1. No category

Randomized, Double-blind, Placebo-controlled, Phase 1b Study of Aducanumab (BIIB037),
an Anti-Aβ Monoclonal Antibody, in Patients With Prodromal or Mild Alzheimer’s Disease:
Interim Results by Disease Stage and ApoE ε4 Status
001
Figure 3
Sevigny J,1 Chiao P,1 Williams L,1 Chen T,1 Ling Y,1 O’Gorman J,1 Hock C,2 Nitsch RM,2 Sandrock A1
Biogen, Cambridge, MA, USA; 2Neurimmune Holding AG, Zurich, and University of Zurich, Zurich, Switzerland
•
Patient disposition is shown in Figure 3.
Figure 3. Patient dispositiona
To present interim safety and Aβ removal (change in florbetapir [18F-AV-45]
positron emission tomography [PET] signal) results with aducanumab by
disease stage and ApoE ε4 status.
Placebo
40
Randomized
Dosed
multiple-dose study (NCT01677572).
b
•
Titration: placebo (Arms 8–9)
Endpoints are presented in Box 1. Assessment timeline is shown in Figure 2.
•
•
•
•
•
CDR-sb, MMSE
Amyloid PET,
change from
baseline to
Week 54
Exploratory – Ongoing
NTB, FCSRT, NPI-Q
Fluid biomarkers
Volumetric MRI
FDG-PET
rs-fMRI
ASL-MRI
•
•
•
•
•
•
ASL-MRI = arterial spin labeling magnetic resonance imaging; CDR-sb = Clinical Dementia
Rating sum of boxes; FCSRT = Free and Cued Selective Reminding Test; FDG-PET =
18
F-fluorodeoxyglucose positron emission tomography; MMSE = mini-mental state examination;
NPI-Q = Neuropsychiatric Inventory-Questionnaire; NTB = Neuropsychological Test Battery;
PK = pharmacokinetic; PET = positron emission tomography; rs-fMRI = resting state functional
magnetic resonance imaging
•
PRIME is ongoing. For this interim analysis, data were analyzed to Week 54
for Arms 1–5 and up to Week 30 for Arms 6 and 7.
Double-blind period
Wk 30
6
2
1
0
3
0
0
0
5
3
0
1
1
0
0
0
12
9
0
0
3
0
0
0
Wk 52-54
MRI
Amyloid PET
Clinical
assessment
LTE = long-term extension; IV = intravenous; PET = positron emission tomography
32
30
32
2/38 (5)
2/31 (6)
3/32 (9)
0/30
2/32 (6)
0/38
1/31 (3)
2/32 (6)
10/30 (33)
13/32 (41)
ApoE ε4 carrier
0/24
1/19 (5)
1/21 (5)
9/21 (43)
11/20 (55)
ApoE ε4 non-carrier
0/14
0/12
1/11 (9)
1/9 (11)
2/12 (17)
ApoE ε4 carrier
0/18
0/10
2/14 (14)
3/12 (25)
5/13 (38)
0/10
0/7
1/11 (9)
2/8 (25)
4/8 (50)
ApoE ε4 non-carrier
0/8
0/3
1/3 (33)
1/4 (25)
1/5 (20)
0/20
1/21 (5)
0/18
7/18 (39)
8/19 (42)
ApoE ε4 carrier
0/14
1/12 (8)
0/10
7/13 (54)
7/12 (58)
ApoE ε4 non-carrier
0/6
0/9
0/8
0/5
1/7 (14)
Mild
Dose- and time-dependent reductions in brain Aβ plaque (evidenced by
SUVR reduction) at Weeks 26 and 54 were generally consistent across mild
and prodromal AD subgroups and across ApoE ε4 carriers and non-carriers
within the doses tested (Figure 4).
AD = Alzheimer’s disease; ARIA (-E) (-H) = amyloid-related imaging abnormalities (-edema)
(-microhemorrhage/hemosiderosis)
a
ARIA based on BioClinicaTM MRI.
Figure 4. Amyloid plaque reduction with aducanumaba (A) Mean composite SUVR over time for PD analysis population. The dashed line indicates a commonly used SUVR
cut-point for florbetapir.3 (B-F) Adjusted mean (±SE) change from baseline in composite SUVR at 26 and 54 weeks among (B) the overall PD analysis population,b (C) ApoE ε4
carriers,c and (D) non-carriers,c and patients with (E) prodromal,b and (F) mild ADb
Figure 4
A
Placebo
(n=40)
1 mg/kg
(n=31)
3 mg/kg
(n=32)
6 mg/kg
(n=30)
10 mg/kg
(n=32)
72.8 ± 7.2
72.6 ± 7.8
70.5 ± 8.2
73.3 ± 9.3
73.7 ± 8.3
13 (42)
17 (53)
15 (50)
15 (47)
31 (100)
31 (97)
28 (93)
30 (94)
70.2 ± 15.1
73.0 ± 11.9
73.0 ± 16.7
73.3 ± 15.4
75.4 ± 18.1
Placebo (n=34, 34, 21)
Aducanumab 1 mg/kg (n=26, 26, 21)
Aducanumab 3 mg/kg (n=29, 27, 26)
Aducanumab 6 mg/kg (n=23, 23, NA)
Aducanumab 10 mg/kg (n=28, 27, 21)
1.40
1.30
1.20
SUVR cut-point for florbetapir = 1.133
1.10
Carriers
26 (65)
19 (61)
21 (66)
21 (70)
20 (63)
Non-carriers
14 (35)
12 (39)
11 (34)
9 (30)
12 (38)
Prodromal
19 (48)
10 (32)
14 (44)
12 (40)
13 (41)
Mild
21 (53)
21 (68)
18 (56)
18 (60)
19 (59)
24.7 ± 3.6
23.6 ± 3.3
23.2 ± 4.2
24.4 ± 2.9
24.8 ± 3.1
MMSE, mean ± SD
0.5
34 (85)
22 (71)
22 (69)
25 (83)
24 (75)
1
6 (15)
9 (29)
10 (31)
5 (17)
8 (25)
2.66 ± 1.50
3.40 ± 1.76
3.50 ± 2.06
3.32 ± 1.54
3.14 ± 1.71
PET SUVR, mean
composite ± SD
1.441 ±
0.173
1.441 ±
0.146
1.464 ±
0.149
1.429 ±
0.199
1.441 ±
0.192
AD medications
use,a n (%)
24 (60)
19 (61)
28 (88)
20 (67)
17 (53)
CDR-sb, mean ± SD
AD = Alzheimer’s disease; CDR = Clinical Dementia Rating; CDR-sb = Clinical Dementia
Rating sum of boxes; MMSE = mini-mental state examination; PET = positron emission
tomography; SD = standard deviation; SUVR = standard uptake value ratio
a
Cholinesterase inhibitors and/or memantine.
Safety
• Adverse events (AE) were reported in 84%–98% of patients across
treatment groups.
The most common AE and serious AE (SAE) was amyloid-related imaging
abnormalities (ARIA; based on MRI) (Table 2); other AEs/SAEs were
consistent with the patient population.
Three deaths were reported (2 with placebo, 1 with aducanumab
10 mg/kg); none were considered treatment related (2 occurred after
study discontinuation).
Incidence of ARIA-edema (ARIA-E) was dose- and ApoE ε4-status–
dependent (Table 2):
–– Among ApoE ε4 carriers: 5%, 5%, 43%, and 55% for 1, 3, 6, and
10 mg/kg aducanumab, respectively, versus 0% for placebo.
–– Among ApoE ε4 non-carriers: 0%, 9%, 11%, and 17% versus 0%.
–– Incidence of isolated ARIA-microhemorrhage/hemosiderosis (ARIA-H)
was low and similar across doses and ApoE ε4 status (data not shown).
0
26
Anaylsis visit (weeks)
C
Global CDR, n (%)
B
Overall population
1.50
23 (58)
•
Figure 5. Aducanumab effect on MMSEa
Placebo (n=37, 36, 23)
Aducanumab 1 mg/kg (n=26, 26, 25)
Aducanumab 3 mg/kg (n=29, 29, 26)
Aducanumab (mg/kg)
Aducanumab (mg/kg)
Placebo 1
3
6
10
(n=22) (n=16) (n=18) (n=17) (n=18)
Placebo 1
3
6
10
(n=12) (n=12) (n=17) (N/A) (n=14)
0
-0.05
-0.1
-0.15
-0.2
-0.25
-0.3
Week 26
E
Difference from placebo
at Week 52
Aducanumab (mg/kg)
Aducanumab (mg/kg)
Placebo 1
3
6
10
(n=17) (n=10) (n=11) (n=10) (n=12)
Placebo 1
3
6
10
(n=10) (n=8) (n=12) (N/A) (n=12)
0
-0.05
-0.1
-0.15
-0.2
-0.25
-0.3
Week 26
0.00
-0.05
-0.10
†
-0.15
Week 54
‡
‡
-0.20
‡
-0.25
-0.30
Week 54
Week 26
0.1
Placebo 1
3
6
10
(n=12) (n=10) (n=9) (n=6) (n=9)
‡
-2
0.92
-3
-4
0
24
Anaylsis visit (weeks)
Figure 6. Aducanumab effect on CDR-sba
Placebo (n=36, 36, 22)
Aducanumab 1 mg/kg (n=28, 28, 23)
Aducanumab 6 mg/kg (n=27, 27, NA)
Aducanumab 10 mg/kg (n=28, 28, 23)
2.00
Placebo (n=37, 36, 23)
Aducanumab 1 mg/kg (n=26, 26, 25)
Aducanumab 3 mg/kg (n=29, 29, 26)
Aducanumab 6 mg/kg (n=28, 28,
NA) 54
at Week
Aducanumab 10 mg/kg (n=30, 29, 25)
1
-0.33
Difference from placebo
at Week 52
-0.71
1.50
0
1.00
*
*
*
-1
0.50
-2
0.00
-3
-0.1
-0.2
-0.25
-0.3
-0.35
Week 26
Week 54
Mild AD
0.1
Aducanumab (mg/kg)
Aducanumab (mg/kg)
Placebo 1
3
6
10
(n=17) (n=16) (n=16) (n=13) (n=15)
Placebo 1
3
6
10
(n=11) (n=13) (n=14) (N/A) (n=9)
0.05
0.92
0
26
Anaylsis visit (weeks)
54
CONCLUSIONS
Aducanumab 1 mg/kg (n=28, 28, 23)
Aducanumab 10 mg/kg (n=28, 28, 23)
The pattern
of the
aducanumab
Aducanumab
3 mg/kg
(n=30, 30, 27)effect versus placebo on Aβ
plaque reduction was generally consistent across disease stage
Difference from placebo
2.50
and ApoE ε4 status.
at Week 54
•
Dose-dependent
slowing of decline on MMSE and CDR-sb was
2.00
observed at 1 year, which reached statistical significance with the
-0.33
highest
aducanumab
dose.
1.50
•
Aducanumab demonstrated an acceptable safety profile over
1.00
54
weeks.
-0.71
–– ARIA was the main safety and tolerability finding and was able
-1.44
*
0.50
to be monitored and managed.
*P<0.05 vs placebo
–0.00
– The incidence of ARIA was dose- and ApoE-ε4-status–dependent.
0
26
54
–– ARIA-E
was usually observed
early in the course of
treatment
Anaylsis visit (weeks)
and was asymptomatic or with mild, transient symptoms.
CDR-sb is an exploratory endpoint. Analyses based on observed data. ANCOVA for change from baseline with factors of treatment, laboratory ApoE ε4 status (carrier and non-carrier), and baseline CDR-sb.
Efficacy analysis population is defined as all randomized subjects who received at least 1 dose of study medication and had at least 1 post-baseline questionnaire assessment.
REFERENCES
0
1. Sevigny J, et al. Presented at: 13th International Geneva/Springfield Symposium
on Advances in Alzheimer Therapy, March 26-29, 2014, Geneva, Switzerland.
2. Ostrowitzki S, et al. Arch Neurol. 2012;69:198-207.
3. Landau SM, et al. J Nucl Med. 2013; 54:70-77.
-0.05
-0.1
-0.15
ACKNOWLEDGEMENTS
-0.2
-0.25
-0.3
-0.35
2.55
2.39
-1.44
Figure 6. Aducanumab Effect on CDR-sb
• A significant dose- and time-dependent reduction of brain Aβ
mg/kg
(n=27, 27, NA)
Placebo
(n=36,
36, 22) was observed Aducanumab
plaques
versus
placebo
based on 6PET
imaging.
-0.05
-0.15
Difference from placebo
*P<0.05 vs placebo
*P<0.05 vs placebo
CDR-sb-4= Clinical Dementia Rating sum of boxes; SE = standard error
a
24
CDR-sb is0an exploratory endpoint. Analyses
based on observed data. 52
ANCOVA for change
Anaylsis
visit
(weeks)
from baseline with factors of treatment, laboratory ApoE ε4 status (carrier and non-carrier),
MMSE is baseline
an exploratory endpoint.
Analyses based on
observed data. ANCOVA
for change from
baseline with factors ofis
treatment,
laboratory ApoE
status randomized
(carrier and non-carrier), andsubjects
baseline MMSE.
and
CDR-sb.
Efficacy
analysis
population
defined
asε4all
who
Efficacy analysis population is defined as all randomized subjects who received at least 1 dose of study medication and had at least 1 post-baseline questionnaire assessment
received ≥1 dose of study medication and had ≥1 post-baseline questionnaire assessment.
•
0
52
*P<0.05 vs placebo
MMSE = mini-mental state examination; SE = standard error
a
MMSE is an exploratory endpoint. Analyses based on observed data. ANCOVA for change
from baseline with factors of treatment, laboratory ApoE ε4 status (carrier and non-carrier),
and baseline MMSE. Efficacy analysis population is defined as all randomized subjects who
received ≥1 dose of study medication and had ≥1 post-baseline questionnaire assessment.
Aducanumab (mg/kg)
Placebo 1
3
6
10
(n=9) (n=9) (n=9) (N/A) (n=7)
0.05
F
0.05
-0.35
Aducanumab (mg/kg)
Placebo 1
3
6
10
(n=21) (n=21) (n=26) (N/A) (n=21)
2.55
2.39
*
*
-1
ApoE ε4 non-carriers
Week 54
Prodromal AD
0.1
Aducanumab (mg/kg)
Placebo 1
3
6
10
(n=34) (n=26) (n=27) (n=23) (n=27)
Aducanumab (mg/kg)
0.05
-0.35
0.05
D
ApoE ε4 carriers
0.1
Overall population
54
Aducanumab 6 mg/kg (n=28, 28, NA)
Aducanumab 10 mg/kg (n=30, 29, 25)
0
2.50
40 (100)
LTE
Wk 42
31
Aducanumab 3 mg/kg
(n=30,
27)
Figure 5. Aducanumab
Effect
on30,MMSE
Race, n (%) white
•
Wk 18 Wk 24-26
7
3
0
0
4
0
0
0
Females, n (%)
IV infusions every 4 weeks over 52 weeks (14 total)
Wk 6
9
3
0
0
1
1
1
3
Baseline demographic and disease characteristics were generally well
balanced across treatment groups (Table 1).
Age years,
mean ± SD
•
Figure 2. Assessment timeline
Screening
32
Aducanumab
Box 1. Endpoints
Safety and tolerability
Secondary
Serum PK
Anti-aducanumab antibodies
Amyloid PET, change from
baseline to Week 26
30
38
exploratory endpoints MMSE (Figure 5) and CDR-sb (Figure 6) at 1 year.
1
Prodromal
volume of 6 regions: frontal, parietal, lateral temporal, sensorimotor, anterior
cingulate, posterior cingulate.2
Clinical stage, n (%)
PK = pharmacokinetic
a
Randomization was stratified by ApoE ε4 status (carrier/non-carrier).
b
Dose escalation was based on external, independent Data Monitoring Committee review
of safety, tolerability, and PK data.
•
32
10 mg/kg
By baseline clinical stage
Brain Aβ Plaque Reduction
• Brain Aβ plaque reduction was evaluated by composite SUVR from a
Table 1. Baseline demographic and disease characteristics
6 mg/kg: placebo (Arms 6–7)
dn4\BID73708
poster Fig03.eps
Exploratory
Primary
31
6 mg/kg
By ApoE ε4
There were no significant changes in chemistry, hematology, urinalysis,
electrocardiogram, or vital signs.
ApoE ε4, n (%)
10 mg/kg: placebo (Arms 4–5)
•
10 mg/kg
32
3 mg/kg
Analysis of data from 1, 3, and 10 mg/kg up to Week 54 and 6 mg/kg up to Week 30.
Weight (kg),
mean ± SD
1 & 3 mg/kg: placebo (Arms 1–3)
ARIA-E, n/N (%)
Composite SUVR
Adjusted mean change from baseline (±SE)
Figure 1. Study designa
Isolated ARIA-H, n/N (%)
1 mg/kg
a
–– Mild AD: MMSE 20–26; global CDR 0.5 or 1.0; meeting National Institute
on Aging and Alzheimer’s Association core clinical criteria for probable
AD; had a positive florbetapir PET scan by visual assessment.
Patients (planned N=188) were randomized to 1 of 9 treatment arms (target
enrollment: n=30 per active treatment arm) in a parallel staggered design at
a ratio of 3:1 active vs placebo (Figure 1).
–– MRI findings typically resolved within 4–12 weeks.
The majority of patients (54%) who developed ARIA-E continued treatment
(93% of those who continued did so at a reduced dose); no patients
developed recurrent ARIA-E.
Composite SUVR
Adjusted mean change from baseline (±SE)
–– Prodromal AD: MMSE 24–30; spontaneous memory complaint; total
free recall score ≤27 on the Free and Cued Selective Reminding Test;
a global Clinical Dementia Rating (CDR) score of 0.5; absence of
significant levels of impairment in other cognitive domains; essentially
preserved activities of daily living and absence of dementia; had a
positive florbetapir PET scan by visual assessment.
Patient with ≥1 postbaseline MRI
Placebo
Adjusted
mean
change from
Adjusted mean
change
from
(± SE)
baseline (+ baseline
SE)
Patients were aged 50–90 years, had stable concomitant medications, had
a Mini-Mental State Examination (MMSE) score ≥20 and met clinical and
radiologic criteria as follows:
Staggered cohort design
6 mg/kg
30
40
Discontinued treatment
Adverse event
Lost to follow-up
Disease progression
Consent withdrawn
Investigator decision
Death
Other
Study Design
• PRIME is a multicenter, randomized, double-blind, placebo-controlled,
•
3 mg/kg
33
•
•
METHODS
•
1 mg/kg
31
–– When present, symptoms typically resolved within 4 weeks.
–– Treatment discontinuations in patients with ARIA-E were consistent
across mild and prodromal subgroups (data not shown).
166
randomized
OBJECTIVE
•
•
Most (92%) ARIA-E events were observed within the first 5 doses; 65%
of ARIA-E events were asymptomatic.
Adjusted mean change from
baseline (± SE)
This Phase 1b study evaluated the safety, tolerability, pharmacokinetics (PK),
and pharmacodynamics of aducanumab in patients with prodromal
or mild AD.
carriers, and 68 (41%) had prodromal AD.
Aducanumab
Adjusted mean change from
baseline (± SE)
A single ascending dose study of aducanumab demonstrated acceptable
safety and tolerability in patients with mild-to-moderate AD at doses up to
30 mg/kg.1
•
Clinical Endpoints
• There was statistically significant dose-dependent slowing of decline on the
Table 2. Summary of ARIAa findings
Composite SUVR
Adjusted mean change from baseline (±SE)
•
Patients
• Of the 166 patients randomized, 165 were dosed; 107 (65%) were ApoE ε4
Composite SUVR
Adjusted mean change from baseline (±SE)
•
Aducanumab (BIIB037) is a human monoclonal antibody selective for
aggregated forms of beta-amyloid (Aβ) peptide, including soluble oligomers
and insoluble fibrils.
There was no apparent difference in incidence of ARIA-E between
subjects with prodromal or mild AD when accounting for ApoE ε4 status
(Table 2).
Composite SUVR
Adjusted mean change from baseline (±SE)
•
•
RESULTS
INTRODUCTION
Mean composite SUVR (±SE)
1
Week 26
Week 54
P values are calculated only for the overall population analyses in Figure (B). *P<0.05; †P<0.01; ‡P<0.001 vs placebo
AD = Alzheimer’s disease; PD = pharmacodynamics; SE = standard error; SUVR = standard uptake value ratio
a
Analyses based on observed data. PD analysis population is defined as all randomized patients who received ≥1 dose of study medication and had ≥1 post-baseline assessment of the parameter.
b
ANCOVA model was fitted with change from baseline as dependent variable and with treatment group, laboratory ApoE ε4 status (carrier and non-carrier) and baseline composite SUVR as
independent variables.
c
ANCOVA model was fitted with change from baseline as dependent variable and with treatment group and baseline composite SUVR as independent variable.
Biogen provided funding for medical writing support in the development of this poster.
Erin Bekes, PhD, (Complete Medical Communications, Hackensack, NJ) wrote the first
draft of the poster based on input from the authors. Biogen reviewed and provided
feedback on the poster. The authors had full editorial control
of the poster and provided their final approval of all content.
DISCLOSURES
JS, PC, LW, TC, YL, JO, AS: employees of Biogen; CH, RN:
employees and shareholders of Neurimmune Holding AG.