumab Steering Committee member. She is supported by NIHR Biomedical Research Centre at UCLH and has acted as a consultant to Biogen, Roche, and IONIS • BV has no conflicts of interest to disclose

2 Forward-looking statements

• This presentation contains forward-looking statements, including statements made pursuant to the safe harbor provisions of the Private Securities Litigation Reform Act of 1995, relating to additional results from the Phase 3 clinical studies of aducanumab; the potential clinical effects of aducanumab; the potential benefits, safety, and efficacy of aducanumab; potential regulatory discussions, submissions, and approvals and the timing thereof; clinical development programs, clinical trials, data readouts, and presentations related to aducanumab; the enrollment of any future clinical studies of aducanumab; the treatment of Alzheimer’s disease; the potential of Biogen’s commercial business and pipeline programs, including aducanumab; the anticipated benefits and potential of Biogen’s collaboration arrangements with Eisai Co, Ltd; and risks and uncertainties associated with drug development and commercialization. These forward-looking statements may be accompanied by such words as “aim,” “anticipate,” “believe,” “could,” “estimate,” “expect,” “forecast,” “intend,” “may,” “plan,” “potential,” “possible,” “will,” “would,” and other words and terms of similar meaning. Drug development and commercialization involve a high degree of risk, and only a small number of research and development programs result in commercialization of a product. Results in early-stage clinical trials may not be indicative of full results or results from later-stage or larger-scale clinical trials and do not ensure regulatory approval. You should not place undue reliance on these statements or the scientific data presented.

• These statements involve risks and uncertainties that could cause actual results to differ materially from those reflected in such statements, including actual timing and content of submissions to and decisions made by the regulatory authorities regarding aducanumab; regulatory submissions may take longer or be more difficult to complete than expected; regulatory authorities may require additional information or further studies, or may fail or refuse to approve or may delay approval of Biogen’s drug candidates, including aducanumab; actual timing and enrollment of future studies of aducanumab; the occurrence of adverse safety events and/or unexpected concerns that may arise from additional data or analysis; risks of unexpected costs or delays; the risks of other unexpected hurdles; uncertainty of success in the development and potential commercialization of aducanumab; failure to protect and enforce Biogen’s data, intellectual property, and other proprietary rights and uncertainties relating to intellectual property claims and challenges; risks relating to the potential launch of aducanumab, including preparedness of healthcare providers to treat patients, the ability to obtain and maintain adequate reimbursement for aducanumab, and other unexpected difficulties or hurdles; product liability claims; third-party collaboration risks; 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 U.S. Securities and Exchange Commission. These statements are based on our current beliefs and expectations and speak only as of the date of this presentation. We do not undertake any obligation to publicly update any forward-looking statements, whether as a result of new information, future developments, or otherwise.

3 Statement on aducanumab

• Aducanumab is an investigational drug whose efficacy and safety have not yet been established. It is not approved for use in any country. • Biogen licensed the worldwide rights to aducanumab from Neurimmune Holding AG in 2007 and is responsible for its development and commercialization. • As of October 22, 2017, Biogen and Eisai are collaborating on the development and commercialization of aducanumab globally.

4 Aducanumab Phase 3 studies EMERGE and ENGAGE

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

Geography/ 3285 patients at 348 sites in 20 countries sample size

▪ Early Alzheimer’s disease (MCI due to Alzheimer’s disease + mild Alzheimer’s disease dementia) Population • MMSE 24-30, CDR-GS 0.5, RBANS DMI score ≤ 85 • Confirmed amyloid pathology

▪ Two dosing regimens (low and high dose) and placebo; Doses randomized 1:1:1 Countries with active sites included: Primary ▪ Change from baseline in CDR-SB score at 18 months Australia, Austria, Belgium, Canada, Denmark, Finland, endpoint France, Germany, Italy, Japan, the Netherlands, Poland, Portugal, South Korea, Spain, Sweden, Switzerland, ▪ Secondary: MMSE, ADAS-Cog 13, ADCS-ADL-MCI Taiwan, United Kingdom, United States ▪ Tertiary (efficacy): NPI-10 Other endpoints ▪ Sub-studies: amyloid PET, tau PET, CSF disease- related biomarkers

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); CDR-GS, Clinical Dementia Rating Scale–Global; CDR-SB, Clinical Dementia Rating–Sum of Boxes; CSF, cerebrospinal fluid; MCI, mild cognitive impairment; MMSE, Mini-Mental State Examination; NPI- 10, Neuropsychiatric Inventory (10-item); PET, positron-emission tomography; RBANS DMI, Repeatable Battery for Assessment of Neuropsychological Status–Delayed Memory Index. 5 ClinicalTrials.gov: https://clinicaltrials.gov/ct2/show/NCT02477800. Accessed November 2019; ClinicalTrials.gov: https://clinicaltrials.gov/ct2/show/NCT02484547. Accessed November 2019. Background

• Two randomized clinical trials, EMERGE and ENGAGE were conducted in 3285 patients with early Alzheimer’s disease • A prespecified interim analysis for futility was conducted, per protocol, after approximately 50% of the participants had the opportunity to complete Week 78 • EMERGE and ENGAGE were halted in March 2019 based on the results of the futility analysis • Based on a larger dataset after the trials were terminated, it was determined that the assumptions in the futility analysis were not valid • After collection of data at safety follow-up visits, databases were locked and analyzed per the prespecified analysis plan; data were censored following the futility announcement • Aducanumab is currently under review by the FDA (US), EMA (EU), and PDMA (Japan)

EMA, European Medicines Agency; EU, European Union; FDA, Food and Drug Administration; PDMA, Product Development and Management Association; US, United States.

6 Baseline demographics

EMERGE ENGAGE Placebo Low dose High dose Placebo Low dose High dose (n=548) (n=543) (n=547) (n=545) (n=547) (n=555) Age in years, mean ± SD 70.8±7.4 70.6±7.4 70.6±7.5 69.8±7.7 70.4±7.0 70.0±7.7 Female, n (%) 290 (53) 269 (50) 284 (52) 287 (53) 284 (52) 292 (53) Race, n (%) Asian 47 (9) 39 (7) 42 (8) 55 (10) 55 (10) 65 (12) White 431 (79) 432 (80) 422 (77) 413 (76) 412 (75) 413 (74) Education years, mean ± SD 14.5±3.7 14.5±3.6 14.5±3.6 14.7±3.7 14.6±3.8 14.6±3.7 Alzheimer’s disease medications used, 282 (51) 281 (52) 285 (52) 299 (55) 317 (58) 313 (56) n (%) ApoE ε4, n (%) Carriers 368 (67) 362 (67) 365 (67) 376 (69) 391 (71) 378 (68) Non-carriers 178 (32) 178 (33) 181 (33) 167 (31) 156 (29) 176 (32) Clinical stage, n (%) MCI due to Alzheimer’s disease 446 (81) 452 (83) 438 (80) 443 (81) 440 (80) 442 (80) Mild Alzheimer’s disease dementia 102 (19) 91 (17) 109 (20) 102 (19) 107 (20) 113 (20) ITT population. ApoE, apolipoprotein E; ITT, intent to treat; MCI, mild cognitive impairment; SD, standard deviation. 7 Baseline disease characteristics

EMERGE ENGAGE Placebo Low dose High dose Placebo Low dose High dose (n=548) (n=543) (n=547) (n=545) (n=547) (n=555) RBANS delayed memory score, mean ± SD 60.5±14.2 60.0±14.0 60.7±14.2 60.0±13.6 59.5±14.2 60.6±14.1 MMSE score, mean ± SD 26.4±1.8 26.3±1.7 26.3±1.7 26.4±1.7 26.4±1.8 26.4±1.8 CDR global score, n (%) 0.5 545 (99) 543 (100) 546 (100) 544 (100) 546 (100) 554 (100) 1 3 (1) 0 1 (0) 1 (0) 1 (0) 0 CDR-SB score, mean ± SD 2.47±1.00 2.46±1.01 2.51±1.05 2.40±1.01 2.43±1.01 2.40±1.01 ADAS-Cog 13 score, mean ± SD 21.87±6.73 22.49±6.76 22.25±7.07 22.48±6.56 22.52±6.30 22.40±6.54 ADCS-ADL-MCI score, mean ± SD 42.6±5.7 42.8±5.5 42.5±5.8 43.0±5.6 42.9±5.7 42.9±5.7 PET substudy population n=159 n=159 n=170 n=204 n=198 n=183 Amyloid PET SUVR, mean composite ± SD 1.37±0.17 1.39±0.18 1.38±0.18 1.38±0.20 1.39±0.19 1.41±0.18

ITT population. 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); CDR, Clinical Dementia Rating; CDR-SB, Clinical Dementia Rating–Sum of Boxes; ITT, intent to treat; MCI, mild cognitive impairment; MMSE, Mini-Mental State Examination; RBANS, Repeatable 8 Battery for Assessment of Neuropsychological Status; PET, positron-emission tomography; SD, standard deviation; SUVR, standardized uptake value ratio. EMERGE: Longitudinal change from baseline in CDR-SB The primary endpoint of change from baseline in CDR-SB at Week 78 was met Week 78 2.00 5 Low dose High dose n=543 n=547 0

1.50 -5 -0.26 -0.39 (-0.569, 0.041) (-0.694, -0.086)

SE) * p=0.0901 p=0.0120 ± -10 1.00 -15

-15% baseline ( baseline -20

0.50 % Difference vs placebo vs Difference % Adjusted mean change from from change mean Adjusted -25 -22% Analysis visit (weeks) * 0.00 -30 0 26 50 78 % Difference from placebo at Week 78 Placebo n=548 532 430 288 (95% CI) Low-dose aducanumab n=543 513 420 290 p value High-dose aducanumab n=547 513 431 299 ITT population. *p <0.05 compared with placebo. Values at each time point were based on an MMRM model, with change from baseline in CDR-SB as the dependent variable and with fixed effects of treatment group, categorical visit, treatment-by-visit interaction, baseline CDR-SB, baseline CDR-SB by visit interaction, baseline MMSE, Alzheimer’s disease symptomatic medication use at baseline, region, and laboratory ApoE ε4 status. ApoE, apolipoprotein E; CDR-SB, Clinical Dementia Rating–Sum of Boxes; CI, confidence interval; ITT, intent to treat; MMRM, mixed model for repeated measure; MMSE, Mini Mental State Examination; SE, standard error. 9 EMERGE: Clinical endpoints at Week 78 High dose aducanumab met all clinical endpoints assessing cognition, function and behavior at Week 78 Primary endpoint Secondary endpoints Tertiary endpoint CDR-SB MMSE ADAS-Cog 13 ADCS-ADL-MCI NPI-10 5 3% 5 -0.26 -0.39 -0.1 0.6 -0.7 -1.4 0.7 1.7 (-0.569, 0.041) (-0.694, -0.086) (-0.65, 0.48) (0.00, 1.13) (-1.76, 0.36) (-2.46, -0.34) (-0.27, 1.73) (0.75, 2.74) -0.5 -1.3 p=0.0901 p=0.0120 p=0.7578 p=0.0493 p=0.1962 p=0.0097 p=0.1515 p=0.0006 -10 (-1.62, 0.64) (-2.45, -0.20) p=0.3921 p=0.0215 -10 -25 -14% -15% -16% * -18% -40 -33% -25 -22% * * -27% -55

% ** -40 Difference from placebo -70 (95% CI) -40%

% Difference % placebo vs p value *** Difference % placebo vs -85 Low-dose aducanumab High-dose aducanumab -87% -55 a a n=543 n=547 -100 * a n=numbers of randomized and dosed patients included in the analysis. *p <0.05, **p <0.01, and ***p <0.001 compared with placebo (nominal for NPI-10). 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); CDR-SB, Clinical Dementia Rating; CI, confidence interval; MMSE, Mini-Mental State Examination; NPI-10, Neuropsychiatric Inventory (10-item). 10 EMERGE: Clinical endpoints at Week 78 High dose aducanumab met all clinical endpoints assessing cognition, function and behavior at Week 78 Primary endpoint Secondary endpoints Tertiary endpoint Treatment effect was also observed on the NPI-10, an exploratory clinical CDR-SB MMSE ADAS-Cog 13 ADCS-ADL-MCI efficacy endpoint NPI-10 5 3% 5 -0.26 Caregivers-0.39 of patients-0.1 who0.6 received-0.7 high-dose-1.4 aducanumab0.7 reported1.7 84% (-0.569, 0.041) (-0.694, -0.086) (-0.65, 0.48) (0.00, 1.13) (-1.76, 0.36) (-2.46, -0.34) (-0.27, 1.73) (0.75, 2.74) -0.5 -1.3 p=0.0901 lessp=0.0120 burden comparedp=0.7578 p=0.0493 with caregiversp=0.1962 ofp=0.0097 patients whop=0.1515 receivedp=0.0006 placebo -10 (-1.62, 0.64) (-2.45, -0.20) p=0.3921 p=0.0215 -10 -25 -14% -15% -16% * -18% -40 -33% -25 -22% * * -27% -55

% ** -40 Difference from placebo -70 (95% CI) -40%

% Difference % placebo vs p value *** Difference % placebo vs -85 Low-dose aducanumab High-dose aducanumab -87% -55 a a n=543 n=547 -100 * a n=numbers of randomized and dosed patients included in the analysis. *p <0.05, **p <0.01, and ***p <0.001 compared with placebo (nominal for NPI-10). 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); CDR-SB, Clinical Dementia Rating; CI, confidence interval; MMSE, Mini-Mental State Examination; NPI-10, Neuropsychiatric Inventory (10-item). 11 EMERGE: Clinical endpoints at Week 78 High dose aducanumab met all clinical endpoints assessing cognition, function and behavior at Week 78 Primary endpoint Secondary endpoints Tertiary endpoint Treatment effect was also observed on the NPI-10, an exploratory clinical CDR-SB MMSE ADAS-Cog 13 ADCS-ADL-MCI efficacy endpoint NPI-10 5 3% 5 -0.26 Caregivers-0.39 of patients-0.1 who0.6 received-0.7 high-dose-1.4 aducanumab0.7 reported1.7 84% (-0.569, 0.041) (-0.694, -0.086) (-0.65, 0.48) (0.00, 1.13) (-1.76, 0.36) (-2.46, -0.34) (-0.27, 1.73) (0.75, 2.74) -0.5 -1.3 p=0.0901 lessp=0.0120 burden comparedp=0.7578 p=0.0493 with caregiversp=0.1962 ofp=0.0097 patients whop=0.1515 receivedp=0.0006 placebo -10 (-1.62, 0.64) (-2.45, -0.20) p=0.3921 p=0.0215 -10 -25 -14% -15% -16% * -18% -40 -33% -25 -22% * The* probability of all four primary and -secondary27% clinical endpoints -55 % being false-positive is 1** in 10,000 -40 Difference from placebo -70 (based(95% CI) on a multivariate normal distribution with between-endpoint correlation set-40% as observed)

% Difference % placebo vs p value *** Difference % placebo vs -85 Low-dose aducanumab High-dose aducanumab -87% -55 a a n=543 n=547 -100 * a n=numbers of randomized and dosed patients included in the analysis. *p <0.05, **p <0.01, and ***p <0.001 compared with placebo (nominal for NPI-10). 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); CDR-SB, Clinical Dementia Rating; CI, confidence interval; MMSE, Mini-Mental State Examination; NPI-10, Neuropsychiatric Inventory (10-item). 12 EMERGE: Sensitivity analyses assessed the robustness of treatment effect with high-dose aducanumab

CDR-SB MMSE ADAS-Cog 13 ADCS-ADL-MCI Favors aducanumab Favors aducanumab Favors aducanumab Favors aducanumab

Primary analysis (ITT) Missing data due to study early termination OTC analysis ITT uncensored Missing data due to subject premature withdrawal

Copy increment from reference Jump to reference Normality Non-parametric test Log-transformation analysis

-2 -1.5 -1 -0.5 0 0.5 2.5 1.5 0.5 -0.5 -1.5 -5.5 -3.5 -1.5 0.5 2.5 6 5 4 3 2 1 0 -1 Adjusted mean change vs placebo (95% CI for difference)

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); CDR-SB, Clinical Dementia Rating; CI, confidence interval; ITT, intent to treat; MMSE, Mini-Mental State Examination; OTC, opportunity to complete. 13 EMERGE: Amyloid PET showed dose- and time-dependent reduction in β-amyloid pathology with aducanumab Baseline SUVR (centiloid) 0.05 1.394 (88.0) 10 1.383 (85.3) 0.00 0

SE -10

± -0.05 *** SE

-20 ± -0.10 Difference vs placebo *** SUVR (centiloid) -30 -0.15 *** -40 -0.20 -0.179 (-41.3) -50

The amyloid level in the high dose composite SUVR, SUVR, composite

-0.25 centiloid scale, aducanumab group was reduced to ~25 *** -60 -0.30 centiloid units at Week 78 -0.278 (-64.2) -70

Adjusted mean change from baseline, baseline, from change mean Adjusted Analysis visit (weeks)

-0.35 -80 baseline, from change mean Adjusted 0 26 52 78 Placebo n=159 129 93 Low-dose adu n=159 129 100 High-dose adu n=170 138 109

18F-florbetapir amyloid PET analysis population. ***p<0.0001 compared with placebo (nominal). Values at each time point were based on an MMRM model, with change from baseline in MMSE as the dependent variable and with fixed effects of treatment group, categorical visit, treatment-by-visit interaction, baseline SUVR, baseline SUVR by visit interaction, baseline MMSE, Alzheimer’s disease symptomatic medication use at baseline, region, and laboratory ApoE ε4 status. 14 adu, aducanumab; ApoE, apolipoprotein E; MMRM, mixed model for repeated measure; MMSE, Mini Mental State Examination; PET, positron emission tomography; SE, standard error; SUVR, standardized uptake value ratio. EMERGE: CSF biomarkers of Alzheimer’s disease and downstream pathology were impacted by aducanumab treatment

Aβ1-42 p-tau t-tau Anti-amyloid target engagement, Pathophysiology of Alzheimer’s disease Neurodegeneration pathophysiology of Alzheimer’s disease

400 0 SE)

SE) -20

SE)

± ±

± -5

300 *** /mL ( /mL /mL ( /mL -60

/mL ( /mL -10 pg

200 pg pg *** -15 -100 100 -20 * ** -140

0 -25

Adjusted mean change mean Adjusted

Adjusted mean change mean Adjusted Adjusted mean change mean Adjusted

from baseline, frombaseline, ** from baseline, frombaseline, from baseline, frombaseline, -30 -180 -100 *** Low High Low High Low High Placebo dose dose Placebo dose dose Placebo dose dose n=28 n=33 n =17 n=28 n=33 n =17 n=28 n=33 n =17

CSF modified analysis population (patients with both baseline and post-baseline CSF assessments). *p<0.05, **p<0.01, ***p<0.001 compared with placebo (nominal). Values were based on an ANCOVA model at Week 78, fitted with change from baseline as the dependent variable, and with categorical treatment, baseline biomarker value, baseline age, and laboratory ApoE ε4 status (carrier and non-carrier) as the independent variables. Aβ, amyloid beta; ANCOVA, analysis of covariance; ApoE, apolipoprotein; CSF, cerebrospinal fluid; p-tau, phosphorylated tau 181; SE, standard error; t-tau, total tau. 15 EMERGE: CSF biomarkers of Alzheimer’s disease and downstream pathology were impacted by aducanumab

treatment Placebo Low dose High dose

Aβ p-tau t-tau

SE) SE)

1-42 SE)

± ± 400 ± 0 -20

300 *** -5

/mL ( /mL ( /mL ( /mL

-10 -60

pg pg 200 pg *** -15 100 -100 -20 -140 0 -25 ** *

-100 -30 *** -180 **

Adjusted mean change Adjusted mean change

Low High Low High Adjusted mean change Low High

from baseline, from baseline, from Placebo dose dose baseline, from Placebo dose dose Placebo dose dose 750 n=28 n=33 n=17 90 n=28 n=33 n=17 400 n=28 n=33 n=17

60 200 500

30

/ml /ml

/ml 0

pg pg 0 pg 250 -200 -30 -400 -60

0

at Week 78,Week at at Week 78,Week at

-90 78,Week at -600

Change baseline from

Change baseline from Change baseline from

-250 -120 -800 0 40 80 120 160 0 40 80 120 160 0 40 80 120 160 Cumulative dose by Week 78, mg/kg Cumulative dose by Week 78, mg/kg Cumulative dose by Week 78, mg/kg CSF modified analysis population (patients with both baseline and post-baseline CSF assessments). *p<0.05, **p<0.01, ***p<0.001 compared with placebo (nominal). Values were based on an ANCOVA model at Week 78, fitted with change from baseline as the dependent variable, and with categorical treatment, baseline biomarker value, baseline age, and laboratory ApoE ε4 status (carrier and non-carrier) as the independent variables. Aβ, amyloid beta; ANCOVA, analysis of covariance; ApoE, apolipoprotein; CSF, cerebrospinal fluid; p-tau, phosphorylated tau 181; SE, standard error; t-tau, total tau. 16 ENGAGE: Longitudinal change from baseline in CDR-SB The primary endpoint of change from baseline in CDR-SB at Week 78 was not met Week 78 2.00 5 2% 0 -0.18 0.03 1.50 (-0.469, 0.110) (-0.262, 0.326)

-5 p=0.2250 p=0.8330

SE) ± -10 1.00 -12% -15

Low dose High dose baseline ( baseline n=547 n=555

0.50 -20 % Difference vs placebo vs Difference %

-25 Adjusted mean change from from change mean Adjusted Analysis visit (weeks) 0.00 -30 % Difference from 0 26 50 78 placebo at Week 78 Placebo n=545 522 455 333 (95% CI) Low-dose aducanumab n=547 529 456 331 p value High-dose aducanumab n=554 532 449 295 ITT population. Values at each time point were based on an MMRM model, with change from baseline in CDR-SB as the dependent variable and with fixed effects of treatment group, categorical visit, treatment- by-visit interaction, baseline CDR-SB, baseline CDR-SB by visit interaction, baseline MMSE, Alzheimer’s disease symptomatic medication use at baseline, region, and laboratory ApoE ε4 status. ApoE, apolipoprotein E; CDR-SB, Clinical Dementia Rating–Sum of Boxes; CI, confidence interval; ITT, intent to treat; MMRM, mixed model for repeated measure; MMSE, Mini Mental State Examination; SE, 17 standard error. ENGAGE: Clinical endpoints at Week 78 Results of the ENGAGE study were partially discordant with those of EMERGE

Primary endpoint Secondary endpoints Tertiary endpoint

CDR-SB MMSE ADAS-Cog 13 ADCS-ADL-MCI NPI-10 8% 5 5 2% 3% -10

-10 -6% -25 -1.0 0.1 -12% -11% -11% (-2.06, -0.02) (-0.98, 1.10) -40 p=0.0460 p=0.9071 -18% -18% -25 -0.18 0.03 0.2 -0.1 -0.583 -0.588 0.7 0.7 (-0.469, 0.110) (-0.262, 0.326) (-0.35, 0.74) (-0.62, 0.49) (-1.5835, 0.4181) (-1.6067, 0.4309) (-0.19, 1.64) (-0.25, 1.61) -55 p=0.2250 p=0.8330 p=0.4795 p=0.8106 p=0.2536 p=0.2578 p=0.1225 p=0.1506 -70 -40 % Difference from placebo placebo vs Difference %

% Difference % placebo vs (95% CI) -85 p value -83% Low-dose aducanumab High-dose aducanumab -55 n=547a n=555a -100 *

ITT population. *p <0.05 with placebo (nominal for NPI-10). an=numbers of randomized and dosed participants included in the analysis. 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); CDR-SB, Clinical Dementia Rating; CI, confidence interval; MMSE, Mini-Mental State Examination; NPI-10, Neuropsychiatric Inventory (10-item). 18 ENGAGE: Amyloid PET showed dose- and time-dependent reduction in β-amyloid pathology with aducanumab

Baseline SUVR (centiloid) Mean 0.05 10 1.385 (85.9) cumulative dose 1.407 (90.8) 0.00 0 at Week 78: ENGAGE SE -10 109.1 mg/kg ± -0.05

1.383 (85.3) *** SE

(EMERGE) -20 ± EMERGE -0.10 Difference vs placebo *** SUVR (centiloid) 118.3 mg/kg -30 -0.15 *** EMERGE Placebo -0.167 (-38.5) -40 EMERGE High-dose The magnitude of -0.20 treatment effect -50

In ENGAGE, the amyloid level in the high -0.232 (-53.5) observed in composite SUVR, SUVR, composite -0.25 dose aducanumab group was reduced to *** -60 centiloid scale, ENGAGE high dose (-0.232) is ~37 centiloid units at Week 78 -0.278 (-64.2) -0.30 -70 16.5% less than (EMERGE) that observed in

Adjusted mean change from baseline, baseline, from change mean Adjusted Analysis visit (weeks) EMERGE high -0.35 -80 baseline, from change mean Adjusted 0 26 78 dose (-0.278) Placebo n=204 168 124 Low-dose adu n=198 169 138 High-dose adu n=183 156 112

18F-florbetapir amyloid PET analysis population. ***p<0.0001 compared with placebo (nominal). Values at each time point were based on an MMRM model, with change from baseline in MMSE as the dependent variable and with fixed effects of treatment group, categorical visit, treatment-by-visit interaction, baseline SUVR, baseline SUVR by visit interaction, baseline MMSE, Alzheimer’s disease symptomatic medication use at baseline, region, and laboratory ApoE ε4 status. 19 adu, aducanumab; ApoE, apolipoprotein E; MMRM, mixed model for repeated measure; MMSE, Mini Mental State Examination; PET, positron emission tomography; SE, standard error; SUVR, standardized uptake value ratio. The effect of high-dose aducanumab CSF biomarkers in ENGAGE was less than in EMERGE Placebo Low dose High dose

Aβ1-42 p-tau t-tau

SE)

SE)

SE)

± ± ± 400 0

-20 /mL ( /mL 300 ( /mL -5

/mL ( /mL *** -60

pg pg

pg 200 -10 100 -15 -100 0 -20 -140

-100 -25 -180

Adjusted mean change Adjusted mean change

Adjusted mean change Low High Low High Low High

from baseline, from from baseline, from from baseline, from Placebo dose dose Placebo dose dose Placebo dose dose n=15 n=19 n=17 n=15 n=20 n=18 n=14 n=18 n=16 750 90 400

60 200

500 30

/ml /ml

/ml 0

pg pg pg 0 250 -200 -30 -400 -60

0

at Week 78,Week at at Week 78,Week at

at Week 78,Week at -90 -600

Change baseline from

Change baseline from Change baseline from

-250 -120 -800 0 40 80 120 160 0 40 80 120 160 0 40 80 120 160 Cumulative dose by Week 78, mg/kg Cumulative dose by Week 78, mg/kg Cumulative dose by Week 78, mg/kg ***p <0.001 compared with placebo (nominal). Aβ, amyloid beta; CSF, cerebrospinal fluid; p-tau, phosphorylated tau 181;SE, standard error; t-tau, total tau. 20 EMERGE & ENGAGE: Aducanumab reduced tau pathophysiology, as measured by MK-6420 tau PET

Medial temporal composite Temporal composite Frontal composite 0.12 0.12 0.12 0.1 0.1 0.1 0.08 0.08 0.08 0.06 0.06 0.06 0.04 0.04 0.04 * 0.02 0.02 0.02 0 0 0 -0.02 -0.02 -0.02

-0.04 -0.04 -0.04

baseline SUVR (SE) SUVR baseline (SE) SUVR baseline (SE) SUVR baseline

-0.06 -0.06 -0.06

Adjusted Adjusted fromchange mean Adjusted fromchange mean Adjusted Adjusted fromchange mean -0.08 * -0.08 * -0.08 -0.1 *** -0.1 -0.1 Placebo Low dose High dose Placebo Low dose High dose Placebo Low dose High dose n=12 n=14 n=11 n=12 n=14 n=11 n=12 n=14 n=11

Pooled tau PET analysis population. 18F-MK6240 Tau PET tracer. *p<0.05; ***p<0.0001 compared with placebo (nominal). PET, positron emission tomography; SE, standard error; SUVR, standardized uptake value ratio. 21 Higher cumulative dose of aducanumab was correlated with a greater reduction in MK-6420 tau PET signal

Medial temporal composite 0.12 0.1 0.2 0.08

0.06 0.1 0.04 0.02 0.0 0 -0.02 -0.1

-0.04 baseline SUVR (SE) SUVR baseline

-0.06

SUVR frombaseline SUVR change Adjusted Adjusted fromchange mean

-0.08 * -0.2 Tau PET medial temporal composite temporal PET medial Tau -0.1 *** 0 20 40 60 80 100 120 140 160 Placebo Low dose High dose Cumulative dose by Week 78, mg/kg n=12 n=14 n=11 Treatment: Placebo Low dose High dose

Pooled tau PET analysis population. *p<0.05; ***p<0.0001 compared with placebo (nominal). PET, positron emission tomography; SE, standard error; SUVR, standardized uptake value ratio. 22 EMERGE, ENGAGE, and PRIME results were largely consistent, excepting the high-dose aducanumab group from ENGAGE

Low-dose aducanumab High-dose aducanumab PRIME

ENGAGE EMERGE ENGAGE EMERGE 10 mg/kg Diff vs Placebo (%) N=547 N=543 N=555 N=547 N=32 p<0.05 favoring aducanumab CDR-SB -0.18 (-12%) -0.26 (-15%) 0.03 (2%) -0.39 (-22%) -1.26 (-67%) Numeric advantage favoring MMSE 0.2 (-6%) -0.1 (3%) -0.1 (3%) 0.6 (-18%) 1.9 (-76%) aducanumab

No numeric ADAS-Cog 13 -0.58 (-11%) -0.70 (-14%) -0.59 (-11%) -1.40 (-27%) advantage favoring aducanumab

ADCS-ADL-MCI 0.7 (-18%) 0.7 (-16%) 0.7 (-18%) 1.7 (-40%)

Amyloid-PET* -0.167 -0.179 -0.232 -0.278 SUVR -0.277 (-38.5) (-41.3) (-53.5) (-64.2) (centiloid unit) (-61.1) N=numbers of randomized and dosed participants. * Number of participants in ENGAGE PET substudy = 585 and EMERGE substudy = 488. 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); 23 CDR-SB, Clinical Dementia Rating–Sum of Boxes; CI, confidence interval; MMSE, Mini-Mental State Examination; PET, positron emission tomography; SUVR, standardized uptake value ratio. The partially discordant results between EMERGE and ENGAGE were extensively investigated • Demographics, disease characteristics, frequency, severity and management of ARIA were all similar between studies • Underlying pharmacology of aducanumab is similar in ENGAGE and EMERGE • Differences between studies were largely driven by: ▪ Lower exposure to 10 mg/kg dosing in ENGAGE ▪ Imbalance in number and distribution of rapid progressing Alzheimer’s disease patients In ENGAGE, patients randomized to groups with the opportunity for full 10 mg/kg dosing had results similar to EMERGE

ARIA, amyloid-related imaging abnormalities.

24 No evidence of functional unblinding from ARIA management was observed across clinical scales CDR-SB MMSE 0.5 1.5

Differences vs placebo with 1.0 respect to primary and 0.0 0.5 secondary endpoints were compared using: 0.0 • primary analysis (x-axis) -0.5 -0.5 • analysis excluding data after -1.0

ARIA onset (y-axis) -1.0 -1.5 Excluding data after ARIAonset after data Excluding Excluding data after ARIAonset after data Excluding -1.0 -0.5 0.0 0.5 -1.5 -1.0 -0.5 0.0 0.5 1.0 1.5 Primary analysis Primary analysis Results show that data points are scattered evenly above ADAS-Cog 13 ADCS-ADL-MCI and below the line of unity, 1.5 3.5 indicating random variability and 1.0 3.0 0.5 no evidence of functional 2.5 0.0 unblinding 2.0 -0.5 1.5 -1.0 EMERGE ENGAGE 1.0 -1.5 high dose carrier high dose non-carrier -2.0 0.5 low dose carrier low dose non-carrier -2.5 0.0

-3.0 -0.5 Excluding data after ARIAonset after data Excluding Excluding data after ARIAonset after data Excluding -3.0 -2.5 -2.0 -1.5 -1.0 0.5 0.0 0.5 1.0 1.5 -0.5 0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 Primary analysis Primary analysis

ARIA, amyloid-related imaging abnormalities; 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); CDR-SB, Clinical Dementia Rating–Sum of Boxes; MMSE, Mini-Mental State Examination. 25 Differences in study enrollment and implementation of protocol amendments reduced exposure to 10 mg/kg Early enrolled patients had lower exposure to 10 mg/kg 1800 ENGAGE EMERGE ENGAGE Target dose 14 1600 14 13 Protocol Version 4 March 2017 12 12 1400 Protocol Version 3 12 ApoE ε4 carriers to 11 July 2016 titrate to 10 mg/kg Patients with ARIA to restart 1200 10 at the same dose or titrate EMERGE: ~600 10 up to the originally assigned ENGAGE: ~800 dose 1000 EMERGE EMERGE: ~250 8 ENGAGE: ~350 7 800 6 5 600 4

4 Number of patients Number of 400 2 1

200 Median Median number 10 of mg/kg doses 0 0 First 200 Patients Patients Patients Patients patients 201-400 401-600 600-800 >800

Early Late

Jun-16 Jun-17 Jun-18

Oct-15 Oct-16 Oct-17

Apr-16 Apr-17 Apr-18

Feb-16 Feb-17 Feb-18

Dec-15 Dec-16 Dec-17

Aug-16 Aug-17 Aug-15 enrollers enrollers ApoE, apolipoprotein E; ARIA, amyloid related imaging abnormalities.

26 Patients who had the opportunity for 14 doses of 10 mg/kg had similar benefit in both studies

Mean Median % diff Week 78 Favors aducanumab cum dose cum dose vs pbo N: number at baseline. n: number at Week 78. (mg/kg) (mg/kg)

Post-PV4, ApoE+ (N=58, n=48) 122.9 150.0 -29% ENGAGE Pre-PV4, ApoE- (N=78, n=66) 123.4 150.0 -3%

Post-PV4, ApoE- (N=25, n=23) 145.9 160.0 -46%

Weighted mean (N=161, n=137) -23%

Post-PV4, ApoE+ (N=65, n=56) 150.0 -25% EMERGE 124.7 Pre-PV4, ApoE- (N=84, n=75) 131.4 160.0 -15%

Post-PV4, ApoE- (N=31, n=29) 134.3 160.0 -34%

Weighted mean (N=180, n=160) -23%

-2.5 -2 -1.5 -1 -0.5 0 0.5 1 CDR-SB Adjusted Mean Change vs Placebo (95% CI for difference) Patients who have had the opportunity to complete week 78 visit by 20 March 2019. ApoE, apolipoprotein E; pbo, placebo; CDR-SB, Clinical Dementia Rating Scale–Sum of Boxes; CI, confidence interval; pbo, placebo, PV4, protocol amendment version 4. 27 Clinical endpoints measure distinct, important symptoms of cognition, function, and behavior

Five clinical rating scales were used in EMERGE and ENGAGE ADAS- • Validated and widely used in early Alzheimer’s disease Cog 13 MMSE • Includes key perspectives: o Expert clinical judgements based on patient examination and caregiver input CDR-SB

o Patient and caregiver reports ADCS-ADL

o Cognitive performance tests -MCI • Collectively they cover the full scope of symptoms NPI-10 experienced by patients with Alzheimer’s disease with minimal overlap

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); CDR, Clinical Dementia Rating–Sum of Boxes; MMSE, Mini-Mental State Examination; NPI-10, Neuropsychiatric Inventory (10-item). 28 High-dose aducanumab increased the percentage of responders using multiple thresholds Odds ratio (95% CI) EMERGE OTCa 0 20 40 60 80 100 Favors Placebo Favors Treatment High dose compared with placebo

CDR-SB ≤ 0.5 33.9 1.41 (1.017, 1.962)

CDR-SB ≤ 1.0* 47.9 1.31 (0.958, 1.798)

off off for Responder

- Cut CDR-SB ≤ 1.5 61.9 1.25 (0.908, 1.709)

0.0 0.5 1.0 1.5 2.0 Estimated percentage of Odds Ratio (CI) responders in placebo group

a Patients with missing values at Week 78 were classified as non-responders. * CDR-SB ≤ 1.0 was post hoc analysis. CDR-SB, Clinical Dementia Rating Scale–Sum of Boxes; CI, confidence interval; OTC, opportunity to complete. 29 High-dose aducanumab improved response vs placebo across clinical endpoints EMERGE OTCa Odds ratio (95% CI) 0.0 20.0 40.0 60.0 80.0 100.0 Favors Placebo Favors Treatment High dose compared with placebo

CDR-SB ≤ 0.5 33.9 1.41 (1.017, 1.962)

MMSE ≥ –1 31.4 1.32 (0.946, 1.837)

off off for responder -

ADAS-Cog 13 ≤ 3 37.1 1.25 (0.906, 1.730)

1.60 (1.166, 2.185)

ADCS-ADL-MCI ≥ –3 47.2 Outcome and cut and Outcome

0.0 0.5 1.0 1.5 2.0 Estimated percentage of responders in placebo group Odds Ratio (CI) a Patients with missing values at Week 78 were classified as non-responders. Responder threshold defined as worsening ≤ 0.5 baseline SD. 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); CDR-SB, Clinical Dementia Rating Scale–Sum of Boxes; CI, confidence interval; MMSE, Mini-Mental State Examination; OTC, opportunity to complete; SD, standard deviation. 30 Composite measures were consistent with primary analyses EMERGE ENGAGE -12 -12 Week 78 Week 78

-10 -10 SE) SE)

SE) SE) -8 -8 ± iADRS-like ± *** *** -6 -6 endpoint Composite results -4 -4 based on total scores 16% less 34% less 16% less 15% less

of ADAS-Cog13 and -2 decline decline -2 decline decline from baseline( from

ADCS-ADL-MCI baseline( from p=0.0781 p=0.1025 Adjusted mean change Adjusted mean change p=0.0858 p=0.0002 0 0 Placebo Low dose High dose Placebo Low dose High dose n=548 n=543 n=547 n=545 n=547 n=555

0.25 0.25

0.2 0.2 SE) SE)

** SE)

± ± ADCOMS 0.15 *** 0.15 Composite results *** based on selected 0.1 0.1 items in ADAS-Cog13,

MMSE and CDR-SB 12% less 22% less 11% less 5% less from baseline( from 0.05 baseline( from 0.05

decline decline decline decline

Adjusted mean change Adjusted mean change p=0.1117 p=0.0049 p=0.1509 p=0.5022 0 0 Placebo Low dose High dose Placebo Low dose High dose n=548 n=543 n=547 n=545 n=547 n=555

n=numbers of randomized and dosed patients included in the analysis. **p <0.01, and ***p <0.001 compared with placebo (nominal). ADAS-Cog 13, Alzheimer’s Disease Assessment Scale–Cognitive Subscale (13-item); ADCOMS, Alzheimer’s Disease Composite Score; ADCS-ADL-MCI, Alzheimer’s Disease Cooperative Study–Activities of Daily Living Inventory (mild cognitive impairment version); CDR-SB, Clinical Dementia Rating Scale–Sum of Boxes; iADRS, The Integrated Alzheimer's Disease Rating Scale; MMSE, Mini-Mental State Examination; SE, 31 standard error. Aducanumab Phase 3 studies EMERGE and ENGAGE

• In EMERGE, high-dose aducanumab resulted in a consistent reduction of clinical decline across all 5 clinical endpoints spanning cognition, daily function and behavioral symptoms in patients with early Alzheimer’s disease • Effects on amyloid PET and downstream biomarkers specific to Alzheimer’s disease (CSF p- tau) and neurodegeneration (CSF t-tau) further support the clinical findings • ENGAGE did not meet its primary endpoint • The partially discordant results between EMERGE and ENGAGE were extensively investigated • Dose and unbalanced distribution of rapid progressors were the primary contributors to the discordant results observed between the two studies in the high dose aducanumab arm • Patients in ENGAGE who had the opportunity for 14 doses of 10 mg/kg had clinical efficacy consistent with EMERGE • Post-hoc analyses of composite scales are reflective of the component scales, and consistent with the primary analyses

Aβ, amyloid beta; 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); CDR-SB, Clinical Dementia Rating Scale–Sum of Boxes; CSF, cerebrospinal fluid; PET, positron-emission tomography; p-tau, phosphorylated tau 181; t-tau, total tau. 32