Treatment of Early AD Subjects With BAN2401,
an Anti-Aβ Protofibril Monoclonal Antibody,Significantly Clears Amyloid Plaque andSignificantly Reduces Clinical Decline
Chad J. Swanson, PhD; Yong Zhang, MS; Shobha Dhadda, PhD;
Jinping Wang, PhD; June Kaplow, PhD; Robert Lai, MA, MB, Bchir;Lars Lannfelt, MD, PhD; Lynn D. Kramer, MD, FAAN; Johan Luthman, DDS, PhD

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1

BAN2401 Study 201 Positioning in the Overall
Development Program
Efficient, Rapid Development Program Despite
Chronic and Slowly Progressing Disease2

Considerations for Trial Design
to Achieve Overall Goal

Innovations Required toAchieve Overall Goal

• Shift toward Early AD• Obtain strong clinical proof-of-concept• Evaluate dose ranging effect andsubgroups• Account for duration of study andmagnitude of treatment effect• Potential for early decision-making(12-month) while preserving 18-monthdisease modification data

• Clinical response driving adaptive
randomization (Bayesian design)• Clinical assessment allowing earlier
detection of clinical change over time
(ADCOMS*) for Early AD*ADCOMS: Alzheimer’s Disease Composite Score.

BAN2401-G000-201: Global* Phase 2b
Population
Early AD: 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)*NA, EU, Asia Pacific regions.
3

Design• Key secondary clinical outcome• Duration and Size: 18 months andassessments
approximately 800 subjects– ADAS-cog, CDR-SB assessed• Treatment: 6 arms
every 3 months(1 Pbo, 5 dose arms, 2 regimens)• Longitudinal biomarkers– All subjects received bi-weekly– Amyloid PET sub study –infusions to maintain the blind
Baseline, 12, and 18 months– All subjects remained on the same
– CSF sub study –randomized dose throughout dosing
Baseline, 12, and 18 months– Active dose arms/regimen:– Volumetric MRI –2.5 mg/kg bi-weekly, 5 mg/kg monthly,
Baseline, 6, 12, and 18 months
5 mg/kg bi-weekly, 10 mg/kg monthly,
10 mg/kg bi-weekly• Safety– All ARIA-E discontinued• Periodic IAs for efficacy/futility
permanently from study drug
– Computer generated algorithm
per protocol (MRI-based)
allocates more subjects to the bestdose(s) at each IA based on ADCOMS• Primary clinical outcome assessment– ADCOMS assessed every 3 months

Clinical Measure Allowing Earlier Detection ofClinical Change: ADCOMSAPPROACH
ADCOMS is a Statistically Derived Score
Designed to Measure Cognition andFunction Longitudinally in Early AD• 4 MCI study datasets• 4 mAD dementia study datasets• ADAS-Cog, MMSE, CDR-SB, NTB, ADLs

ELEMENTS
Modeling was Performed to Maximize
Responsiveness to Clinical Progression
and Treatment in Early AD• Total of 12 items identified from CDR-SB (6),ADAS-cog (4), and MMSE (2)ADCOMS Items

PERFORMANCEADCOMS Predicted 20% or More
Improvement in Responsiveness Over
Existing Clinical Outcome Measures• Now replicated in 3 settings (Roche SCarlett
RoAD; Elenbecestat Poster #: P4-389,
AAIC 2018; BAN2401 Study 201)
Wang J, Logovinsky V., et al. J Neurol Neurosurg Psychiatry. 2016;87:993–999. doi:10.1136/jnnp-2015-312383.
4

CDR

ADAS-cog

MMSE

Personal Care

Delayed Word Recall

Orientation to Time

Community Affairs

Orientation

DrawingHome and Hobbies

Word Recognition

MemoryWord Finding Difficulty

Orientation
Judgement andProblem Solving

BAN2401 Analyses
Secondary Endpoints(12- and 18-month Final Analysis)Primary Endpoint(Interim Analysis)
ADCOMS as clinicaloutcome assessment
using longitudinal data
through 12 months with
Bayesian analysis

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(Aβ1-42, total-Tau, etc.)

5Subgroup
Analyses Using
Similar
Methodologies

Subject Disposition
Subjects enrolled and screened
N=3267
Subjects randomized
N=856
Treated*
N=854

Placebo
N=245
Completed treatment: 186 (75.9%)
Early discontinuation: 58 (23.7%)
Primary Reason for Discontinuation
Non-ARIA-E AE
13 (5.3%)
ARIA-E AE
2 (0.8%)per protocol
Subject choice
23 (9.4%)
Inadequate
therapeutic effect
1 (0.4%)Other
19 (7.8%)*Not treated N=2 (both in placebo arm).
6

BAN2401
N=609
Completed treatment: 384 (63.1%)
Early discontinuation: 219 (36.0%)
Primary Reason for Discontinuation
Non-ARIA-E AE
34 (5.6%)
ARIA-E AE
46 (7.5%)
per protocol
Subject choice77 (12.6%)
Inadequate
therapeutic effect
2 (0.3%)Other
32 (5.3%)
Forced discontinuation 26 (4.3%)

Discontinuations due to non-ARIA-E
AEs were similar between
placebo and BAN2401
Subject choice and inadequate
treatment effect were similar between
placebo and BAN2401

Ex US Health Authority Requested (July 2014)• APOE4+ subjects no longer be randomized
to 10 mg/kg bi-weekly• Discontinue APOE4+ subjects on 10 mg/kg
bi-weekly who had not reached 6 months
treatment– 26 asymptomatic subjects without ARIA-E

Demographic and Baseline Characteristics Similar
Between Placebo and BAN2401 Treatment Groups
BAN2401
0%

20%

40%

Placebo
60%

80%

100%
(Mean±SD)

54%

Male

42%
64%
65%

MCI

72%
71%

*APOE4+
54%
54%

AChEI/Memantine

BAN2401(N=587)

Placebo(N=238)ADCOMS

0.378±0.158

0.370±0.166

ADAS-cog#22.2±7.4

22.6±7.7

CDR-SB

2.95±1.37

2.89±1.45

MMSE

25.6±2.426.0±2.3

PET SUVr*

1.41±0.16

1.40±0.16#N=586 in BAN2401, N=237 in Placebo*PET sub study; N=214 in BAN2401, N=98 in Placebo

86%
84%

CDR Global=0.5

Mean Age = 71.4 and 71.1, range 50-90 and 50-89(BAN2401 and Placebo)
BAN2401 has more male subjects (53.7% vs 42.4%).
*Proportion of APOE4+ subjects is general for clinical studies in this population.
7

Bayesian Results for Change From Baseline
in ADCOMS
Top Two Doses Identified Early as Meaningful – Thus Received Most Subjects
Number Randomized Per Dose
Placebo247

2.5 mg/kg
Bi-weekly
52

5 mg/kgMonthly51

5 mg/kg
Bi-weekly
92

10 mg/kg
Monthly253

10 mg/kg
Bi-weekly
161
414

Total
856

• 12-month Bayesian model identified 10 mg/kg bi-weekly as the best dose (ED90*)– This time point had 98% probability of being superior to placebo• Threshold for success at 12-month (primary endpoint)– Pre-specified: 80% probability of being superior to placebo by 25% reduction– Actual results: 64% probability of being superior to placebo by 25% reduction• Bayesian results and conventional statistics are consistent at the end of the study*ED90: dose producing 90% of maximum treatment effect.
8

BAN2401 Reduces Amyloid Burden• Dose dependent reduction in amyloid PET values(Florbetapir tracer)• Similar results with SUVr and Centiloid measuresacross all reference regions analyzed–• BAN2401 significantly reduced amyloid PET values
across all doses

Reference regions analyzed: SWM, WC mask, WC derived,
WC/WM correction, CG, Composite• Top dose: observed baseline mean (74.5), observed
18-month mean (5.5)

Centiloid
10

0.00

0
*

–0.05

****

–0.10

**

–0.15

****

****

****

****

Placebo–0.20

5 mg/kg bi-weekly
2.5 mg/kg bi-weekly–0.25

10 mg/kg monthly

–0.30

****
****

5 mg/kg monthly

0

12Visit (months)

*

–10

****

–20

**

–30

18

****

****

****

****

–40
–50
–60

****
****

–70
****

10 mg/kg bi-weekly–0.35

Adjusted Mean Change
From Baseline (±SE) †0.05

IMPROVEMENT

Adjusted Mean Change
From Baseline (±SE) †IMPROVEMENTPET SUVr

****

–80
0

12
Visit (months)

18

Global Cortical Average versus Whole Cerebellum Reference*P<0.05, **P<0.01, ***P<0.001, ****P<0.0001. †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.
970 units
reduction

Significant Conversion of Amyloid Positive to
Negative With Visual Read
Florbetapir Tracer Visual Read

• BAN2401 significantly
converted subjects
from amyloid positive
to negative acrossmost doses

Proportion (±SE) of PET Positive Subjects (%)• Dose dependent
conversion fromamyloid positive tonegative vs placebo

IMPROVEMENT

100
90
80
70

**

60

*

****

50

**

***

40

Placebo30

5 mg/kg bi-weekly
2.5 mg/kg bi-weekly

20

****

****

10 mg/kg monthly

10

***

81%
conversion

5 mg/kg monthly
10 mg/kg bi-weekly

0

0

12
Visit (months)*P<0.05, **P<0.01, ***P<0.001, ****P<0.0001.
Baseline images were read at time of inclusion; longitudinal 12 and 18 month reads were conducted after all subjects completed 18 months of treatment. Fisher’s exact test was used to compare each dosevs placebo.
10

****

18

BAN2401 Slowed Cognitive Decline on ADCOMSOver 18 Months (1)Each Dose vs Placebo
Adjusted Mean Change From Baseline (±SE)• Dose dependent
reduction in decline
on ADCOMS overtime; starting at
6 months oftreatment

WORSENING

0.00

*
0.05

*
0.10

*
Placebo0.15

5 mg/kg bi-weekly
2.5 mg/kg bi-weekly

10 mg/kg monthly

0.20

5 mg/kg monthly
10 mg/kg bi-weekly

0

6

12
Visit (months)*P<0.05.
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.
1118

BAN2401 Slowed Cognitive Decline on ADCOMSOver 18 Months (2)Top Two Doses vs Placebo
Adjusted Mean Change From Baseline (±SE)• Less decline on
ADCOMS for
10 mg/kg bi-weekly
dose (green) vsplacebo (black)across all time points

WORSENING

0.00

*
0.05

*

30% reduction
P=0.034

0.10

*

0.15
Placebo
10 mg/kg monthly

0.20

10 mg/kg bi-weekly
Red line shows projected 25% less decline vs placebo over time (protocol defined)

0

6

12
Visit (months)*P<0.05.
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.
1218

BAN2401 Slowed Cognitive Decline on ADAS-cog
Over 18 Months
Top Two Doses vs Placebo• Slower decline on
ADAS-cog 10 mg/kg
bi-weekly dose
(green) vs placebo(black) across alltime points

Adjusted Mean Change From Baseline (±SE)• Dose dependent
reduction in decline
on ADAS-cog overtime; starting at
6 months

WORSENING

–2
–1

*

0
#

1

47% reduction
P=0.017*2
3
4
5

Placebo
10 mg/kg monthly

6

10 mg/kg bi-weekly
Red line shows projected 25% less decline vs placebo over time (protocol defined)

7

0

6

12
Visit (months)#P<0.1 (P=0.073), *P<0.05.
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.
13

18

BAN2401 Slowed Cognitive Decline on CDR-SB
Over 18 Months
Top Two Doses vs Placebo• Slower decline (>25%)
on CDR-SB for
10 mg/kg bi-weekly
dose (green) vsplacebo (black)across all time points

Adjusted Mean Change From Baseline (±SE)• Dose dependent
reduction in decline
on CDR-SB over time;
starting at 6 monthsof treatment

WORSENING

0.0

#

0.5

26%
reduction
1.0

1.5
Placebo
10 mg/kg monthly
10 mg/kg bi-weekly
Red line shows projected 25% less decline vs placebo over time (protocol defined)

2.0

0

6

12
Visit (months)#P<0.1 (P=0.077).
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.
1418

Placebo Decline Similar to Other Larger AD Trials
in Similar Populations
Change From Baseline in CDR-SB for Placebo

Change From Baseline

0.0

0.5

1.0

1.5

2.0

ADNI MCI plus MILD AD
Ganteneurumab Scarlet RoAD
Avagecestat Phase 2 Prodromal AD
BAN2401 Study 201
Mean ± SE Plots
0

3

6

9
Visit (months)

12

1. ADNI analysis on matched population on file in house.
2. Suanne Ostrowitzki, et al. A phase III randomized trial of gantenerumab in prodromal Alzheimer’s disease, Alzheimer's Research & Therapy. 2017;9:95.
3. Coric V., et al. Targeting Prodromal Alzheimer Disease With Avagacestat: A Randomized Clinical Trial, JAMA Neurology. 2015;72:1324–33.
15

15

18

Cerebrospinal Fluid (CSF) Aβ1-42 Demonstrates
Target Engagement
Each Doses vs Placebo: CSF Aβ
1-42• Dose dependent
increase in Aβ1-42– Increase expected
due to antibody
binding prolonging
half-life of Aβ1-42
species– Investigation ongoing
to determine free andbound versus total
fractions

Adjusted Mean Change From Baseline (±SE) (pg/mL)

500

****

Placebo400

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

300

5 mg/kg monthly****

10 mg/kg bi-weekly

****

200

**
**#

100

Total N =92 in CSF sub study

–100

12
Visit (months)**P<0.01, ***P<0.001, ****P<0.0001.

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.
16

*

0

0
#P<0.1 (P=0.067), *P<0.05.

**

18Significant Reduction in Cerebrospinal Fluid (CSF)
Total-Tau Over Time at the Combined Top Two Doses
Top Two Doses vs Placebo: CSF Total-Tau
Change From Baseline in Total-Tau (pg/mL)

400

Placebo
Combined 10 mg/kg

300
200
100

Placebo0

BAN2401–100

P<0.05 (testing slope)

–200
–300

–400

Total N =92 in CSF sub study012Visit (months)
Based on linear regression model testing the slope of change from baseline; post-hoc statistical analysis utilized due to small sample size.
17

18

Pre-specified Subgroup Analyses are Ongoing• Clinical subgroup(MCI due to AD, Mild AD)• Presence or absence ofongoing AD treatment atbaseline• APOE4 status(positive, negative)• Age• Region• Gender• Ethnicity• Race• Anti-drug antibody

Eisai’s initial priority has been to conduct and communicate these topline analyses
contained in this presentation to the scientific community here at AAIC.
Further, we are working to conduct subgroup analyses to ensure athorough understanding of this rich dataset.

18

Treatment Emergent Adverse Events
BAN2401

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 (%)

Any TEAE

216 (88.2)

46 (88.5)

48 (94.1)

81 (88.0)

238 (94.1)

139 (86.3)

Treatment-related TEAE

65 (26.5)

23 (44.2)

25 (49.0)

31 (33.7)

135 (53.4)

76 (47.2)

Serious Adverse Event

43 (17.6)

10 (19.2)

4 (7.8)16 (17.4)

31 (12.3)

25 (15.5)

Deaths2 (0.8)2 (3.8)0

1 (1.1)2 (0.8)0

AE leading to discontinuation

15 (6.1)

7 (13.5)

4 (7.8)10 (10.9)47 (18.6)

24 (14.9)

Infusion reaction leading
to discontinuation*

2 (0.8)000

5 (2.0)4 (2.5)• Incidence rates of AE, SAE and TEAE consistent with patient population and balanced across placebo and
BAN2401 treatment groups• Most common TEAE were infusion reaction and ARIA (amyloid-related imaging abnormality)• No changes in labs, ECGs, or vital signs*Events included in AEs leading to discontinuation.
19

Amyloid-Related Imaging Abnormalities-Edema(ARIA-E) Summary
BAN2401

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%)

Most ARIA-E occurred within first
3 months of treatment
Mostly mild to moderate in severity(radiographic)
MRI findings typically resolved
within 4-12 weeks
Severity represents radiographic findings.
20

5/48 (~10%) Cases of Symptomatic ARIA-E
Included headache, visual disturbances, or confusion• (1) Severe at 2.5 mg/kg bi-weekly; Non serious AE• (1) Mild at 10 mg/kg monthly; SAE• (1) Moderate at 10 mg/kg bi-weekly; SAE• (2) Severe at 10 mg/kg bi-weekly; both SAE

Overall Summary of BAN2401 Study 201• First large clinical trial to support
the amyloid hypothesis• Response adaptive randomization
identified top two doses early with
10 mg/kg bi-weekly as the best dose

• Dose-dependent, statisticallysignificant reduction in brain amyloid
by 70 units in Centiloid analysis on
top dose [observed baseline mean
(74.5), observed 18-month mean (5.5)]• Majority of subjects at top dose
became amyloid negative on
visual read with statistical significant
conversion of 81%
21• Dose-dependent, clinically meaningful
and statistically significant slower
decline on clinical outcome measures ofcognition and function at 18 months on
ADCOMS with 30% less decline on top
dose and ADAS-cog with 47% lessdecline on top dose; and dosedependent, clinically meaningful slower
decline at 18 months on CDR-SB with
26% less decline on top dose
• Dose-dependent, statistically significant
effect on CSF Aβ1-42 and statisticallysignificant longitudinal reduction in
CSF total-Tau• Generally well-tolerated with ARIA-E
incidence <10% at highest dose

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 CORE TEAM
Chad J. Swanson
Heather Bradley
Shobha Dhadda
Gordon Espie
Robert Gordon
Marin Hsuan
June Kaplow
Robert Lai

22

Johan Luthman
Kiran Putti
Martin Rabe
Cheryl Ruburiano
Kenchiro Totsuka
Kate Tranotti
Jinping Wang
Yong Zhang

Eisai and Biogen are in a collaboration to jointly develop and commercialize BAN2401.
BAN2401 is a result of a strategic research alliance between Eisai and BioArctic.
Berry Consultants helped with design and implementation of the study.