Sage Therapeutics, Inc. (SAGE): Lead Drug Is More Than Just A "Band-Aid" - A Scientific Response To The Short Report
$SAGE
A short report published on March 23 challenged the virtues of Sage’s lead drug candidate, SAGE-547. We consulted with one of our scientific advisors to revisit our assessment of the company’s lead program. The following report provides a more in-depth scientific analysis of SAGE-547 that rectifies the salient misconceptions presented in the short thesis.
-
The use of SAGE-547 is NOT intended to address the
underlying etiology of SRSE, but rather to help halt the seizure and wean the
patient off of the anesthetic. It is
just as imperative to halt the seizure and stop the administration of an
anesthetic as it is to address the underlying etiology. The longer a
patient is in SE/RSE/SRSE the greater the probability that he/she will
experience permanent neurological damage or death.
- Although SAGE-547 is a positive modulator of the GABAA receptor, such as many of the other GABAergic agents, the mechanism of action and the binding sites are in fact NOT identical to that of standard drugs used for SE/RSE/SRSE.
- Not only does SAGE-547 act as a positive allosteric modulator, but it also acts as an agonist with distinct binding sites from GABA, which is a unique property not shared with other allosteric modulators of GABAA receptors.
-
Any attempt to compare data from the SAGE-547 Phase
1/2 study with those of an ongoing prospective study with only preliminary
results published will be met with serious difficulties due to a
lack of consistency in protocol, definitions, and other important variables
such as quality of health management, availability, quality, and condition of
medical equipment used, and experience in dealing with SE/RSE/SRSE.
While all Phase 3 studies inherently involve a significant level of risk, assessing the likelihood of success of STATUS based on the superficial analysis from the short report poses a daring and unwise proposition.
Rather, the scientific virtues of SAGE-547 described in this analysis that debunk the salient features of the short report should be considered to better weigh the risk-reward of its outcome when it reports topline data in the second half of the year.
Sage Therapeutics, Inc. (SAGE):
Lead Drug
Is More T
han Just A “Band
-
Aid”
A Scientific Response To The Short Report
March 27, 2016
|
1
Sage Therapeutics, Inc. (SAGE)
Lead Drug
Is More
Than
Just
A “Band
-
Aid”
A
Scientific
Response
To
The
Short
Report
A
short
report publish
ed on March 23
challenged
the virtues of
Sage
’s
lead drug
candidate,
SAGE
-
547.
W
e consulted wi
th one of our
scientifi
c advisor
s
to revisit our
a
ssessment
of the company
’s lead program
.
The following re
port
provides a
more
in
-
depth
scientific analysis
of SAGE
-
547
that
rectifies
the
salient
misconceptions
presented
in the short thesis.
More Than Just A “Band
-
Aid”
By m
aking reference to SAGE
-
547 and other
pharmacological
agents used to control
seizures as
“
Band
-
A
ids
,
”
the short report
presents
a
considerable
dearth of knowledge
in (i) epilepsy and seizures, (ii) medical
approaches to handling seizures
and the reasons
fo
r th
ose protocols
, (iii)
the factual and theoretical reasons for entering refractory and
super refractory status epilepticus
and the urgency to remove the patients from
the state
of seizure
,
(iv)
the need to find new pharmacological age
nts that can reduce
the time a
patient remains
on an anesthetic and help wean
him/her
off the anesthetic without
seizure reoccurrence
, and
(v) the proposed role of SAGE
-
547 in SRSE.
SAGE
-
547 is
more than
just
a “Band
-
Aid” as
the reduction in
excitatory
brain activity is
exa
c
tly what is needed
for patients with epileptic disorders
. T
h
e GABA system is
inhibitory, yet
,
when
the
necessary inhibitory mechanism
does not occur
and there is
an
unsuccessful termination of seizure
activity
within an allocated time frame,
the
patien
t
d
evelop
s
a
condition known as
status epilepticus (SE)
.
A prominent leader in the field
has stressed the importance of dealing with SE quickly and effectively in a recent review
article:
“The therapeutic principle ‘time is brain’ applies not only for strok
e but also
for status epilepticus, as the prognosis of status epilepticus worsens with
increasing duration of seizure activity.”
1
While
resolving
the underlying etiology is
the ultimate goal
,
halting the seizures as
quickly as possible
, however,
is of gr
eat clinical relevance.
Sage Therapeutics, Inc. (SAGE):
Lead Drug
Is More T
han Just A “Band
-
Aid”
A Scientific Response To The Short Report
March 27, 2016
|
2
The State of Status Epilepticus
Since
a precise
definition of status epilepticus
(SE)
is currently evolving
1
,
it is more
appropriate to
encapsulate
this population under the umbrella of
patients with
general
seizure
s
,
including
tonic
-
clonic
seizures
,
which last
longer than five
minutes
.
Tonic
-
clonic status
affects 120,000
–
200,000 people in the U.S. annually.
2
The Neurocritical Care Society has published guidelines for physicians on how to treat
SE based on a consensus statem
ent and it includes a protocol with the following drug
regimen
3
:
1)
Treatment with 1
st
line drugs
lorazepam IV, midazolam IM, and rectal diazepam
2)
Followed by 2
nd
line drugs
IV fosphenytoin, valproate sodium, or levetiracetam
3)
Then 3
rd
line
treatment which re
commends
anesthetic drugs be titrated to burst
s
uppression or isoelectric EEG;
anesthetics used include
midazolam,
propofol,
pentobarbital/thiopental, isoflurane, and ketamine.
When 1
st
and 2
nd
lines of therapy fail
,
the SE becomes refractory and RSE is
established
.
When SE conti
nues or recurs after 24 hours on
3
rd
line drug dosing, the patient is
then
referre
d to as super RSE (SRSE).
It is estimated that 14.4K
–
86k of SE patients become
RSE.
3
The use of the term SRSE is new and has not
yet
caught
on
4
,
therefore, to estimate
the exact size of that population in the U.S. on an annual basis is
a
difficult
endeavor
.
Multiple mechanisms of drug resistance for SE have been deduced including events that
affect the activity of a particular ion chann
el called GABA
A
receptor. The family of
GABA
A
receptors
is heterogeneous and complex.
Overall, each GABA
A
receptor is
comprised of 5
-
protein subunits (fig. 1).
The subunits of the GABA
A
receptor are the
α
,
β
,
γ
,
δ
,
ε
,
ρ
,
θ
,
and
π
.
There are at least
19
subunits from which each receptor can be comprised of (fig. 2).
5
Sage Therapeutics, Inc. (SAGE):
Lead Drug
Is More T
han Just A “Band
-
Aid”
A Scientific Response To The Short Report
March 27, 2016
|
3
In general, the assembled 5
-
protein GABA
A
receptor is comprised of 2 α
-
subunits, 2 β
-
sub
units, and one γ
-
subunit.
The δ
and ε
-
su
bunits can substitute for the γ
-
subuni
t and it
i
s believed that the θ
-
subunit can substitute for the β.
5
-
6
As such,
multiple
“
flavors
”
of
the GABA
A
receptor
can be assembled
and each may have distinct
biophysical and
kinetic
behavior
,
distinct
regulation,
and a distinct response to pharmacological
agent
s (drugs).
7
As stated above, the GABA
A
receptor is involved in mechanisms underpinning drug
resistance in SE and this includes (i) loss of γ
-
aminobutyric acid (GABA) mediated
inhibition (ii) and GABA
A
receptor internalization. Receptor internalization mo
ves
the
receptor from the
cell
m
embrane into the cell where the receptors
can no longer mediate
chloride ion movement and the inhibitory effect.
Addressing
Criticisms
Within
The
Proper Context
With a clearer background of the GABA
A
receptor sys
tem,
we can address
the
criticisms
that have recently surfaced
within the proper context
.
A)
The use of
SAGE
-
547
is NOT
intended to
address
th
e underlying etiology of
SRSE, but rather to
help
halt the seizure and
wean
the patient
off of the
anesthetic
.
It
is just as imperative to halt the seizure
and stop the
administration of an anesthetic
as it is to ad
dress the underlying etiology.
The
Sage Therapeutics, Inc. (SAGE):
Lead Drug
Is More T
han Just A “Band
-
Aid”
A Scientific Response To The Short Report
March 27, 2016
|
4
longer a patient is in SE/RSE/SRSE the g
reater the probability that he/she
will
experience permanent neurological damag
e or death.
B)
Although SAGE
-
547 is a positive modulator of the GABA
A
receptor, such as
many of the other
GABAergic
agents, t
he mechanism of action
and the binding
sites
are
in fact NOT
identical to that of
standa
rd drugs used for SE/RSE/SRSE.
Additionally,
t
he
recent
criticism
states
,
“
a body of scientific research shows that
other anesthetics such as midazolam and propofol
” also work on both synaptic
and extra
-
synaptic GABA
A
receptors
.
W
hile this may be correct, one needs to
take into
account the “flavor” of GABA
A
receptor present at each of these sites,
the local concentration of each receptor type present
,
and their properties
.
Several
points of clarification can rectify
th
e misleading aspects of the
statement
s
.
I.
SAGE
-
547 binds to
multiple sites including
different site
s
th
an the other
agents mentioned.
A
ccording to
a
review article
which cites
work
published
in a tier
-
1 scientific journal
:
“Recently, studies have reported the presence of two distin
ct allopregnanolone
binding sites on the GABA
-
A receptor (Hosie et al., 2006) that are highly
conserved in all
α
subtypes of the GABA
-
A receptor.” (Hosie et al., 2009). These
domains mediate the potentiating and direct activation effects of neurosteroids by
binding to the α
-
subunit transmembrane domains and interfacial residues
between α and β
-
subunits, respective
ly. The authors suggest that significant
receptor activation by neurosteroids relies on occupancy of these domains (Hosie
et al., 2006).”
8
The aforementioned binding sites are unique and distinct
.
Not
only does
SAGE
-
547 act as a positive allosteric modulator, but it also acts as an
agonist with distinct binding sites from GABA
.
8
Moreover
,
a genetically modified mouse that has the δ subunit deleted (δ
−
/−
)
displays a dramatic reduction in sensitivity
to neurosteroids in vivo
as compared to mice that have the δ subunit (δ +/+)
when tested in an
assay for duration of sleep
after administration of neurosteroids
; this
indicates
that δ
-
containing GABA
A
receptors are an important target for
neurosteroids. I
n contrast
,
the δ −/− mice failed to
display
differences in
sleep time produced by
administration of
propofol, pentobarbital,
etomidate and ketamine when compared to δ +/+ mice,
indicat
ing
that
the
neur
osteroid
-
GABA
A
receptor physical interaction
s differ from the drugs
mentioned above
and some of its effects
are
mediated through unique
Sage Therapeutics, Inc. (SAGE):
Lead Drug
Is More T
han Just A “Band
-
Aid”
A Scientific Response To The Short Report
March 27, 2016
|
5
mechanism
(s)
that differs from other GABAergic agonists and
modulators
.
9
II.
Unlike benzodiazepines,
which enh
ance the channel o
pen frequency, or
barbiturates,
which
inc
rease the channel open duration
,
neurosteroids
increase
both the frequency and duration of the chloride channel
opening
.
10
-
15
III.
As stated above
,
multiple “flavors” of the GABA
A
receptor can be
assembled and each may have distinct biophy
sical and kinetic
behavior, distinct regulation, and a distinct response to
pharmacological agents (drugs).
Many of the extra
-
synaptic
GABA
A
receptors contain the
δ
-
subunit.
Drugs that bind to the benzodia
zepine
binding site require a γ
-
subunit and therefo
re do not modulate the
activity of those GABA
A
receptors.
A
s another example,
benzodiazepines
do not bin
d if the receptor contains the α
4
or α6
-
subunit.
Lastly,
ketamine
’s
a
llosteric properties
of GABA
A
receptors
are
limited to
the
α6β2δ and α6β3δ receptor
s.
1
6
Numerous additional examples abound
based on combinatorial factors, nevertheless, the point is clearly evident:
SAGE
-
547 binds to the receptors mentioned above and has the ability
to bind
a wide variety of
GABA
A
receptors because of the conserve
d
bind
ing sites present in all α
-
subunits, which certainly
makes it
unique.
8
C)
SA
GE never purported that SAGE
-
547 could “rewire axons”; they
only claim
that
it can
help stop and prevent seizures from coming back
during the period of
weaning the patients off of
an
esthetics.
D)
Many drugs,
not limited to but
including benzodiazepines
17
,
have the potential of
becoming tolerant; this
feature
is
hardly
unique to SAGE
-
547.
Tolerance
is
dependent on the dosage taken and made bioavailable, as well as the duration of
dosing.
At the proper exposure levels and duration of exposure to SAGE
-
547
,
tolerance
will
be a nonissue
.
E)
The c
ritics
inappropriately concluded from
an article published
in a scientific
journal
1
8
that
benzodiazepines and neurosteroids have the same
pharmac
ological
and
side effect profiles.
It
requires considerable emphasis that thes
e results are
conclusions for m
ice treated a particular way
to induce seizure
that
cannot
translate over to
humans
in SE.
A close read of the study and the methodology
used unque
stionably eliminates
the study
for use as a comparison between the
Sage Therapeutics, Inc. (SAGE):
Lead Drug
Is More T
han Just A “Band
-
Aid”
A Scientific Response To The Short Report
March 27, 2016
|
6
safety and efficacy of midazolam
and
SAGE
-
547
in human SRSE
.
The study cited
induces seizures in mice using picrotoxin, which binds to GABA receptors and
behaves as a negative allosteric mo
dulator
.
The experimental animal model of
epilepsy that uses picrotoxin to induce seizure is classified as a “simple partial,
acute” model of epilepsy.
Generalized seizure animal models, which include
“generalized tonic
-
clonic” and “generalized status epil
epticus”, are extremely
different.
1
9
Again, t
he
experimental model of seizures
that compared the efficacy
of allopregnanolone (SAGE
-
547) and midazolam differs greatly
from
seizures
seen in humans
in SRSE
;
thus,
the data cited by the critic is
inappropriate
for
comparison
and
not
translat
able
to humans
in SRSE
.
F)
The criticism failed to draw attention to the positive properties of
SAGE
-
547
such
as it
s
higher potency
than
m
any of the anesthetics
used as a
3
rd
line treatment
.
SAGE
-
547 is active at
nanomolar (nM) concentrations whereas pentobarbital and
propofol
and other commonly used drugs
require micromolar
(μM) to
millimolar
(mM) concentrations to reach si
milar efficacy thus making it
much more potent.
8
G)
An
y
attempt to compare data from the SAGE
-
547
Phase 1/2
study
with
those of
an ongoing prospective study with
only
preliminary results
published
20
will
be
met with serious
difficult
ies
due to a lack of
consistency in protocol, definitions,
and other important variables
such as quality of health management, availabili
ty
,
quality,
and condition of medical equipment used, and experience in dealing
with SE/RSE/SRSE
.
For example
,
the protocol for
initially treating
SE upon
diagnosis was not consistent:
Only 33% of
the cases used a 1
st
line drug
treatment
while
61% used 2
nd
line drugs and 6% used a 3
rd
line drug
at the start of
treatment. Also,
only
56%
of the cases used two or more
2
nd
line drugs
while
479
patients were reported to
receive an anesthetic. S
ince
the treatment
protocol
regimen
was not consistent
, the
74% recov
ery rate cited
cannot definitively
conclude which
patients
(SE or RSE or SRSE)
on what drug
therapy w
ere
part of
that statistic.
Furthermore, approximately 350 patients received a second anesthetic at
unknown variable time points and kept on the anesthet
ic for an unknown
duration of time (lack of consistency
, reporting,
and protocol)
; again, the status
of these patients (SE or RSE or SRSE) is not clear
.
The study also classified 413
patients into 3 categori
es: (i) recovered from SE (74%) (ii) patient die
d (22%)
(iii)
patie
nt withdrew from therapy (4%).
The category referring to ‘recovered from
SE’ is defined as seizure control only and does not include the time frame the
patient remained
on the anesthetic, or whether they were SE or RSE or SRSE,
nor
the n
eurological outcomes
.
As
has been made
evident, the
analysis of clinical
Sage Therapeutics, Inc. (SAGE):
Lead Drug
Is More T
han Just A “Band
-
Aid”
A Scientific Response To The Short Report
March 27, 2016
|
7
data
from the referenced study
used to compare results from
the SAGE
-
547
phase
1/
2 study lacks the proper scientific rigor
to be conclusive
and therefore
should not be considered
comp
arable
, as agreed by the authors of the study
when they made the following statement:
“
As a registry, it would not be possible to reach any definitive conclusion about efficacy
of treatments of refractory status epilepticus from these data.
”
20
H)
Moreover
, the author
s
from the
2012
published study
21
them
sel
ves
acknowledged
the pitfalls o
f any direct comparisons to
the data in
their
study
because of the
uncertainty of the q
uality and accurac
y of the data
used to create the statistical
profile of each drug
.
They
write
:
“These were, as mentioned above, largely anecdotal reports and each drug
cannot be compared with the others. Furthermore, a number of significant
potential b
iases exist.”
CONCLUSION
T
he salient misconceptions presented by the short report regarding SAGE
-
547 have
herein been shown
to be unfounded; 547 has not only clearly elucidated its unique
mechanism compared to other GABAergic agents, but rather it has also
thereby
substantiated the
phase 1/2
clinical results s
upporting
its
unique
mechanistic effects.
Furthermore, the short re
port draws conclusions with no solid evidence to defend its
claims
as well as
referenc
es
studies that are incongruous for proper comparison
,
which
translates to
an improper
assess
ment
of
the probability of success
of
the
upcoming
Phase
3 study
call
ed
STATUS
.
While all Phase 3 studies inherently
involve a significant level of risk,
assessing
the
likelihood of success
of STATUS
based on the superficial analysis from the short report
poses
a daring and unwise proposition.
Rather, the scientific
virtues of SAGE
-
547
described in th
is
analysis that debunk the salient features of the short report should be
considered to better weigh the risk
-
reward of its outcome
when it reports topline data
in
the second half of the year.
SCIENTIFIC ADVISORS
Pete
Stavropoulos, PhD, currently serves as a Senior Research Associate at The
Rockefeller University. He is also a scientific consultant to Asclepia Capital providing
his expertise in the field of pharmacology
and the biological sciences
in assessing the
virt
ues of potential drug candidates like SAGE
-
547.
Sage Therapeutics, Inc. (SAGE):
Lead Drug
Is More T
han Just A “Band
-
Aid”
A Scientific Response To The Short Report
March 27, 2016
|
8
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Is More T
han Just A “Band
-
Aid”
A Scientific Response To The Short Report
March 27, 2016
|
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-
refractory convulsive status epilepticus and recommendations for therapy.
Brain. 2012 Aug;135(Pt 8):2314
-
28.
Sage Therapeutics, Inc. (SAGE):
Lead Drug
Is More T
han Just A “Band
-
Aid”
A Scientific Response To The Short Report
March 27, 2016
|
10
DISCLOSURES
As of the publication date of this report, Asclepia Capital LLC
(
“Asclepia”)
has a
long
position in the stock of Sage
Therap
eutics, Inc. (“SAGE”) and
stand
s
to realize gains in the event that the price of the stock increases. Following
the
p
ublication of the report, Asclepia may transact in the securities of the company covered herein. All content in this report
represent the opinions of Asclepia. Asclepia has obtained all information herein from sources it believes to be accurate
and reliabl
e. Asclepia makes no representation, express
ed
or implied, as to the accuracy, timeliness, or completeness of
any such information or with regard to the results obtained from its use. All expressions of opinion are subject to change
without notice, and Asc
lepia does not undertake to update or supplement this report or an
y information contained herein.
This document is for informational p
urposes only and
is not intended as an official confirmation of any transaction. The
information included in this document
is based upon selected public market data and reflects prevailing conditions and
Asclepia’s views as of this date, all of which are accordingly subject to change. Asclepia’s opinions and estimates
constitute a best efforts judgment and should be regarded
as indicative, preliminary and
for illustrative purposes only.
Any investment involves substantial risks, including, but not limited to, pricing volatility, inadequate liquidity, and the
potential complete loss of principal. This report’s estimated fundame
ntal value only represents a best efforts estimate of
the potential fundamental valuation of a specific security, and is not expressed as, or implied as, assessments of the
quality of a security, a summary of past performance, or an actionable investment s
trategy for an investor. This document
does not in any way constitute an offer or solicitation of an offer to buy or sell any investment, security, or commodity
discussed herein or of any of the affiliates of
Asclepia. Also, this document does not in a
ny way constitute an offer or
solicitation of an offer to buy or sell any security in any jurisdiction in which such an offer would be unlawful under the
securities laws of such j
urisdiction. To the best of
Asclepia’s abilities and beliefs, all information
contained h
erein is
accurate and reliable.
The information contained in this document may include, or incorporate by reference, forward
-
looking statements, which would include any statements that are not statements of historical fact. Any or all of Asclep
ia’s
forward
-
looking assumptions, expectations, projections, intentions or beliefs about future events may turn out to be
wrong. These forward
-
looking statements can be affected by inaccurate assumptions or by known or unknown risks,
uncertainties and othe
r factors, mos
t of which are beyond
Asclepia’s control. Investors should conduct independent due
diligence, with assistance from professional financial, legal and tax experts, on all securities, companies, and commodities
discussed in this document and dev
elop a stand
-
alone judgment of the relevant markets prior to making any investment
decision.
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