Clinical and Biomarker Updates from BAN2401
Study 201 in Early AD
Chad J. Swanson, PhD; Yong Zhang, MS; Shobha Dhadda, PhD;
Jinping Wang, PhD; Akihiko Koyama, PhD; June Kaplow, PhD;
Robert Lai, MA, MB, Bchir; Heather Bradley, MPH;
Martin Rabe, MSc; Robert Gordon; Lars Lannfelt, MD, PhD;
Lynn D. Kramer, MD, FAAN; Johan Luthman, DDS, PhD

Disclosures• Chad J. Swanson, Yong Zhang, Shobha Dhadda, Jinping Wang, Akihiko Koyama,June Kaplow, Robert Lai, Heather Bradley, Martin Rabe, Robert Gordon, Lynn D.
Kramer, and Johan Luthman are employees of Eisai Inc.
• Lars Lannfelt is affiliated with BioArctic and Uppsala University• Jeffrey Cummings is affiliated with Cleveland Clinic

2

Presented at the 11th Clinical Trials on Alzheimer's Disease (CTAD) Conference October 24-27, 2018

Agenda for Today
1. BAN2401 Study 201 Study Design and Topline Results– Professor Jeffrey Cummings, Cleveland Clinic

2. Pre-specified Subgroup Analysis in BAN2401 Study 201– Dr. Chad Swanson, Eisai Inc.

3. Effect of BAN2401 on Underlying AD Pathophysiology– Dr. Chad Swanson, Eisai Inc.

4. Totality of Results from BAN2401 Study 201 (Clinical Outcome Measures,
Amyloid PET, CSF Biomarkers)– Professor Jeffrey Cummings, Cleveland Clinic

5. Q&A– Professor Jeffrey Cummings, Cleveland Clinic; Dr. Chad Swanson and Dr. Akihiko Koyama, Eisai Inc.

3

Presented at the 11th Clinical Trials on Alzheimer's Disease (CTAD) Conference October 24-27, 2018

Communication 1

BAN2401 Study 201 Design and Topline Results

Professor Jeffrey Cummings, MD, ScD
Center for Neurodegeneration and Translational Neuroscience
Cleveland Clinic Lou Ruvo Center for Brain Health
Las Vegas, Nevada, USA

4

Presented at the 11th Clinical Trials on Alzheimer's Disease (CTAD) Conference October 24-27, 2018

What is BAN2401?
• BAN2401 is an antibody with a low affinity for Aβ monomers and high affinity for aggregated Aβ
species (>1000x)– This is in contrast to many of the other anti-Aβ mAbs, which have generally had higher affinity for monomers
in addition to affinity for aggregated Aβ species– High concentration of monomers in CNS/plasma limits antibody engagement with aggregated Aβ species• Among aggregated species, BAN2401 shows preferential activity for Aβ protofibrils over fibrils (>10x)• BAN2401 both neutralizes the large soluble aggregates and clears aggregated Aβ species from thebrain via Fc-mediated phagocytosis
BAN2401

Monomer

Dimer

OligomerProtofibril

FibrilAmyloidplaqueAb

Neurogranin

Neurofilament L
p-Tau

Source: Internal Eisai data
5

Presented at the 11th Clinical Trials on Alzheimer's Disease (CTAD) Conference October 24-27, 2018

Bayesian Design Selected for BAN2401 Study 201 in Early
Alzheimer’s Disease Population• There were multiple questions to be addressed in the Phase 2 study for BAN2401– Dose regimen and response– Treatment effect size
– Sample size required– Duration of therapy required to show disease-modifying effect• Bayesian adaptive design uses ongoing analysis of existing blinded study data
– FDA draft guidance1 entitled “Adaptive Designs for Clinical Trials of Drugs and Biologics” issued
on September 28, 2018 highlights use of adaptive trial designs– Adaptive trial designs are often used in oncology2,3, previously used in Alzheimer’s disease4,5,
and recently used for an approval in diabetes6, 7

Source: 1FDA Guidance. Adaptive design for clinical trials of dugs and biologics. 2018; 2Berry D. Nat Rev Clin Oncology 2011; 9: 199-207; 3Berry S et al. Clin Trials 2010; 7: 121-135; 4Lenz R et al. Alz Dis
Assoc Dis 2015; 29: 192-199; 5Finger E et al. Alz Res & Therapy 2018: 10; 102-110.; 6FDA Summary Review for Trulicity; 7Diabetes Obes Metab. 2014 Aug;16(8):748-56.
6Presented at the 11th Clinical Trials on Alzheimer's Disease (CTAD) Conference October 24-27, 2018

Bayesian Design Allowed Flexible Allocation of Subjects to Most
Meaningful Doses Based on Robust Ongoing Assessments ofTreatment Effects, with Conventional Analysis at End of Study• Conventional and Bayesian approaches are both rigorous statistical methods• Bayesian analysis allowed for early decision making through rapid detection of treatment effect byusing accumulated data to make timely and appropriate subject to dose allocations– The primary endpoint of Study 201 was set at 12 months with super superiority to placebo needed topotentially accelerate time to Phase 3 with frequent interim Bayesian analyses to identify proof-of-concept
as early as possible– Study 201 satisfies the key principles of September 2018 FDA draft guidance on adaptive trials1– Allowed efficient utilization of accumulating data in allocating new subjects to doses that work best
– The study maintained integrity and allowed interpretability by using pre-defined design, with limited accessof comparative interim results (only to external experts) and well controlled Type I error contributing to
reproducible treatment effects• Conventional (per protocol) statistical analysis was used to assess the observed data at the end of
the double-blinded treatment period (18 months) and identify magnitude of treatment effects after
the study was unblinded
Source: 1FDA Guidance. Adaptive design for clinical trials of dugs and biologics. 20187

Presented at the 11th Clinical Trials on Alzheimer's Disease (CTAD) Conference October 24-27, 2018

ADCOMS* Utilized to Detect Changes in Earlier AD Population• Mild disease requires strategies with the ability todetect changes in cognition and function in an earlypatient population• ADCOMS combines data from recognized endpoints(CDR-SB, MMSE, ADAS-Cog) and leverages
specific items that are more likely to be impacted
earlier in the disease– Based on analysis of MCI trials to identify items thatwere most sensitive to progression– Incorporates all six components of CDR-SB plus
select cognitive components of MMSE and ADAS-Cog*ADCOMS: Alzheimer’s Disease Composite Score
8

J Neurol Neurosurg Psychiatry. 2016 Sep; 87(9): 993–999.
Presented at the 11th Clinical Trials on Alzheimer's Disease (CTAD) Conference October 24-27, 2018

BAN2401-G000-201: Global* Phase 2b
Population

Assessments

Early AD:• Primary clinical outcome assessment– ADCOMS assessed every 3 months• Key secondary clinical outcome
assessments– ADAS-Cog, CDR-SB assessed
every 3 months• Longitudinal biomarkers– Amyloid PET sub study – Baseline,
12, and 18 months– CSF sub study –Baseline, 12, and 18 months– Volumetric MRI –Baseline, 6, 12, and 18 months• Safety– All ARIA-E discontinued permanently
from study drug per protocol (MRIbased)

MCI due to AD or
Mild Alzheimer’s dementia(NIA-AA Criteria)• Amyloid pathology confirmed
by amyloid PET or CSF• MMSE range: 22-30• CDR global range:
0.5 (MCI); 0.5-1.0 (mAD)

Endpoints
Primary Endpoint(Interim Analysis)

ADCOMS as clinical outcome assessment

Secondary Endpoints(18-month Final Analysis Using Conventional
Statistics [MMRM])• Change from baseline in PET SUVr(amyloid load)• Conversion from amyloid positive
to negative (visual read)• Change from baseline in ADCOMS• Change from baseline in ADAS-Cog• Change from baseline in CDR-SB• Change from baseline in CSF measures*NA, EU, Asia Pacific regions
9

Presented at the 11th Clinical Trials on Alzheimer's Disease (CTAD) Conference October 24-27, 2018

Allocation of Subjects According to Response Adaptive
Randomization
Top Two Doses Identified Early as Meaningful – Thus Received Most Subjects
Number of Subjects Randomized Per DoseAPOE4
StatusAll

Placebo

2.5 mg/kg
bi-weekly

5 mg/kgmonthly

5 mg/kg
bi-weekly

10 mg/kg
monthly

10 mg/kg
bi-weekly

Total

247

52

51

92

253

161

856

+

175

38

40

84

225

48

610

-

72

14

11

8

28

113

246

Number of subjects randomized

Impact of July 2014 healthauthority request

260
240
220
200
180
160
140
120
100
80
60
40
20

‒

APOE4 carriers no longer be
randomized to 10 mg/kg biweekly‒

APOE4 carriers on 10 mg/kg biweekly who had not reached 6months treatment be
discontinued

414 total pooled

2.5 mg/kg bi-weekly
5 mg/kg monthly
5 mg/kg bi-weekly
10 mg/kg monthly
10 mg/kg bi-weekly
Placebo•

Interim analysis by number of subjects randomized
10• A health authority requested inJuly 2014 that:

Interim analysis by time

Presented at the 11th Clinical Trials on Alzheimer's Disease (CTAD) Conference October 24-27, 2018

Implementation of this request
resulted in an imbalance of
APOE4 carriers at 10 mg/kg
monthly and bi-weekly doses

Probability of Success on ADCOMS at 12 Months Under Bayesian
Statistical Models• Bayesian model defined “success” as an at least 25%
difference in disease progression from baseline versus
placebo at 12 months on ADCOMS– Pre-specified primary endpoint was an 80%
probability of success at 12 months– Bayesian results at 12 months showed a 64%
probability of success• Using the Study 201 Bayesian model, the 10 mg/kg biweekly dose had a 97.7% probability of being superior toplacebo by any magnitude• The study continued in a blinded fashion through 18
months; no unblinding occurred with the 12 monthanalysis

Probability of success with most meaningful dose• 12-month Bayesian model identified 10 mg/kg bi-weekly
as the most meaningful dose

Probability of Achieving Threshold Levels of Successat 12 Months
97.7%

100%
90%
80%

80%

70%

64%

60%
50%
40%
30%
20%
10%
0%
25% difference in decline
vs. placebo from baseline
Primary endpoint

11

Presented at the 11th Clinical Trials on Alzheimer's Disease (CTAD) Conference October 24-27, 2018

Superior to placebo
Actual results

BAN2401 Reduces Amyloid Burden Over 18 Months
Global Cortical Average Vs. Whole Cerebellum Reference
Adjusted mean change from baseline (±SE)

IMPROVEMENT

0.05

PET SUVr
0.01 increase in PET SUVr

0.00
–0.05
–0.10
–0.15
–0.20

0.22 reduction in PET SUVr
P<0.0001

–0.25
–0.30

0.30 reduction in PET SUVr
P<0.0001

Placebo
10 mg/kg monthly–0.35

10 mg/kg bi-weekly–0.40
0N with PET data
Placebo
10 mg/kg monthly
10 mg/kg bi-weekly

12

12

18

96
88
43

88
82
37

Visit (months)
98
88
44

Adjusted mean change from baseline by Mixed Model Repeated Measures (MMRM). The Mixed Model Repeated Measures (MMRM) uses treatment group, visit, clinical subgroup (MCI due to AD,
Mild AD), the presence or absence of ongoing AD treatment at baseline, APOE4 status (positive, negative), region, treatment group-by-visit interaction as factors, and baseline value as covariate.
For PET analysis N=306 at 12 months and N=277 at 18 months.
Presented at the 11th Clinical Trials on Alzheimer's Disease (CTAD) Conference October 24-27, 2018

BAN2401 Slows Disease Progression on Clinical Outcome
Measures Over 18 Months
P= 0.160
P= 0.050

Adjusted mean change from baseline (± SE)

WORSENING

P= 0.033

P= 0.077
P= 0.073

P= 0.027

30% less
decline
P=0.034

47% less
decline
P=0.017

ADAS-Cog

ADCOMS
Analysis visit (months)

CDR-SB

Analysis visit (months)
Placebo

10 mg/kg monthly

N with data
Placebo
10 mg/kg monthly
10 mg/kg bi-weekly

0 mo.
238
246
152

6 mo.
216
208
130

Analysis visit (months)
10 mg/kg bi-weekly

12 mo. 18 mo.
187
160
165
146
93
79

Analyses were based on protocol-specified Mixed Model Repeated Measures (MMRM) models.
13

26% less
decline
P=0.125

Presented at the 11th Clinical Trials on Alzheimer's Disease (CTAD) Conference October 24-27, 2018

rp = 0.838

Adjusted mean difference from placebo group in PET SUVr

ADAS-Cog

CDR-SBrp = 0.694

Adjusted mean difference from placebo group in PET SUVr

Adjusted mean difference from placebo group in CDR-SB

Adjusted mean difference from placebo group in ADCOMS

CLINICAL IMPROVEMENTADCOMS

Adjusted mean difference from placebo group in ADAS-Cog

Amyloid Clearance (PET SUVr) Correlates with Clinical Efficacy

rp = 0.808

Adjusted mean difference from placebo group in PET SUVr

AMYLOID CLEARANCE

N with 18 mo. PET data

14

2.5 mg/kg
bi-weekly
23

5 mg/kgmonthly23

5 mg/kg biweekly
24

10 mg/kg
monthly82

10 mg/kg
bi-weekly37

Note: rp is Pearson’s correlation coefficient
Adjusted mean was based on a protocol-specified mixed effects model with repeated measures (MMRM). The MMRM model included baseline as a covariate, with treatment group, visit, region,
randomization stratification variables (clinical stage, concurrent AD medication, APOE4 status), and treatment group-by-visit interaction as fixed effects. Data shown are for subjects enrolled in the PET
sub-study with PET SUVr and clinical data at 12 or 18 months (N=288).
Presented at the 11th Clinical Trials on Alzheimer's Disease (CTAD) Conference October 24-27, 2018

BAN2401-G000-201 Safety Summary• Incidence rates of AE, SAE and TEAE consistent
with patient population and balanced acrossplacebo and BAN2401 treatment groups•

5/48 (~10%) cases of symptomatic ARIA-E‒

Included headache, visual disturbances, orconfusion•• Most common TEAEs were infusion reaction and
ARIA (amyloid-related imaging abnormality)

60% of ARIA-E occurred within first 3 months oftreatment•~89% of cases were mild to moderate in severity(radiographic)• No changes in labs, ECGs, or vital signs•

MRI findings typically resolved within 4-12 weeks

BAN2401

15

Category

Placebo(N=245)n (%)

2.5 mg/kg
bi-weekly(N=52)n (%)

5 mg/kgmonthly(N=51)n (%)

5 mg/kg
bi-weekly(N=92)n (%)

10 mg/kg
monthly(N=253)n (%)

10 mg/kg
bi-weekly(N=161)n (%)

ARIA-E

2 (0.8)1 (1.9)1 (2.0)3 (3.3)25 (9.9)

16 (9.9)

APOE4+

2/173 (1.2%)

1/38 (2.6%)

1/40 (2.5%)

3/84 (3.6%)

23/225 (10.2%)

7/48 (14.6%)

APOE4-

0/72

0/14

0/11

0/8

2/28 (7.1%)

9/113 (8%)

Presented at the 11th Clinical Trials on Alzheimer's Disease (CTAD) Conference October 24-27, 2018

Overall Summary of Study 201• BAN2401 showed statistically meaningful differences on the primary outcome(ADCOMS) at 18 months• BAN2401 showed efficacy at reducing brain amyloid at 18 months• The effect of BAN2401 on amyloid PET clearance correlates with clinical efficacy• Outstanding questions from topline data presentation will be addressed today,
including:– Impact of APOE4 status allocation and pre-specified subgroup analyses– Biomarker analyses related to neurodegeneration

16

Presented at the 11th Clinical Trials on Alzheimer's Disease (CTAD) Conference October 24-27, 2018

Communication 2

Pre-specified Subgroup Analysis in BAN2401 Study 201

Chad J. Swanson, PhD
Senior Director, Clinical Research, Neurology Business GroupEisai Inc.
Woodcliff Lake, NJ, USA

17

Presented at the 11th Clinical Trials on Alzheimer's Disease (CTAD) Conference October 24-27, 2018

Placebo Data Show that APOE4 Carriers and Non-Carriers inStudy 201 Progressed at a Similar Rate
Adjusted mean change from baseline (± SE)

Placebo Data on ADCOMS by APOE4 Status and Overall
APOE4 noncarriers slope:0.008221• APOE4 status is a risk factor for ageof onset of disease1, but has limited
effect on disease progression at thisstage of disease in amyloid positive
subjects2

APOE4
carriers slope:0.009989
Overallslope:
0.009105
ADCOMS [p=0.3808] comparing slopes for APOE4 carriers and non-carriers
Analysis visit (months)
Overall

N with data
Placebo overall
APOE4 carriers
APOE4 non-carriers

238
168
70

226
161
65

APOE4 non-carriers
216
150
66

201
141
60

APOE4 carriers
187
134
53

172
124
48

• Clinical decline for APOE4 carrier
and non-carrier placebo groupsaligned around that of the overall
placebo group and were notstatistically different from each otheron ADCOMS, ADAS-Cog, or CDR-SB

160
113
47

Source: 1Liu, et. al., 2013; 2Steenland, et. al., 2018
Analyses were based on protocol-specified Mixed Model Repeated Measures (MMRM) models. Slopes shown represent change in ADCOMS per month.
18

Presented at the 11th Clinical Trials on Alzheimer's Disease (CTAD) Conference October 24-27, 2018

P-value of each prognostic factor

Not a contributing factor in disease progression

Disease Progression at 18 Months is Not Driven by APOE4
Status
1.00
0.95
0.90
0.85
0.80
0.75
0.70
0.65
0.60
0.55
0.50
0.45
0.40
0.35
0.30
0.25
0.20
0.15
0.10
0.05
0.00

Impact of Key Factors on Disease Progression as
Measured by ADCOMS in Protocol-specified
Conventional Statistical Analysis‒ APOE4 status was not a contributing factor in
driving disease progression while clinical stage,concomitant AD medication, and baseline
ADCOMS were

• Additional statistical analyses were run toevaluate the contribution of key factors bythemselves or in combination, to diseaseprogression

p=0.68‒ APOE4 status was not a significant contributor
in any analysis tested• Results are consistent across ADCOMS, ADASCog, and CDR-SB

Contributing factors have p<0.05
p=0.03p=<0.01
APOE4 status

19• According to the protocol-specified conventional
statistical analysis:

Clinical stage

p=<0.01• Thus, effect of 10 mg/kg bi-weekly was driven bytreatment with BAN2401 and not an imbalance insubject allocation by APOE4 status

Ongoing AD meds Baseline ADCOMS

Analyses were based on protocol-specified Mixed Model Repeated Measures (MMRM) models.
Presented at the 11th Clinical Trials on Alzheimer's Disease (CTAD) Conference October 24-27, 2018

Clinical Effects in APOE4 Carriers and Non-carriers at 18
MonthsAPOE4carriers

Overall

Adjusted mean change from baseline (±SE)

WORSENING

ADCOMS

0.20

0.00
9.00

30%

% less decline vs. placebo:

ADAS-Cog

APOE4
non-carriers

63%

7%

6.00

3.00

0.00

47%

% less decline vs. placebo:

CDR-SB

84%

43%

2.00

1.00

0.00

26%

% less decline vs. placebo:-7%

N with 18 month data

160

79

113

10

47

69

N randomized

247

161

175

48

72

113

Placebo
2060%

10 mg/kg bi-weekly• Treatment effect for the 10 mg/kg biweekly dose was not due to an imbalancein subject allocation by APOE4 status,
and the imbalance may haveunderestimated the overall BAN2401
treatment effect• Pooling the 10 mg/kg bi-weekly and 10
mg/kg monthly doses corrects APOE4
imbalance and results in less decline on
ADCOMS vs. placebo at 18 months of:‒‒‒‒

21% overall (n*=414)
25% for APOE4 carriers (n*=273)
6% for APOE4 non-carriers (n*=141)
PK modeling suggests that Cavg is a key
driver of dose response between 10
mg/kg bi-weekly and monthly*n = number of subjects randomized to 10 mg/kg bi-weekly and 10 mg/kg monthly dose groups combined
Analyses were based on protocol-specified Mixed Model Repeated Measures (MMRM) models with longitudinal assessment of data for all subjects.
Presented at the 11th Clinical Trials on Alzheimer's Disease (CTAD) Conference October 24-27, 2018

Clinical Effects in Both MCI and Mild AD Subjects at 18 Months
MCI due toADOverall

Adjusted mean change from baseline (±SE)

WORSENING

ADCOMS

Mild AD

0.20

0.00

30%

% less decline vs. placebo:

33%

35%

• Treatment effect did not differ
between MCI and mild AD on
ADCOMS and was comparable on
ADAS-Cog

ADAS-Cog 6.00
3.00

0.00

47%

% less decline vs. placebo:

CDR-SB

58%

41%• Effect on CDR-SB seen in both MCI
and mild AD subjects, though, as
expected, treatment effect in mild AD
subjects was numerically larger

2.00

1.00

0.00

26%

% less decline vs. placebo:

51%

N with 18 month data

160

79

111

47

49

32

N randomized

247

161

160

95

87

66

Placebo21

14%

10 mg/kg bi-weekly

Analyses were based on protocol-specified Mixed Model Repeated Measures (MMRM) models with longitudinal assessment of data for all subjects.
Presented at the 11th Clinical Trials on Alzheimer's Disease (CTAD) Conference October 24-27, 2018

Clinical Effects in Subjects Who Began the Study with andWithout Concomitant AD Medications
Overall

Adjusted mean change from baseline (±SE)

WORSENING

ADCOMS

With
concomitant
AD meds

Without
concomitant
AD meds

23%

41%

0.20

0.00

9.00
% less decline vs. placebo:

ADAS-Cog

30%

6.00

3.00

0.00

% less decline vs. placebo:

CDR-SB

47%

39%

59%

26%

20%

45%

• Treatment effect was meaningful
regardless of whether subjects started
the study with or without concomitant
AD medications

2.00

1.00

0.00

% less decline vs. placebo:
N with 18 month data

160

79

80

39

80

40

N randomized

247

161

132

82

115

79

Placebo22

10 mg/kg bi-weekly

Analyses were based on protocol-specified Mixed Model Repeated Measures (MMRM) models with longitudinal assessment of data for all subjects.
Presented at the 11th Clinical Trials on Alzheimer's Disease (CTAD) Conference October 24-27, 2018

Significant Brain Amyloid Clearance Across Pre-specified
Subgroups
Adjusted mean change from baseline (±SE)

IMPROVEMENT

Amyloid PET SUVr
Based on the reference region of whole cerebellum

0.10
0.05
0.00
-0.05
-0.10

-0.15
-0.20
-0.25
-0.30
-0.35
-0.40

Overall

APOE4carriers

APOE4
noncarriers

N with 18 mo. PET data

88

37

65

4

23

33

64

N enrolled in PET sub-study

98

44

72

9

26

35

72

ADCOMS % less decline vs. placebo: 46%

72%

29%
Placebo

Mild ADWith
concom.
AD meds

Without
concom.
AD meds

23

24

14

38

16

50

21

27

26

17

44

20

54

24

MCI due to
AD

52%

52%

52%

37%

10 mg/kg bi-weekly• ADCOMS data for subjects in the PET sub-study are consistent and meaningful across subgroups

23

Analyses for the overall population were based on protocol-specified Mixed Model Repeated Measures (MMRM) models with factors of treatment, visit, clinical stage, the presence of ongoing AD
treatment at baseline, ApoE ε4 status, region, treatment-by-visit interaction and baseline value. The corresponding stratification factor was removed in the subgroup analyses.
SE=standard error.
Presented at the 11th Clinical Trials on Alzheimer's Disease (CTAD) Conference October 24-27, 2018

BAN2401 Study 201 Subgroup Analysis Summary• Statistically meaningful effect of 30% less decline in disease progression seenfor 10 mg/kg bi-weekly dose versus placebo at 18 months on ADCOMS was
driven by BAN2401 treatment effect and not an imbalance in subject allocation
by APOE4 status‒ Placebo disease progression was similar in amyloid positive APOE4 carriers and noncarriers‒ APOE4 status was not a contributing factor to change from baseline in disease progression‒ Imbalance of APOE4 carriers in the 10 mg/kg bi-weekly dose group may have actually
underestimated the overall treatment effect• Effect on disease progression at 18 months was meaningful across subgroupsof clinical stage and concomitant AD medication• Impact on brain amyloid was significant across subgroups
24

Presented at the 11th Clinical Trials on Alzheimer's Disease (CTAD) Conference October 24-27, 2018

Communication 3

Effect of BAN2401 on Underlying AD Pathophysiology

Chad J. Swanson, PhD
Senior Director, Clinical Research, Neurology Business GroupEisai Inc.
Woodcliff Lake, NJ, USA

25

Presented at the 11th Clinical Trials on Alzheimer's Disease (CTAD) Conference October 24-27, 2018

Change of CSF Biomarkers in Combined 10 mg/kg Groups
Compared to Placebo Suggest Impact on Neurodegeneration• CSF collected at baseline, 12 months, and 18 months in biomarker subgroup• CSF biomarkers were measured by ELISA– Synaptic damage: Neurogranin– Downstream tau pathway: Phosphorylated Tau181 (p-Tau)– Axonal degeneration: Neurofilament Light Chain (NfL)• 10 mg/kg bi-weekly and 10 mg/kg monthly groups were combined to increase thesample size in CSF subgroup26

Presented at the 11th Clinical Trials on Alzheimer's Disease (CTAD) Conference October 24-27, 2018

BAN2401 Reduces Neurogranin in CSF
Combined 10 mg/kg Vs. Placebo:
CSF NeurograninMedian change from baseline at 18m in neurogranin, all subjects• Neurogranin is a synaptic protein and a CSF
marker of synaptic damage• CSF neurogranin levels are elevated insubjects with early AD1– Baseline for control subjects is reported2 to be~236-496 pg/ml– Overall baseline for all subjects in CSF substudy was 530 pg/ml (median)• BAN2401 reduces CSF neurogranin levels by
11% (58 pg/ml median reduction frombaseline) over 18 months

Median change from baseline (pg/ml)

20

+13.5

10
0
-10
-20
-30
-40
-50

-60
-70
N with 18 mo. data
Interquartile range (Q1, Q3)-58
Placebo

Combined 10 mg/kg

16

23(-91, 32)(-97, 8)Source: 1Kvartsberg H et al. Alzheimer’s Dementia 2015; 11(10):1180-90; 2Willemse EAJ et al. Clin Chem. 2018;64(6):927-937.; Analysis conducted using same assay as Study 201 data.
Neurogranin ELISA assay (ADx/Euroimmun) was measured by in Vrije Universiteit Amsterdam (CV = 6.7%).
For regression analysis over time, the slope difference via a Robust Wald Test, p<0.0001.
27

Presented at the 11th Clinical Trials on Alzheimer's Disease (CTAD) Conference October 24-27, 2018

BAN2401 Reduces Phospho-Tau (p-Tau) in CSF
Combined 10 mg/kg Vs. Placebo:
CSF p-TauMedian change from baseline at 18m in p-Tau, all subjects
2• CSF p-Tau level is elevated in subjects with
AD1
– Baseline for control subjects is reported2 to be~35-48 pg/ml– Overall baseline for all subjects in CSF
sub-study was 89 pg/ml (median)• BAN2401 significantly reduces CSF p-Tau
levels by 13% (12 pg/ml median reduction
from baseline) over 18 months

Median change from baseline (pg/ml)+0.01• Phospho-Tau181 (p-Tau) is a CSF marker that
correlates with tau pathology

0
-2
-4
-6
-8
-10
-12
-12
-14
Placebo

N with 18 mo. data
Interquartile range (Q1, Q3)

Combined 10 mg/kg

16

23(-2, 12)(-20, 1)

Source: 1Zetterberg H et al. J Alzheimers Dis. 2007 Nov;12(3):255-60; 2Hampel et al. Alzheimers Dement. 2018:492-501.; Analysis conducted using same assay as Study 201 data.
INNOTEST® PHOSPHO-TAU(181P) was measured by Laboratoire CERBA/BARC, Saint-Ouen-l'Aumône (CV = 2.7%).
For statistical analyses at 18 months performed via Wilcoxon Test, p=0.0124. For regression analysis over time, the slope difference via a Robust Wald Test, p<0.0001.
28

Presented at the 11th Clinical Trials on Alzheimer's Disease (CTAD) Conference October 24-27, 2018

BAN2401 Slows Increase of Neurofilament Light Chain (NfL)
Combined 10 mg/kg Vs. Placebo:from Baseline
CSF NfL
Median change from baseline at 18m in NfL, all subjects
200– Baseline for control subjects is reported2 tobe ~516-773 pg/ml– Overall baseline for all subjects in CSF substudy was 1094 pg/ml (median)• BAN2401 slows increase in NfL in the CSF
by 48% (median difference) compared toplacebo over 18 months

180
Median change from baseline (pg/ml)• Neurofilament light chain (NfL) is a neuronal
structural scaffold protein and a CSF marker
of axonal degeneration1• CSF NfL levels are elevated in subjects withAD

160

48% observed mediandifference vs. placebo

+156

140

120
100
+75

80
60
40
20
0

N with 18 mo. data
Interquartile range (Q1, Q3)

Placebo

Combined 10 mg/kg

16

23(92, 195)(16, 188)

Source: 1Khali M et al. Nat Rev Neurol. 2018; 14(10):577-589; 2Hampel et al. Alzheimers Dement. 2018:492-501.; Analysis conducted using same assay as Study 201 data.
NF-light® ELISA assay (UmanDiagnostics AB) was measured by Vrije Universiteit Amsterdam (CV = 6.3%).
For regression analysis over time, the slope difference via a Robust Wald Test, p<0.001.
29

Presented at the 11th Clinical Trials on Alzheimer's Disease (CTAD) Conference October 24-27, 2018

BAN2401 Significantly Slows Rate of Disease Progression Over
18 Months at 10 mg/kg Bi-weekly Dose
Slope Analysis of ADCOMS for the Overall Population
Over 18 Months• ADCOMS measured every 3monthsWORSENING• Significant slope difference for
10 mg/kg bi-weekly dose groupcompared to placebo (p<0.001)

Estimated mean change from baseline

0.00

-0.05

-0.10

Slope = 0.0060
P<0.001-0.15

Slope = 0.0083

Placebo
10 mg/kg bi-weekly
-0.20
0

6

Linear regression model testing the slope of change from baseline. Slopes shown represent change in ADCOMS per month.
30

Presented at the 11th Clinical Trials on Alzheimer's Disease (CTAD) Conference October 24-27, 20181218

Summary of the Effects of BAN2401 on Underlying AD
Pathophysiology• CSF biomarkers are consistent in showing treatment of underlying disease
pathophysiology– Reduction in synaptic damage (neurogranin)– Reduction in downstream tau pathway (p-Tau)– Reduction in increase of axonal degeneration (NfL)• BAN2401 treatment at the 10 mg/kg bi-weekly dose significantly slows the rate of
disease progression over time

31

Presented at the 11th Clinical Trials on Alzheimer's Disease (CTAD) Conference October 24-27, 2018

Communication 4

Totality of Results from BAN2401 Study 201

Professor Jeffrey Cummings, MD, ScD
Center for Neurodegeneration and Translational Neuroscience
Cleveland Clinic Lou Ruvo Center for Brain Health
Las Vegas, Nevada, USA

32

Presented at the 11th Clinical Trials on Alzheimer's Disease (CTAD) Conference October 24-27, 2018

Study 201 Satisfied Key Principles of FDA Guidance on Adaptive
Trials and Study Result was Driven by BAN2401 Treatment Effect• Bayesian analysis allowed for early decision making through rapid detection oftreatment effect by using accumulated data to make timely and appropriate
subject to dose allocations while conventional statistical analysis was used, perprotocol, to analyze actual observed magnitude of treatment effect after the
study was unblinded at 18 months• Effect observed in 10 mg/kg bi-weekly dose was driven by treatment with
BAN2401 and not an imbalance in subject allocation by APOE4 status, and, therequired randomization adjustment that impacted APOE4 carrier allocation tothat dose may have actually underestimated the treatment effect for BAN2401

33

Presented at the 11th Clinical Trials on Alzheimer's Disease (CTAD) Conference October 24-27, 2018

Consistency of Data on Clinical Outcome Measures, Brain Amyloid,
and CSF Biomarkers Supports Treatment EffectBAN2401
Treatment Effect in Early AD
1

Clinical Outcome
Measures2

Brain Amyloid• Slowing of diseaseprogression over timeobserved across clinicaloutcome measures at thehighest dose, including
30% on ADCOMS• Significant amyloid
clearance on PET overall• Slowing of diseaseprogression observed
across subgroups• Amyloid PET data
significant acrosssubgroups• Over 80% of subjects at
highest dose converted
from positive to negative on
amyloid PET

3

CSF Biomarkers• All CSF biomarkers
demonstrate beneficial
impact on AD
pathophysiology– Synaptic damage(neurogranin)– Downstream tau pathway(p-Tau)– Axonal degeneration (NfL)

Targeting Aggregated Aβ Species with Low Affinity to Monomers
34

Presented at the 11th Clinical Trials on Alzheimer's Disease (CTAD) Conference October 24-27, 2018

Acknowledgements
We thank all the patients and their family members
participating in the BAN2401-201 study as well as theinvestigators and their staff conducting the study
BAN2401-201 STUDY SITES
Abington Neurological Associates

CHU Strasbourg - Hôpital Hautepierre

Hospital de Cruces

Medical College of Wisconsin, Inc.

Praxis Dr. med. Volker Schumann

Advanced Memory Research Institute of NJ, PC

CHU Toulouse - Hôpital Casselardit

Hospital General de Catalunya

Memory Enhancement Center of America, Inc.

Akademiska Sjukhuset

Clinical Trial Network

Hospital San Vicente

Miami Jewish Health Systems

Praxis Dres. Bittkau
Psychiatry and Alzheimer's Care of Rochester.
PLLC

Alexian Brothers Medical Center - Neuroscience
Research Institute
Alzheimer's Research and Treatment Center
American Neuropsychiatric Research Institute Inc
ANI Neurology, PLLC d/b/a Alzheimer's Memory
CenterClinical Trials of Texas, Inc.

Hospital Universitario Clinico San Carlos

Michigan State University

Quantum Laboratories Inc.

Collaborative Neuroscience Network, LLC
Columbus Regional Medical Center

Hospital Universitario Virgen Macarena
Hotel Dieu Hospital

Quest Research InstituteRenstar Medical Research

Cutting Edge Research Group, Inc.

Hyogo Brain and Heart Center

Asan Medical Center

Dent Neurologic InstituteHyogo College of Medicine Hospital

ASCLEPES Research Centers, P.C.

Diakoniekrankenhaus Henriettenstiftung gGmbH

INACTIVE Margolin Brain InstituteAtlanta Center for Medical ResearchDong-A University Hospital

Indiana University School of Medicine

Axiom Clinical Research of Florida

Elkhart Clinic

Infinity Clinical Research, LLC

Misael Gonzalez, MD
National Clinical Research Inc.-Richmond
Neuro Rive Sud Clinic/Center for Diagnosis &Research on Alzheimer's Disease
Neurocare, Inc., dba Neurocare Center for
Research
Neuropsychiatric Research Center of Southwest
FloridaNeuroStudies.net, LLC
New Orleans Center for Clinical Research /Volunteer Research Group, an AMR company

Azienda Ospedaliera di Perugia Ospedale S. Mariadella Misericordia
Azienda Ospedaliero Universitaria di Parma
Azienda Ospedaliero Universitaria Pisana

Berma Research Group

Emory University Cognitive Neurology Clinic &ADRC
Empire Neurology, PC
Florida Atlantic University
Fondazione IRCCS CA' Granda Ospedale
Maggiore Policlinico
Fondazione Santa Lucia IRCCS

Bezirkskrankenhaus Guenzburg

Azienda Ospedaliero Universitaria San Martino

Sahlgrenska Universitetssjukhuset, Mölndal
Sjukhus
Saneikai Tsukazaki Hospital
Senior Adult Specialty Research
Seoul National University Bundang Hospital

Innovative Clinical Trials

New York University Medical Center

Seoul National University Hospital

Institute for Neurodegenerative Disorders
IRCCS Centro San Giovanni di Dio Fatebenefratelli

NHO Hiroshima-Nishi Medical Center
Oregon Health & Science University

Severence Hospital, Yonsei University
Sharp Mesa Vista Hospital

The Regents Of The University Of California
The University of Texas Health Science Center at
San Antonio
Tokyo Medical University HospitalTokyo Metropolitan Geriatric Hospital
Toronto Memory Program (Neurology Research
Inc.)
Torrance Clinical Research Institute, Inc.
Umberto I Pol. di Roma-Università di Roma La
Sapienza
University of Alabama at Birmingham
University of Arizona
University of Kansas Medical Center ResearchInstitute, Inc. - Master
University of Kentucky Medical Center
University of Michigan

Ishikawa Clinic

Osaka Saiseikai Nakatsu Hospital

Shinjuku Research Park Clinic

University of Rochester

JEM Research Institute

Osaka University HospitalSkånes Universitetssjukhus

USF Suncoast Gerontology Center

Fukuoka University Hospital

Katayama Medical Clinic

Pacific Institute of Medical Research

St. Joseph's HC- Parkwood Institute

Bioclinica Orlando

Fundacio ACE

Kawartha Centre - Redefining Healthy Aging

Pacific Neuroscience Medical Group

Stedman Clinical Trials, LLC

Bioclinica The Villages

FutureSearch Trials of Dallas, LP

Klinikum rechts der Isar der TU Muenchen

Palm Beach Neurological Center

Summit Research Network (Oregon) Inc.

Valley Medical Primary Care
Weill Cornell Medical College New York
Presbyterian HospitalWest London Cognitive Disorders Treatment andResearch Unit

Boston University School of Medicine

Galiz Research, LLC

Kobe University Hospital

Bradenton Research Center, Inc.

Gesundheitszentrum Hoppegarten

Konkuk University Medical Center

Brain Matters Research

Glasgow Memory Clinic Ltd

Kotobukikai Tominaga Hopital

Great Lakes Clinical Trials

Lahey Clinic Inc.

Brain Research Center
Brigham and Women's Hospital
CCM Clinical Research Group, Inc.

35

Rhode Island Mood & Memory Research Institute

The National Hospital for Neurology &Neurosurgery
The Neurology Group, LLP

Groupe hospitalier Broca - La Rochefoucauld - La
Collégiale
Henry Ford Hospital

Parkinson's and Neurodegenerative Disorders
ClinicParkinson's Disease and Movement Disorders
CenterPharmacology Research Institute
Pharmakologisches Studienzentrum Chemnitz
GmbH

Suncoast Neuroscience and Associates, Inc.

Xenoscience Inc.

Synapse Saitama Neuropsychiatry Center

Yale University School Of Medicine

Synexus Clinical Research US, Inc.
Texas Neurology, PA

Lynn Health Science Institute

Policlinica Guipuzcoa

The Clinical Trial Center, LLC

MD Clinical

Praxis Dr. med. Peter Franz

The Memory Clinic

Presented at the 11th Clinical Trials on Alzheimer's Disease (CTAD) Conference October 24-27, 2018

Acknowledgements

BAN2401-201 CORE TEAM
Heather Bradley
Shobha Dhadda
Cindy Dobrinski
Gordon Espie
Robert Gordon
Marin Hsuan
June Kaplow
Akihiko Koyama
Robert Lai

Johan Luthman
Kiran Putti
Martin Rabe
Cheryl Ruburiano
Chad Swanson
Keiichiro Totsuka
Kate Tranotti
Jinping Wang
Yong Zhang

COLLABORATORS
Lars Lannfelt, BioArctic and Uppsala
University
Vrije Universiteit Amsterdam
Eisai and Biogen are in a collaboration to
jointly develop and commercialize BAN2401
BAN2401 is a result of a strategic researchalliance between Eisai and BioArctic
Berry Consultants helped with design andimplementation of the study

36

Presented at the 11th Clinical Trials on Alzheimer's Disease (CTAD) Conference October 24-27, 2018

Communication 5

Q&A
Professor Jeffrey Cummings, MD, ScD
Cleveland Clinic
Chad J. Swanson, PhD
Senior Director, Clinical Research, Neurology Business GroupEisai Inc.

Akihiko Koyama, PhD
Executive Director, Global Head of Translational Science
Eisai Inc.
37

Presented at the 11th Clinical Trials on Alzheimer's Disease (CTAD) Conference October 24-27, 2018