1. The
role
of
stabilized
neuropep3des
derived
from
hyperimmune
caprine
sera
(HICS)
in
motor
neuron
disease
–
implica3ons
for
a
novel
therapeu3c
strategy
in
ALS
pa3ents
Ahtoniemi
T.,
Oksman
J.,
Leh3mäki
K.,
Cerrada-­‐Gimenez
M.,
Westlake
A.,
Haq
M.,
Var3ainen
N.,
McIntosh
D,
Moore
C.,
Force
T,
Heinman-­‐Paderson
T,
and
Syed
Haq
United
Kingdom,
Portsmouth
Hospitals
NHS
Trust,
Hampshire,
United
Kingdom,
Center
for
Transla4onal
Charles
River
Discovery
Research
Services,
Kuopio,
Finland,
Maidstone
and
Tunbridge
Hospital
NHS
Trust,
Kent,
1
1
1
1
6
1
2
1
6
2
4
5
6
3
4
Medicine
Temple
University,
Philadelphia
PA,
USA,
5Drexel
University
College
of
Medicine,
Philadelphia
PA,
USA
and
6Daval
Interna4onal
Limited,
Eastbourne,
East
Sussex,
United
Kingdom
6
To
determine
if
targe.ng
of
the
extra-­‐hypothalamic
and
hypothalmo-­‐
pituitary-­‐adrenal
axis
by
a
protein-­‐pep.de
complex
of
α-­‐2
macroglobulin
and
cor.cotrophin
releasing
hormone
in
human
ALS
pa.ents
could
elicit
measurable
efficacy
as
part
of
an
open-­‐label
study
2
Primary
Endpoints
Survival
ALSFRS-R
BACKGROUND
• Hyper-­‐immune
caprine
serum
(HICS)/AIMSPRO®
is
raised
to
inac.vated
HIV
IIIB
viral
lysate
-­‐
subjected
to
stringent
tes.ng
regimens
before
dispatch
§ Serum
is
obtained
from
a
herd
of
cer.fied
prion-­‐free
goats
raised
&
housed
at
a
TGA-­‐approved
facility
in
Tasmania
§ AIMSPRO®/SSR-­‐CRH
is
manufactured
in
an
approved/MHRA
audited
facility
in
the
UK
§ The
serum
is
frac.onated
&
diafiltered
to
preserve
immunoglobulin
species
&
therapeu.cally-­‐ac.ve
small
molecular
weight
components
§ The
drug
is
a
finished
product
supplied
as
a
frozen
1.1mL
(4.5mg/ml)
clear
solu.on
for
subcutaneous
injec.on
A.
α-­‐2
macroglobulin
is
composed
of
four
iden.cal
subunits.
Protease
enzymes
naturally
target
CRH,
thereby
under
normal
circumstances
leading
to
a
foreshortened
half-­‐life
in
vivo.
B.
Degrada.on
is
prevented
as
the
protease
molecules
bind
to
the
CRH
/
α-­‐2
macroglobulin
complex
on
a
specific
thiol
group,
rendering
the
proteases
inert
under
certain
circumstances.
C.
This
allows
the
complex
to
protect
CRH
from
proteoly.c
degrada.on
prior
to
release
in
vivo
by
covalently
binding
and
“caging”
the
protease
from
ac.ve
CRH
5
•
SVC
Secondary Endpoints
ALSAQ-40
Measurements
Description of results
! Length of survival with reference
to historical survival statistics
Stable disease state with no
deterioration on a F/U duration > 612 months
Increase of 7.8%
! Amyotrophic Lateral Sclerosis
Functional Rating Scale is scored
from 0-48 at the start and end of
the study to measure rate of
decline
! Twelve question questionnaire
asking about daily activities and
how much help a patient needs
with each and some questions are
asked about specific symptoms
! Slow Vital Capacity measurement
of respiratory decline taken using
formal lung function testing
Measurements
!
METHODOLOGY
!
Study Design - ALS
Rx Group – AIMSPRO® once daily dosing
MANUFACTURING/QUALITY
CONTROL
Open-Label Phase AIMSPRO®
Screening
ALSS – Jablecki
!
N = 20+ subjects
Bulbar (10%): Limb (90%) onset
0
4 hours
3 months
Baseline Samples,
Samples,
Measures & Scores
Measures & Scores
The
molecular
and
proteomic
analysis
of
AIMSPRO®/SSR-­‐CRH
has
been
carried
out
using
SELDI-­‐TOF
mass
spectrometry
and
1-­‐D
and
2-­‐D
gel
electrophoresis
with
proteomic
analysis.
Pep.de
capture
from
AIMSPRO®
using
immobilised
monoclonal
or
polyclonal
an.bodies
(where
appropriate)
was
used
to
detect
peaks
that
matched
the
predicted
molecular
mass
for
specific
molecular
species.
Specificity
was
demonstrated
and
confirmed
with
the
use
of
a
number
of
irrelevant
control
an.bodies
3
Kine3cs
of
SSR-­‐CRH
Murine
Serum
CRH
-­‐
PK
Study
30
HICS
P<0.002
25
Naïve
Sera
CRH
pg/mL
20
15
10
5
0
0.5
1
3
Time
(hr)
6
24
48
q SSR-­‐CRH
–
stabilised-­‐slow
release
CRH
q hCRH
has
a
normal
–
t
½
=
4.5
min
q SSR-­‐CRH
–
t
½
=
24hr
q Single
dose
study
(100µg
stat)
q n=6
animals
per
.me
point
q Naïve
sera
control
q P<0.002
ANOVA
6 months
Samples,
Measures & Scores
9 months
Samples,
Measures & Scores
12 months
Samples,
Measures &
Scores
The
primary
objec.ve
of
the
study
was
to
prospec.vely
analyse
the
safety,
tolerability
and
efficacy
of
hyperimmune
caprine
serum
(AIMSPRO®)
in
confirmed
ALS
that
was
conducted
in
a
mul.-­‐centre
study
in
the
UK,
Brazil,
France,
Portugal,
Ireland,
Australia
and
South
Africa
by
registered
clinicians
(neurologists
and
physicians)
with
con.nued
follow-­‐up
and
analysis
Criteria
for
Evalua3on:
The
pa.ents
were
both
ambulant
and
non-­‐ambulant,
aged
≥18
years,
with
independently
confirmed
Amyotrophic
Lateral
Sclerosis
and
treated
on
a
daily
basis
with
1mL
(4.5mg/mL)
of
AIMSPRO®
§ A
prospec.ve
analysis
of
pa.ents
was
undertaken
by
mul.ple
clinicians
with
experience
in
the
diagnosis
and
management
of
ALS
§ A
number
of
standardised
criteria
were
used
to
assess
the
progress
of
pa.ents
from
the
.me
of
enrolment
to
the
present
day.
These
include
func.onal
assessments
and
ra.ng
scales;
ALSFRS-­‐R,
ALSAQ-­‐40,
ALS
score
of
Hillel
and
the
ALS
score
of
Jablecki,
together
with
repeat
full
blood
profiles
(at
entry
and
serially
at
intervals
of
every
three
months),
ECG,
respiratory
func.on
tes.ng
(SVC,
FVC
and
FEV1)
and
clinical
examina.on
by
several
clinicians
at
each
study
site
§ The
ALSFRS-­‐R
refers
to
the
Amyotrophic
Lateral
Sclerosis
Func.onal
Ra.ng
Scale
and
is
scored
from
0-­‐48
at
the
start
and
end
of
the
study
to
measure
rate
of
decline.
Twelve
ques.on
ques.onnaire
asking
about
daily
ac.vi.es
and
how
much
help
a
pa.ent
needs
with
each
and
some
ques.ons
are
asked
about
specific
symptoms
§ Forced
Vital
Capacity
(FVC)
measurement
of
respiratory
decline
was
taken
using
formal
lung
func.on
tes.ng
and
independently
performed
at
all
.mes
in
a
lung
func.on
laboratory
§ The
ALSAQ-­‐40
(ALS
assessment
ques.onnaire-­‐40)
is
a
40
item/ques.on
profile
in
which
5
areas
are
assessed;
physical
mobility
(x10),
ac.vi.es
of
daily
living
and
independence
(x10),
ea.ng
and
drinking
(x3),
communica.on
(x7)
and
emo.onal
reac.ons
(x10)
-­‐
pa.ents
are
asked
to
think
about
the
difficul.es
they
may
have
experienced
during
the
last
two
weeks
and
to
indicate
the
frequency
of
each
event
by
selec.ng
one
of
5
op.ons
on
the
Likert
scale:
never,
rarely,
some.mes,
osen,
always
or
cannot
do
at
all
§ The
ALS
score
of
Jablecki
is
used
to
monitor
a
pa.ent's
decline
in
ability
over
.me
by
assessing
12
areas:
speech,
swallowing,
respira.on,
ambula.on,
upper
extremity
strength
right,
upper
extremity
strength
les,
upper
extremity
survey
score
right,
upper
extremity
survey
score
les,
lower
extremity
strength
right,
lower
extremity
strength
les,
lower
extremity
survey
score
right
and
lower
extremity
survey
score
les
Scored
from
0-­‐40,
where
the
higher
the
score
the
greater
the
disability
Score
can
be
used
to
calculated
percentage
improvement
from
baseline
§ Digital
strain-­‐gauge
is
used
for
evalua.ng
subjects’
maximum
strength
of
grip
§ Safety
–
adverse
events
were
recorded
and
collated
as
change
from
baseline
(prior
to
therapy)
and
post-­‐dose
during
the
en.re
treatment
period
!
!
Digital dynamometer (fixedhand)
BMI
7
RESULTS
(1)
!
!
FVC
!
AE/SAE
!
Mean change in ALSFRS-R predose -0.523±0.069
Mean change in ALSFRS-R postdose 0.51±0.158
Statistics
(Open)
-
A
P<0.05
P<0.0001
10
2
1
0
-1
0
-10
-20
-30
-40
Pre-AIMSPRO
Post-AIMSPRO
Pre-AIMSPRO Post-AIMSPRO
p<0.0001
p<0.0001
No change from baseline
-
Statistics
Improvement of 15.0% from baseline
(Open)
P<0.05
A.
The
mean
monthly
rate
of
change
in
ALSFRS-­‐R
score
pre
and
post
the
administra.on
of
AIMSPRO
was
measured.
22
pa.ents
received
AIMSPRO
with
varying
numbers
of
doses
over
different
.me
periods.
The
ALSFRS-­‐R
deteriora.on
in
pa.ents
pre
AIMSPRO
treatment
was
observed
with
a
mean
decline
of
-­‐0.523±0.069
units
per
month.
However,
during
the
treatment
phase
AIMSPRO
pa.ents
showed
a
dis.nct
stabilisa.on
and
0.516±0.158
units
per
month
improvement
in
ALSFRS-­‐R
score
This
result
was
a
sta.s.cally
significant
change
(p<0.0001)
B.
Absolute
change
in
ALSFRS-­‐R
pre-­‐treatment
was
-­‐12.8±2.1
units,
whilst
post-­‐treatment
showed
sta.s.cally
significant
stabilisa.on
(+0.778±0.962
units,
p<0.0001)
C
D
2
0
Improvement of 11.4% from baseline
P<0.05
-2
10
0
-10
-4
-20
-6
-30
Pre-AIMSPRO
Post-AIMSPRO
Pre-AIMSPRO
Increase of 9.6% from baseline
P<0.05
Increase of 4.2% from baseline
Mean%-change in BMI pre-dose -9.8%
Mean %-change in BMI post-dose +1.57%
Mean change in FVC pre-dose -17.0±5.0%
Mean change in FVC post-dose +5.2±3.0%
P<0.05
No recorded AEs/SAEs
-
P<0.002
P<0.011
C.
The
change
in
BMI
has
been
shown
to
be
a
prognos.c
indicator
in
ALS.
When
measured
pre
and
post
AIMSPRO
treatment,
the
rate
of
decline
of
BMI
was
-­‐2.16±0.54
kg/m2
compared
to
+0.38±0.31
kg/m2
(p=0.002)
D.
The
change
in
BMI
pre
and
post
the
administra.on
of
AIMSPRO
shows
deteriora.on
of
pa.ents
pre
AIMSPRO
treatment
(mean
9.80%
decline
in
BMI)
and
dis.nct
stabilisa.on
post
AIMSPRO
treatment
(1.57%
improvement
in
BMI)
(p=0.002)
D
T2W
MRI
–
TG
mice
The
majority
of
adverse
events
centred
around
a
mild
skin
site
reac.on
from
the
subcutaneous
delivered
injec.on.
The
effect
was
only
temporary
and
was
noted
within
the
first
dozen
injec.ons.
Aser
which
.me
the
issue
resolved
with
importantly
no
recurrence.
In
terms
of
serious
adverse
events
(deaths),
no
recorded
deaths
was
noted
over
the
study.
It
should
be
noted
that
a
longer
analysis
period
and
larger
cohort
should
be
monitored
to
determine
the
relevance
of
this
finding.
Post-AIMSPRO
p=0.002
p=0.002
In
Study
Adverse
Events
T2W
MRI
–
WT
mice
B
3
-2
Description of results
40 items/questions in 5 areas are assessed:
physical mobility (x10), activities of daily living
and independence (x10), eating and drinking
(x3), communication (x7) and emotional
reactions (x10)
Patients are asked to think about the difficulties
they may have experienced during the last two
weeks and to indicate the frequency of each
event by selecting one of 5 options on the
Likert scale: never, rarely, sometimes, often,
always or cannot do at all
Used to monitor a patient's decline in ability
over time by assessing 12 areas: speech,
swallowing, respiration, ambulation, upper
extremity strength right, upper extremity
strength left, upper extremity survey score
right, upper extremity survey score left, lower
extremity strength right, lower extremity
strength left, lower extremity survey score right
and lower extremity survey score left
Scored from 0-40, where the higher the score
the greater the disability
Score can be used to calculated percentage
improvement from baseline
Digital strain-gauge is used for evaluating
subjects’ maximum strength of grip
Proxy for estimating human body fat based on
the function of an individual's weight divided by
height
Pulmonary Function Testing incorporating
standard spirometry was used to determine
Forced Vital Capacity (%pred or litre)
Adverse Event and Serious Adverse Event
reporting
RESULTS
(2)
Change in ALSFRS-R
MECHANISM
OF
ACTION
% Change in BMI
4
Mean monthly rate of change
(ALSFRS-R)
OBJECTIVES
Change in BMI
1
0.25
3
8
D.
The
average
pre-­‐AIMSPRO
treatment
rate
of
deteriora.on
in
absolute
FVC
was
-­‐17.0±5.0,
whilst
pa.ents’
post-­‐AIMSPRO
treatment
showed
significant
stabilisa.on
(+5.2±3.0).
This
was
a
sta.s.cally
significant
result
(p=0.0011)
CONCLUSION
HICS/AIMSPRO®
showed
efficacy
in
humans
with
ALS
in
ALSFRS-­‐R,
BMI
and
FVC
with
no
safety
concerns
or
serious
adverse
event
recorded.
This
confirmed
the
safety
profile
of
the
drug
once
again
as
seen
in
two
separate
phase
II
clinical
trials
recently
completed
(please
refer
to
www.clinicaltrials.gov.
#Correspondence:
Professor
Syed
Haq,
Daval
Interna.onal
Ltd.,
4a
Gildredge
Road,
Eastbourne,
East
Sussex,
BN21
4RL
United
Kingdom
Email:
syed.haq@davalinterna4onal.com