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Therapeutic Factor IX (FIX) Activity After Single
Treatment With AMT-060 (AAV5-FIX) In Hemophilia B
Patients With Pre-existing Anti-AAV5 Humoral
Immunity
Anna Majowicz, Bart Nijmeijer, Margit Lampen, Lisa Spronck, Martin de Haan,
Harald Petry, Sander van Deventer, Christian Meyer, Marco Tangelder,
Valerie Ferreira
A S G C T 2 0 1 8 1 9 M a y 2 0 1 8 | 33
▪ 1:5 anti-AAV8 NAB titer totally blocks in vivo liver transduction in Non-
human Primates (NHP) with AAV8-hFIX (Jiang et al., Blood 2006)
▪ 1:17 titer of pre-existing anti-AAV2 NAB is described to “modulate linear
dose response” in humans to AAV2-hFIX treatment:
1:17 mean hFIX activity of 3%
1:2 mean hFIX activity of 11%
(Manno et al., Nature Medicine 2006)
▪ 1:1 titer of bioengineerd AAV-Spark100 capsid was reported to be
associated with reduced therapeutic efficacy (George et al., NEJM 2017)
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AAV5
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Patient # FIX activity (basal) Pre-existing anti-AAV5
NAB titer, GFP-based
assay
Total pre-existing anti-AAV5
(ELISA)
Low dose cohort (5e12 gc/kg)
1 < 1% Negative Negative
2 < 1% Negative Negative
3 < 1% Negative Positive (87)
4 1.5% Negative Positive (256)
5 < 1% Negative Negative
High dose cohort (2e13 gc/kg)
6 < 1% Negative Negative
7 < 1% Negative Negative
8 1% Negative Negative
9 1% Negative Negative
10 1% Negative Negative
A S G C T 2 0 1 8 1 9 M a y 2 0 1 8 | 6
n= 50 healthy donors
GFP-based assay
1/50 tested positiveLUC-based assay
32/50 tested positive
an
ti-A
AV
5 N
AB
tit
er
1 0 1
1 0 2
1 0 3
1 0 4
2
Inh
ibit
ion
of
tra
ns
du
cti
on
(% r
ela
tiv
e t
o c
on
tro
l)
-6 0
-4 0
-2 0
0
2 0
4 0
T o ta l a n t ib o d ie s a g a in s t A A V 5 - O D (4 5 0 n m )
an
ti-A
AV
5 N
AB
tit
er
0 .0 0 .2 0 .4 0 .6 0 .8 1 .0 1 .2 1 .4 1 .6 1 .8 2 .0 2 .2 2 .4 2 .6 2 .8 3 .0 3 .2
1 0 0
1 0 1
1 0 2
1 0 3
1 0 4
r=0.85 (p<0.0001)
****
Total anti-AAV5 (ELISA) and anti-AAV5 NAB measured
with a LUC-based assay show strong correlation
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Patient # * FIX activity
(basal)
* Median FIX acivity post
treatment (min-max)
* Pre-existing
anti-AAV5 NAB
titer, GFP-
based assay
Pre-existing
anti-AAV5
NAB titer,
LUC-based
assay
* Total pre-existing anti-AAV5 (ELISA)
Low dose cohort (5e12 gc/kg)
1 < 1% 6.6% (5.2-8.8) Negative < 4 Negative
2 < 1% 4.9% (4.0-7.2) Negative < 4 Negative
3 < 1% 1.3% (1.1-1.4) Negative 210 Positive (87)
4 1.5% 7.0% (5.6-11.5) Negative 340 Positive (256)
5 < 1% 3.1% (2.1-4.5) Negative 21 Negative
High dose cohort (2e13 gc/kg)
6 < 1% 11.9% (10.3-14.4) Negative < 4 Negative
7 < 1% 6.6% (3.2-10) Negative < 4 Negative
8 1% 7.8% (4.3-9.8) Negative < 4 Negative
9 1% 3.3% (2.7-5.5) Negative < 4 Negative
10 1% 6% (4.9-8.7) Negative < 4 Negative
siblings
* Leekbeek et.al, 2017 American Society of Hematology
A S G C T 2 0 1 8 1 9 M a y 2 0 1 8 | 8
0 5 1 0 1 5 2 0 2 5 3 0 3 5 4 0 4 5 5 0
0
21 0 4
41 0 4
61 0 4
81 0 4
11 0 5
1 .21 0 5
w e e k
To
tal
an
ti-A
AV
5 a
b
Ig G
Ig M
NAB: -
TAB: -
Patient 1 Patient 4
NAB: 210
TAB: + (87)
NAB: 340
TAB: + (256)
Patient 3
0 5 1 0 1 5 2 0 2 5 3 0 3 5 4 0 4 5 5 0
0
21 0 4
41 0 4
61 0 4
81 0 4
11 0 5
1 .21 0 5
w e e k
To
tal
an
ti-A
AV
5 a
b
0 5 1 0 1 5 2 0 2 5 3 0 3 5 4 0 4 5 5 0
0
21 0 4
41 0 4
61 0 4
81 0 4
11 0 5
1 .21 0 5
w e e k
To
tal
an
ti-A
AV
5 a
b
Patient 5
0 5 1 0 1 5 2 0 2 5 3 0 3 5 4 0 4 5 5 0
0
21 0 4
41 0 4
61 0 4
81 0 4
11 0 5
1 .21 0 5
w e e k
To
tal
an
ti-A
AV
5 a
b
NAB: 21
TAB: -
A S G C T 2 0 1 8 1 9 M a y 2 0 1 8 | 99
▪ Anti-AAV5 NAB titer as high as 340 did not impair the
efficacy of AAV5-FIX (AMT-060) therapy in human.
▪ The patient with the highest anti-AAV5 NAB titer had the
highest FIX activity in his dose cohort.
A S G C T 2 0 1 8 1 9 M a y 2 0 1 8 | 10
GROUPS IV injection of AAV5-FIX [gc/kg]
1. n=3 5 e11
2. n=5 5 e12
3. n=3 2.5 e13
4.n=3 9 e13
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No inhibition of liver transduction by AAV5 in NHP with pre-existing
anti-AAV5 NAB up to titer of 1030
% o
f h
FIX
in
th
e p
las
ma
A S G C T 2 0 1 8 1 9 M a y 2 0 1 8 | 1212
▪ Anti-AAV5 NAB titer as high as 340 did not impair the
efficacy of AAV5-FIX (AMT-060) therapy in human.
▪ Anti-AAV5 NAB titer as high as 1030 did not impair the
efficacy of AAV5-FIX (AMT-060) liver transduction in
NHP.
A S G C T 2 0 1 8 1 9 M a y 2 0 1 8 | 13
?
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97%
< 3 4 0 > 3 4 0
0
2 0
4 0
6 0
8 0
1 0 0
a n ti-A A V 5 (1 6 0 ) N A B t ite r
Nu
mb
er o
f s
am
ple
s
9 2 %
8 %
n = 1 0 0
< 1 0 3 0 > 1 0 3 0
0
2 0
4 0
6 0
8 0
1 0 0
a n ti-A A V 5 (1 6 0 ) N A B t ite r
Nu
mb
er o
f s
am
ple
s
9 7 %
3 %
n = 1 0 0
anti-AAV5 NAB titer in healthy donor sera
92% eligible
1 00
1 01
1 02
1 03
1 04
an
ti-
AA
V5
NA
B t
ite
r
1 0 3 0
3 4 0
2
n=100
53 donors (53%) <2
anti-AAV5 NAB 340 cut-off
97% eligible
anti-AAV5 NAB 1030 cut-off anti-AAV5 NAB >247%, median titer = 27
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anti-AAV5 titer
NAB >2: 47%
median titer = 27
mean titer= 453.9
anti-AAV8 titer
NAB >2: 37%
median titer = 87
mean titer= 805.6
anti-AAV2 titer
NAB >2: 49%
median titer = 97
mean titer= 4504
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anti-AAV5 titer
NAB >2: 47%
median titer = 27
mean titer= 453.9
anti-AAV8 titer
NAB >2: 37%
median titer = 87
mean titer= 805.6
anti-AAV2 titer
NAB >2: 49%
median titer = 97
mean titer= 4504
*
**
*Jiang et al., Blood 2006
** Manno et al., Nature Medicine 2006
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▪ 97% of all individuals can benefit from AAV5-based gene therapy
▪ 37% of individuals would be excluded from AAV8-based studies;
91.9% of these can still benefit from AAV5-based gene therapy
▪ 49% of individuals would be excluded from AAV2-based studies;
93.9% of these can still benefit from AAV5-based gene therapy
A S G C T 2 0 1 8 1 9 M a y 2 0 1 8 | 18