Biogen : Aducanumab data review and Q&A with Alzheimer's Disease International

ADI- Alzheimer's Disease International 2021 Webinar

Aducanumab Data Review

Samantha Budd Haeberlein, PhD

Senior Vice President, Head Neurodegeneration Development Unit Biogen

January 14th 2021

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 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 treatment of
  Alzheimer's disease; the potential of Biogen's pipeline programs, including aducanumab; 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; 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 Biogen's most recent annual or quarterly report and in other reports Biogen has filed with the U.S. Securities and Exchange Commission. These statements are based on Biogen's current beliefs and expectations and speak only as of the date of this presentation. Biogen does not undertake any obligation to publicly update any forward-looking statements, whether as a result of new information, future developments or otherwise.

Statement on Aducanumab

Aducanumab is an investigational drug that is currently under regulatory review. It is not approved for use in any country at this time.

Thank you to everyone who has contributed to Alzheimer's Disease Research!

Aducanumab Phase 3 trials included 3285 patients at 348 sites in 20 countries

Countries with active sites included:

Australia, Austria, Belgium, Canada, Denmark, Finland, France,

Germany, Italy, Japan, the Netherlands, Poland, Portugal, South

Korea, Spain, Sweden, Switzerland, Taiwan, United Kingdom,

United States

Biogen Position on the FDA Advisory Committee

Biogen stands behind the analyses and results of aducanumab:

• • The core joint briefing book (FDA & Biogen) is the first ever in the neurology division
  • The totality of data provides substantial evidence of clinical effectiveness of aducanumab, as demonstrated by study 302 (EMERGE) and supported by study 103 (PRIME)
  • Biogen and the FDA concluded that partially discordant results of study 301 (ENGAGE) do not meaningfully detract from the persuasiveness of study 302
• We have applied the highest scientific rigor and integrity in the analyses submitted
• We recognize the complexity of the dataset and the challenges associated with the first positive Ph3 study in Alzheimer

Alzheimer's Disease Presents a Significant Unmet Medical

Need

• As of 2018, there were about 50 million people living with dementia worldwidea
• Progressive neurological disorder resulting in memory loss, behavioral symptoms, and loss of ability to perform daily activities
• In advanced stages of dementia patients become completely dependent
• Alzheimer's disease is ultimately fatal
• No available treatment that alters the course of disease

1. 2018 Alzheimer's Disease International .

The Two Pathological Hallmarks of Alzheimer's Disease in the Brain Are Aβ Plaques and Neurofibrillary Tangles

1. Amyloid beta peptides are released extraneuronally as

monomers

APP

Processing

2) Aggregation of Aβ

Monomers

Oligomers

1. Intraneuronal tau phosphorylation and aggregation

Microglia

4) Synaptic dysfunction, inflammation and neuronal death

Dysfunctional

Microglia

Fibrils	Dying Neuron
	Amyloid β Plaque

Tau Fibrils and

Tangles

Tau protein

Microtubule	Aggregated
p-Tau

Aβ=amyloid beta; APP=amyloid precursor protein.

Based on Pospich S, Raunser S. Science. 2017;358(6359):45-46.

Aducanumab: Targeting Alzheimer's Disease Pathology

Healthy Neuron

Microglia

Amyloid β

Aggregation

	Amyloid Plaque
Monomers	Reduction

Oligomer

Fibrils		Dysfunctional and
	Amyloid β Plaque
	Dying Neurons

Aducanumab Treatment:

Reduced Progression of

Alzheimer's Disease

Aducanumab

No treatment

Dysfunctional Microglia

Aducanumab Is Differentiated From the First Generation of Anti-Aβ Antibodies

Molecular Characteristics of

Aducanumab

• Specificity for neurotoxic aggregated forms of Aβ
• Effector-functionenabling immune cell-mediated clearance of aggregated Aβ

Key Clinical Trial Design Elements

• Inclusion of patients with biomarker-confirmed early symptomatic Alzheimer's disease
• Demonstration of robust reduction in pathology
• Appropriate clinical outcome measures

• Aducanumab was the first of this generation of antibodies to demonstrate proof of concept before initiating phase 3 trials
• Aducanumab is the only program at this time to have read out with positive results in phase 3 trials*

*Primary and secondary endpoints were met in Study 302. In Study 301, patients with the opportunity for full 10mg/kg dosing had results similar to Study 302.

Aducanumab Clinical Development Program

Phase 1b/2 Phase 1

Phase 3/3b

2011

2012

2013

2014

2015

2016

2017

2018

2019

2020

2021

2022

2023

H1

H2

H1

H2

H1

H2

H1

H2

H1

H2

H1

H2

H1

H2

H1

H2

H1

H2

H1

H2

H1

H2

H1

H2

H1

H2

Study 101, n=53

Single ascending dose

Study

Bioavailability, n=28

102

Study 104, n=21

Japanese phase 1

Study 103, n=197

Proof-of-Concept

Study 103 Long-term extension (LTE)

Study

Safety study, n=52

205

Study 301, n=1653

Study 301 Long-term extension (LTE)

Study 302, n=1643

Study 302 Long-term extension (LTE)

Study 304, n=max 2400

Phase 1b Study 103

Aducanumab was the First Program where Proof-of- Concept was Demonstrated Prior to Phase 3

Baseline

One year

Placebo

3 mg/kg

6 mg/kg

10 mg/kg

Change in CDR-SB

		2.5
Adjusted mean change from	baseline at Week 54 (SE)	2.0
1.5
*
*
1.0
0.5
		0.0
		Placebo 1 mg/kg 3 mg/kg 6 mg/kg Titration 10 mg/kg

Image reprinted with permission from Springer Nature: Nature. The antibody aducanumab reduces Aβ plaques in Alzheimer's disease. Sevigny J, Chiao P, Bussière T, et al. Copyright 2016.

*p<0.05, compared with placebo (nominal)

Phase 3 Studies

Aducanumab Phase 3 Trial Design

Studies 301 and 302

Studies	Two 18-month, randomized, double-blind,
	placebo-controlled, Phase 3 studies
Geography/ 3285 patients at 348 sites in 20 countries
Sample size
Population	• Early Alzheimer's disease (MCI due to
		Alzheimer's disease + mild Alzheimer's
		disease dementia)
		‒ MMSE 24-30,CDR-G 0.5, RBANS
		≤ 85, with confirmed amyloid pathology
Doses	•	Two dosing regimens (low and high) and
		placebo; randomized 1:1:1
Primary	•	CDR-SB at 18 months
endpoint
Other	•	Secondary: MMSE, ADAS-Cog 13,
endpoints		ADCS-ADL-MCI
	•	Sub-studies: amyloid PET, tau PET, CSF
		disease-related biomarkers

Countries with active sites included:

Australia, Austria, Belgium, Canada, Denmark, Finland, France, Germany, Italy, Japan, the Netherlands, Poland, Portugal, South Korea, Spain, Sweden, Switzerland, Taiwan, United Kingdom, United States

Phase 3 Target Dose: 10 mg/kg With 6-Month Titration

Studies 301 and 302

10 mg/kg 6 mg/kg

3 mg/kg

1 mg/kg

Week	0	4	8	12	16	20	24	28	32	36	40	44	48	52	56	60	64	68	72	76	80
Dose mg/kg	1	1	3	3	6	6	10	10	10	10	10	10	10	10	10	10	10	10	10	10	10

24-week titration to reduce	14 doses of 10 mg/kg
incidence of ARIA	as in Study 103

Dose Regimen

Studies 301 and 302

Early enrolled patients in the high-dose arm received a lower dose

ApoE ε4+	3 mg/kg

Low dose 1 mg/kg

	6 mg/kg
ApoE ε4−	3 mg/kg
Low dose
1 mg/kg

ApoE ε4+	10 mg/kg
6 mg/kg
and ApoE ε4−	3 mg/kg
High dose
	1 mg/kg
	0	4	8	12	16	20	24	28	32	36	40	44	48	52	56	60	64	68	72	76	80
Expected # of 10 mg/kg in high-dose group		by Week 26:						by Week 50:								by Week 78:
		1 dose									7 doses											14 doses

Median cumulativedose

at Week 78

56 mg/kg

98 mg/kg

153 mg/kg (post-PV4)

116 mg/kg (pre-PV4)

ApoE=apolipoprotein E; PV4=Protocol Version 4.

Phase 3 Studies Were Prematurely Terminated Following What Was Later Determined To be An Inaccurate Futility Prediction

• Conditional power: probability that primary efficacy endpoint analysis would be statistically significant at final analysis
• Two key assumptions did not hold, and futility analysis did not accurately predict the future results

1. Assumption 1: Identically designed studies would lead to similar study results. Therefore, pooled conditional power is appropriate

• o Assumption 2: Treatment effect will remain consistent over time

• At the time of futility analysis, Study 302 was trending positive, whereas Study 301 was not

Clinical Endpoints Measure Distinct, Important Symptoms of Cognition, Function, and Behavior

Five clinical rating scales were used in Studies 301 and 302

• Validated and widely used in early

Alzheimer's disease

• Covers the full scope of symptoms

experienced by patients with Alzheimer's

disease

• Include a range of paradigms:

Overlap of scales is only 5% to 25%

ADAS-
Cog 13	MMSE

• Expert clinical judgements based on patient
	examination and caregiver input
•	Patient and caregiver reports
•	Cognitive performance tests

CDR

NPI

ADCS-ADL-MCI

• Together they cover a range of important and distinct dimensions with minimal overlap

Study 302: High Dose Aducanumab Met Primary Objective of CDR-SB at Week 78

% Difference vs placebo

5

0 -5-10-15-20-25-30-35-40-45

-15%

-0.26
(-0.569, 0.041)	-22%
p=0.0901	-0.39

(-0.694,-0.086)

p=0.0120

Low dose	High dose
n=543	n=547

Low-dose aducanumab High-dose aducanumab

%

Difference from placebo

(95% CI)

p value

n=numbers of randomized and dosed participants included in the analysis

Study 302: All Items Measured in Primary Endpoint (CDR- SB) Were Improved by High-Dose Aducanumab

Worsening

Treatment difference (%)

Orientation

Community affairs

Home and hobbies

Judgment and problem solving

Memory

Personal care

0.34

0.26

0.31

0.24

0.29

0.23

0.28

0.21

0.25

0.17

0.2

0.17

0	0.05	0.1	0.15	0.2	0.25	0.3	0.35
	Adjusted mean change from baseline at week 78
		Placebo			High-dose aducanumab

-0.08(-24%)

-0.07(-23%)

-0.07(-24%)

-0.07(-25%)

-0.07(-28%)

-0.03(-15%)

Study 302: High-dose Aducanumab Met All Clinical Endpoints Assessing Cognition and Function at Week 78

		Primary Endpoint		Secondary Endpoints
		CDR-SB	MMSE		ADAS-Cog13	ADCS-ADL-MCI
	5			3%
placebo	0
-5			-0.1
-10			(-0.65, 0.48)
			p=0.7578
vs	-15
-15%				-14%
-20				-16%
Difference
-0.26		-18%		-0.7
-25	-22%		0.7
(-0.569, 0.041)	0.6	(-1.76, 0.36)
(-0.27, 1.73)
-30	p=0.0901	-0.39	(0.00, 1.13)		p=0.1962
	-27%	p=0.1515
	p=0.0493
-35	(-0.694,-0.086)
		-1.4
	p=0.0120
%	-40				(-2.46,-0.34)
Low-dose aducanumab	High-dose aducanumab
	p=0.0097	-40%
	-45
		%
						1.7
		Difference from placebo (95% CI)
					(-0.75, 2.74)
		p value
					p=0.0006

Low-doseHigh-dose	Low-doseHigh-dose	Low-doseHigh-dose	Low-doseHigh-dose
n=543	n=547	n=543	n=547	n=543	n=547	n=543	n=547

n=numbers of randomized and dosed participants included in the analysis

Study 302: Treatment Effect Observed in Exploratory Clinical Endpoint of NPI-10 Assessing Behavior at Week 78

vs placebo

0 -10-20-30-40

Neuropsychiatric Inventory 10 (NPI-10)	Caregivers of patients who
			received high-dose
			aducanumab reported 84%
			less burden compared with
			caregivers of patients who
			received placebo
-33%

% Difference

-50-60-70-80-90

-0.5(-1.62, 0.64)

p=0.3921

Low-dose aducanumab

High-dose aducanumab

	%
	Difference from placebo (95% CI)
-87%	p value

-100

-1.3(-2.45,-0.20)

p=0.0215

Low-doseHigh-dose

n=543n=547

n=numbers of randomized and dosed participants included in the analysis

Study 302: Amyloid PET Shows Aducanumab Dose- Dependent Reduction in β-Amyloid Pathology

Adjusted mean change from baseline (±SE)

0.05
0.00
								***
-0.05
-0.10
				***
-0.15
-0.20								Placebo
-0.25
							Low-dose aducanumab
-0.30
							High-dose aducanumab
-0.35
0	26

Analysis visit, week

Diff. from placebo, Week 78

***

-0.179

• -0.278
  78

Placebo	159	129	93
Low-dose aducanumab	159	129	100
High-dose aducanumab	170	138	109

*** p<0.001 (nominal)

Study 302: Aducanumab Reduced Biomarkers of Alzheimer's Disease-specific Tau Pathophysiology and Neurodegeneration

Tau pathophysiology		Neurodegeneration
			CSF p-Tau					CSF t-Tau
from		0			from		0
	-5				-20
						-40
changemeanAdjusted	(SE)baseline				changemeanAdjusted
-10			(SE)	-60
		-15				baseline	-80
		-20				-100
					-120
			**			*
		-25
					-140
		-30		***		-160		**
		Placebo	Low dose	High dose			Placebo	Low dose	High dose
		n=28	n=33	n=17			n=28	n=33	n=17

*p<0.05, ** p<0.01 , *** p<0.001 (nominal)

n=numbers of randomized and dosed participants included in the analysis

Aducanumab Reduced Biomarkers of Tau Neurofibrillary tangles in the Brain

Pooled Data, Studies 301 and 302

Medial temporal composite

		0.12				0.12
		0.1				0.1
Adjusted mean change		0.08		Adjusted mean change		0.08
from baseline (SE)	0.06		from baseline (SE)	0.06
0.04		0.04
0.02		0.02
0		0
-0.02		-0.02
-0.04		-0.04
-0.06		-0.06
		-0.08	*	***		-0.08
		-0.1			-0.1

Placebo Low-doseHigh-dose

n=12 n=14 n=11

Temporal composite

*

Placebo Low-doseHigh-dose

n=12 n=14 n=11

		Frontal composite
		0.12
		0.1
changemeanAdjusted	(SE)baselinefrom	0.08
0.06		*
		0.04
		0.02
		0
		-0.02
		-0.04
		-0.06
		-0.08
		-0.1
		Placebo	Low-doseHigh-dose
		n=12	n=14	n=11

* p<0.05, *** p<0.001 (nominal).

n=numbers of randomized and dosed participants included in the analysis

Study 302: Aducanumab-related Biomarker Changes Are Associated With Slowing in Clinical Decline

Aducanumab

β-amyloid

(Composite

SUVR)

0.19 *	-0.24 *
(CDR-SB)	(MMSE)
0.20 *	-0.29 *
(ADAS-Cog13)	(ADCS-ADL-MCI)

Clinical

outcomes

0.52 *

Tau (CSF p-Tau)

0.20	-0.39 *
(CDR-SB)	(MMSE)
0.11	-0.44 *
(ADAS-Cog13)	(ADCS-ADL-MCI)

* p<0.05 (nominal)

All associations are partial Spearman correlation of change from baseline to Week 78 between each variable

Results of Study 301 were Partially Discordant

% Difference vs placebo

5

0 -5-10-15-20-25-30-35-40-45

		Primary Endpoint				Secondary Endpoints
		CDR-SB		MMSE	ADAS-Cog-13	ADCS-ADL-MCI
					2%			3%
					0.03			-0.1
					(-0.262, 0.326)			(-0.62, 0.49)
					p=0.8330	-6%	p=0.8106
		-12%		0.2		-11%	-11%
			(-0.35, 0.74)
				-0.583	-0.588
	-0.18		p=0.4795		-18%	-18%
		(-0.469, 0.110)				(-1.5835,	(-1.6067,
				0.4181)	0.4309)
		p=0.2250				0.7	0.7
					p=0.2536	p=0.2578
									(-0.19, 1.64)	(-0.25, 1.61)
					Low-dose aducanumab	%			p=0.1225	p=0.1506
					Difference from placebo
					High-dose aducanumab
					(95% CI)
								p value
		Low-doseHigh-dose	Low-doseHigh-dose	Low-doseHigh-dose	Low-doseHigh-dose
		n=547	n=555		n=547	n=555	n=547	n=555	n=547	n=555

n=numbers of randomized and dosed participants included in the analysis

Biomarker Response in High Dose Aducanumab is Lower in Study 301 than in Study 302

		0.05								Amyloid PET
change	(±SE)								***
-0.05
meanAdjusted	baselinefrom	0.00
-0.10
							***			***
		-0.15
		-0.20								Placebo	-0.170
		-0.25
									***
										Low-dose aducanumab
		-0.30								High-dose aducanumab	-0.235
		-0.35
		0					26			78
										Analysis visit,	week
Patients, n
Placebo	204			168			124
Low-dose	198			169			138
High-dose	183			156			112

• Treatment effect 16.5% smaller
• Cumulative dose 10.4% smaller

CSF p-Tau

		0
Adjusted mean change	from baseline, pg/mL (SE)	-5
-10
-15
-20
-25	p=0.2726	p=0.3019
		-30
		Placebo	Low-dose	High-dose
		n=15	n=20	n=18

• Treatment effect 51.2% smaller
• Cumulative dose 20.3% smaller

*** p<0.001 (nominal)

Study 301 High-Dose Group Diverged From an Otherwise Consistent

Association Between Aβ Reduction and Slowing of Clinical Decline

Studies 301, 302, and 103

Favors treatment Favors placebo	SB adjusted mean difference from placebo
	CDR-

301

high

0.5

						301					103
0.0							302 low					1 mg/kg
						low
302	103
			high			103
-0.5					6 mg/kg	103		3 mg/kg
							titration
103			(avg. 5.3 mg/kg)
-1.0			10 mg/kg
						Bubble size represents sample size at baseline
				-0.25	-0.20	-0.15	-0.10	-0.05

Amyloid PET composite SUVR adjusted mean difference from placebo

• Greater extent of amyloid removal

Results in Study 301 and 302 Were Partially Discordant

	Low dose
	clinical
	Low dose
	β-amyloid
Supports	PET
Low dose
efficacy of
CSF Tau
aducanumab
	302
	High dose
	Exposure
	response
	relationship

301 high dose discordant with the set

Summary of Efficacy and Biomarker Results

Studies 301, 302, and 103

		Study 301		Study 302		Study 103
Diff vs Placebo (%)		Low dose	High dose		Low dose	High dose		10 mg/kg
	N=547	N=545		N=543	N=547		N=32
CDR-SB		-0.18(-12%)	0.03 (2%)		-0.26(-15%)	-0.39(-22%)		-1.26(-67%)
		0.2 (-6%)
MMSE		-0.1 (3%)		-0.1 (3%)	0.6 (-18%)		1.9 (-76%)
ADAS-Cog13		-0.583(-11%)	-0.588(-11%)		-0.70(-14%)	-1.40(-27%)
ADCS-ADL-MCI		0.7 (-18%)	0.7 (-18%)		0.7 (-16%)	1.7 (-40%)
Amyloid-PET*		-0.167	-0.232		-0.179	-0.278		-0.277
SUVR (centiloid)		(-38.476)	(-53.472)		(-41.250)	(-64.182)		(-61.363)

Dark green = p<0.05 favoring aducanumab

Light green = numeric advantage favoring aducanumab

N=numbers of randomized and dosed participants

1. Number of participants in 301 PET substudy = 585 and 302 substudy = 488

Biogen | Confidential and Proprietary	31

Differences in Study 301 Are Sufficiently Understood so as Not to Detract From Study 302

• Demographics, disease characteristics, frequency, severity and management of ARIA were all similar between studies
• Underlying pharmacology of aducanumab is similar in Studies 301 and 302
• Differences between studies were largely driven by:
• • Lower exposure to 10 mg/kg dosing in Study 301
  • Imbalance in number and distribution of rapid progressing Alzheimer's disease patients

In Study 301, patients randomized to groups with the opportunity for full

10mg/kg dosing had results similar to Study 302

Patients Who Had the Opportunity for 14 Doses of 10 mg/kg Had Similar Benefit in Both Studies

Week 78	Mean	Median	% diff
Favors aducanumab	cum dose cum dose	vs pbo
(mg/kg)	(mg/kg)

N: number at baseline. n: number at Week 78.
Study 301	Post-PV4, ApoE+ (N=58, n=48)							122.9	150.0	-29%
	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%
Study 302	Post-PV4, ApoE+ (N=65, n=56)							124.7	150.0	-25%
	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.

Safety

Amyloid-Related Imaging Abnormalities (ARIA)

ARIA refers to radiographic abnormalities observed with anti-Aβ antibodies

• ARIA-Edema(ARIA-E): vasogenic edema or sulcal effusion
• ARIA-Hemorrhage(ARIA-H): brain microhemorrhages or localized superficial siderosis
• May result from increased cerebrovascular permeability as a consequence of antibody binding to deposited amyloid-beta

Greenberg SM, et al. Nature Rev Neurol. 2020;16(1):30-42.

Most Common Adverse Events with Aducanumab

Studies 301 and 302 Placebo-Controlled Period

			Patients, n (%)
			Aducanumab
	Placebo	10 mg/kg
	N=1087	N=1033
Adverse events	945	(86.9)	946	(91.6)
ARIA-E	29	(2.7)	362	(35.0)
Headache	165	(15.2)	212	(20.5)
ARIA-H Brain microhemorrhage	71	(6.5)	197	(19.1)
Fall	128 (11.8)	155	(15.0)
ARIA-H Superficial siderosis	24	(2.2)	151	(14.6)
Diarrhea	74	(6.8)	92	(8.9)

• Serious hypersensitivity reactions to aducanumab had an incidence of <0.1%
• Compared to placebo, aducanumab treatment was not associated with abnormalities in vital signs, clinical labs, or ECGs

Clinical and MRI Characteristics of ARIA-E

Studies 301 and 302 Placebo-Controlled Period

		Patients, n (%)
		Aducanumab
	Placebo	10 mg/kg
	N=1076	N=1029
Patients with ARIA-E	29	362
Asymptomatic	26 (89.7)	268 (74.0)
Symptomatic	3 (10.3)	94 (26.0)

• The most common symptoms were headache, confusion, dizziness, and nausea
• Most symptoms were mild (68%) or moderate (28%) in clinical severity
• MRI findings of ARIA-E were typically mild (30%) or moderate (58%) in severity and transient (98% resolved)

Each participant counted once, at maximum symptomatic status and severity.

Study 302: Aducanumab Impacts Multiple Clinically

Meaningful Dimensions of Alzheimer's Disease

High dose outcomes at week 78 versus placebo

CDR-SB

Primary Endpoint

22% relative reduction in decline from baseline in the Clinical Dementia Rating Scale Sum of Boxes (CDR-SB)

Secondary Endpoints (Cognition)

MMSE: 18% relative reduction

ADAS Cog: 27% relative reduction

Functional

Independence

Cognition &

Function

Neuropsychiatric

ADCS-ADL-MCI

Secondary Endpoint

40% relative reduction in decline in AD Cooperative Study-Activitiesof Daily Living Inventory Mild Cognitive Impairment Version (ADCS-ADL-MCI)

NPI-10

Exploratory Endpoint 87% relative reduction in

decline the Neuropsychiatric Inventory-10(NPI-10)

Establishing the Safety and Efficacy of Aducanumab

Study 302 A positive study with robust and internally consistent results

Study 103 An independent, second study providing supportive evidence

Study 301 A failed study with reasons for difference between studies in results understood and post hoc subgroups supportive of Study 302 and 103

Consistent exposure to 10 mg/kg aducanumab is effective at reducing

the clinical decline in patients with early symptomatic Alzheimer's

disease and has a favorable benefit/risk profile

Conclusion

• Aducanumab targets underlying pathology of disease and is the first investigational drug to show a reduction in clinical decline in patients with Alzheimer's disease
• Based on prespecified analyses, Study 302 is a robustly positive study, while Study 301 is a failed study
• Differences between Study 301 and 302 were largely driven by:
• • Lower exposure to 10 mg/kg dosing in Study 301
  • Imbalance in number and distribution of rapid progressing Alzheimer's disease patients
• In Study 301, patients with the opportunity for full 10mg/kg dosing had results similar to Study 302
• A small earlier clinical trial, Study 103, demonstrated a treatment effect on clinical and biomarker endpoints
• Consistent exposure to 10 mg/kg aducanumab is effective at reducing the clinical decline in patients with early symptomatic Alzheimer's disease and has a favorable benefit/risk profile