Epilepsia Open,
Journal Year:
2025,
Volume and Issue:
unknown
Published: May 24, 2025
Abstract
By
targeting
the
underlying
etiology,
precision
therapies
offer
an
exciting
paradigm
shift
to
improve
stagnant
outcomes
of
drug‐resistant
epilepsies,
including
developmental
and
epileptic
encephalopathies.
Unlike
conventional
antiseizure
medications
(ASMs)
which
only
treat
symptoms
(seizures)
but
have
no
effect
on
disease,
potential
suppress
not
seizures
also
disabling
comorbidities,
cognitive
behavioral
abnormalities,
share
same
causative
mechanisms.
Monogenic
epilepsies
are
attractive
target
for
because
their
well‐defined
molecular
mechanisms
can
be
tested
in
vitro
counteracted
by
specific
drugs.
Unfortunately,
however,
vast
majority
proposed
therapies,
evidence
clinical
efficacy
is
either
non‐existent
or
limited
uncontrolled
observational
accounts.
Everolimus
sole
therapy
with
a
seizure‐related
indication
class
I
efficacy,
highlighting
practical
ethical
challenges
obtaining
high‐level
evidence.
Here,
we
review
landscape
candidate
repurposed
innovative
treatments
currently
development,
discuss
lessons
learned
from
use,
highlight
strategies
application
evaluation
setting.
Plain
Language
Summary
Precision
new
approach
monogenic
that
is,
caused
defect
single
gene.
traditional
medications,
cause
disease
seizure
control
concomitant
conditions
such
as
disorders.
To
date,
derived
use
most
limited.
This
explores
current
advance
development.
Epilepsia,
Journal Year:
2024,
Volume and Issue:
65(10), P. 2831 - 2857
Published: July 15, 2024
Abstract
For
>30
years,
the
Eilat
Conference
on
New
Antiepileptic
Drugs
and
Devices
has
provided
a
forum
for
discussion
of
advances
in
development
new
therapies
seizures
epilepsy.
The
EILAT
XVII
conference
took
place
Madrid,
Spain,
May
5–8,
2024.
Participants
included
basic
scientists
clinical
investigators
from
industry
academia,
other
health
care
professionals,
representatives
lay
organizations.
We
summarize
this
article
information
treatments
preclinical
early
discussed
at
conference.
These
include
AMT‐260,
gene
therapy
designed
to
downregulate
expression
Glu2K
subunits
kainate
receptors,
treatment
drug‐resistant
associated
with
mesial
temporal
sclerosis;
BHV‐7000,
selective
activator
heteromeric
Kv7.2/7.3
potassium
channels,
focal
epilepsy;
ETX101,
recombinant
adeno‐associated
virus
serotype
9
increase
Na
V
1.1
channel
density
inhibitory
γ‐aminobutyric
acidergic
(GABAergic)
neurons,
SCN1A
‐positive
Dravet
syndrome;
GAO‐3‐02,
compound
structurally
related
synaptamide,
which
exerts
antiseizure
activity
least
part
through
an
action
cannabinoid
type
2
receptors;
LRP‐661,
structural
analogue
cannabidiol,
Lennox–Gastaut
syndrome,
tuberous
sclerosis
complex;
OV329,
inactivator
GABA
aminotransferase,
seizures;
PRAX‐628,
functionally
potent
sodium
modulator
preference
hyperexcitable
state
RAP‐219,
negative
allosteric
transmembrane
α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic
acid
receptor
regulatory
protein
γ‐8,
rozanolixizumab,
humanized
anti‐neonatal
Fc
monoclonal
antibody,
LGI1
autoimmune
encephalitis.
Treatments
more
advanced
are
summarized
Part
II
report.
Biomedical Chromatography,
Journal Year:
2025,
Volume and Issue:
39(2)
Published: Jan. 17, 2025
ABSTRACT
Bexicaserin
is
a
highly
selective
agonist
at
the
5‐HT
2c
receptor
in
clinical
development
for
treatment
of
seizures
associated
with
developmental
and
epileptic
encephalopathies
(DEEs).
We
report
an
LC–MS/MS
method
quantitative
estimation
bexicaserin
human
plasma
urine.
The
sample
preparation
involves
extraction
internal
standard
(
13
CD
2
‐bexicaserin;
IS)
from
150
μL
50
urine
using
solid
phase
method.
chromatographic
separation
IS
was
achieved
on
Poroshell
EC‐C18
column
5
min
gradient
program.
calibration
curve
ranged
0.1
to
100
ng/mL
1.0
1000
Intraday
interday
precision
accuracy,
linearity,
matrix
effect,
recovery,
carry‐over,
dilution
integrity,
battery
stability
studies,
incurred
reanalysis
were
performed
both
intraday
accuracy
well
within
acceptable
limits
matrices.
Stability
studies
showed
that
stable
bench
24
h,
autosampler
over
54
five
freeze–thaw
cycles,
long‐term
storage
−20°C
−80°C
>
368
days.
validated
methods
successfully
applied
study.
CNS Drugs,
Journal Year:
2025,
Volume and Issue:
unknown
Published: Jan. 24, 2025
Voltage-gated
Kv7
potassium
channels,
particularly
Kv7.2
and
Kv.7.3
play
a
critical
role
in
modulating
susceptibility
to
seizures,
mutations
genes
that
encode
these
channels
cause
heterogeneous
epilepsy
phenotypes.
On
the
basis
of
this
evidence,
activation
has
long
been
considered
an
attractive
target
search
for
novel
antiseizure
medications.
Ezogabine
(retigabine),
first
Kv7.2/3
activator
introduced
2011
treatment
focal
was
withdrawn
from
market
2017
due
declining
use
after
discovery
its
association
with
pigmentation
changes
retina,
skin,
mucosae.
A
formulation
ezogabine
pediatric
(XEN496)
recently
investigated
children
KCNQ2-related
developmental
epileptic
encephalopathy,
but
trial
terminated
prematurely
reasons
unrelated
safety.
Among
openers
clinical
development,
azetukalner
shown
dose-dependent
efficacy
against
drug-resistant
seizures
good
tolerability
profile
no
evidence
pigmentation-related
adverse
effects
early
studies,
it
is
now
under
investigation
phase
III
trials
generalized
tonic-clonic
major
depressive
disorder.
Another
activator,
BHV-7000,
completed
I
studies
healthy
subjects,
excellent
at
plasma
drug
concentrations
exceed
median
effective
preclinical
model
anticonvulsant
activity,
data
patients
are
available
date.
other
activators
development
as
potential
medications,
pynegabine
CB-003
have
safety
pharmacokinetic
results
not
yet
reported.
Overall,
interest
targeting
indications
remains
strong.
Future
breakthroughs
area
could
come
exploitation
mechanistic
differences
action
activators,
molecules
combine
mechanisms
action.
Pharmacology & Therapeutics,
Journal Year:
2025,
Volume and Issue:
unknown, P. 108808 - 108808
Published: Feb. 1, 2025
Out
of
37
antiseizure
medications
(ASMs)
currently
in
the
market,
17
are
chiral
molecules
and
an
additional
one
(oxcarbazepine)
is
a
prodrug
compound
licarbazepine.
Of
ASMs,
six
(ethosuximide,
fenfluramine,
methsuximide,
mephobarbital,
stiripentol
vigabatrin)
marketed
as
racemates,
remainder
licensed
enantiomerically
pure
medicines.
note,
all
ASMs
introduced
prior
to
1990
were
racemates.
Stiripentol,
fenfluramine
vigabatrin
only
racemic
approved
by
FDA
>10
years
after
release
regulatory
guidelines
on
development
Despite
fact
that
pharmacokinetic
pharmacodynamic
differences
between
enantiomers
have
been
recognized
for
decades,
importance
chirality
understanding
biological
actions
not
widely
appreciated,
many
recent
publications
refer
these
if
they
single
molecular
entity.
In
present
article,
we
provide
critical
review
developed
1920s,
when
mephobarbital
was
introduced,
2022,
last
ASM
(ganaxolone)
approved.
We
summarize
available
data
stereoselective
pharmacokinetics
pharmacodynamics
also
discuss
aspects
related
introduction
medicines
within
current
scenario
Europe
U.S.,
focusing
stiripentol,
examples
different
approaches.
identified
number
knowledge
gaps
relevant
use
drugs
epilepsy,
including
remarkable
lack
published
information
comparative
pharmacokinetics,
toxicity
activity
most
ASMs.
The
clinical
discussed,
together
with
rationale
follow-up
compounds
potentially
improved
efficacy,
safety
commercial
viability.
Deleted Journal,
Journal Year:
2025,
Volume and Issue:
unknown
Published: Jan. 15, 2025
Zusammenfassung
Zur
Behandlung
der
Epilepsien
stehen
zahlreiche
anfallssuppressive
Medikamente
(ASM)
zur
Verfügung,
die
auf
Basis
klinischer
Studien
für
bestimmte
Indikationen
und
Altersgruppen
zugelassen
sind.
Allerdings
erfordert
Vielzahl
verschiedener
Epilepsietypen
Syndrome
häufig
einen
Off-label-Einsatz
von
ASM,
wenn
Patienten
unter
aktuellen
Therapie
nicht
anfallsfrei
werden
oder
diese
vertragen.
Ähnliches
gilt
Verwendung
verschiedenen
immunsuppressiven
Medikamenten
Anfällen
Epilepsien,
infolge
autoimmuner
Enzephalitiden
auftreten,
mit
dem
Unterschied,
dass
hier
bisher
keinerlei
zugelassene
Substanzen
existieren.
Der
Off-label-Use
beschreibt
Anwendung
eines
Medikaments
außerhalb
zugelassenen
Indikationen,
Dosierungen
Altersgruppen.
Insbesondere
in
Epilepsietherapie
tritt
dies
auf,
etwa
bei
Kindern
Zulassungsalter,
generalisierten
entwicklungsbedingten
epileptischen
Enzephalopathien.
Obwohl
zusätzliche
Behandlungsoptionen
bietet,
führt
es
zu
einigen
Herausforderungen
klinischen
Praxis.
Es
fehlen
oft
klinische
Daten
Sicherheit
Wirksamkeit,
was
Unsicherheiten
Bezug
Dosierung
Nebenwirkungen
führen
kann.
Eine
sorgfältige
Aufklärung
ihrer
Angehörigen
über
Nutzen
Risiken
ist
daher
essenziell,
ebenso
wie
eine
umfassende
Dokumentation
Entscheidungsfindung.
Da
regelhaft
den
Kostenträgern
übernommen
wird,
–
insbesondere
kostenintensiven
neueren
Patentschutz
vorherige
Klärung
Kostenübernahme
sinnvoll,
um
wirtschaftliche
vermeiden.
Clinical Pharmacology in Drug Development,
Journal Year:
2025,
Volume and Issue:
unknown
Published: March 27, 2025
Abstract
Soticlestat
(TAK‐935)
is
a
cholesterol
24‐hydroxylase
inhibitor.
A
physiologically‐based
pharmacokinetic
model
has
been
developed
to
predict
potential
soticlestat
drug–drug
interactions
(DDIs)
using
the
Simcyp
v20
Population‐based
Simulator
and
verified
with
data
from
single‐/multiple‐rising‐dose
clinical
DDI
studies.
Simulated
area
under
plasma
concentration–time
curve
0
infinity
(AUC
0‐inf
)
maximal
drug
concentration
(C
max
based
on
were
generally
within
2‐fold
of
observed
values
for
all
doses.
Model‐simulated
versus
AUC
C
geometric
mean
ratios
(GMRs)
with/without
itraconazole
(potent
cytochrome
P450
[CYP]
3A
inhibitor),
mefenamic
acid
UDP
glucuronosyltransferase
[UGT]
1A9
inhibitor)
≤1.10‐fold.
As
primarily
metabolized
by
UGT
enzymes
incorporates
rifampin's
induction
CYP3A
only,
underpredicted
soticlestat's
rifampin.
However,
user‐defined
rifampin
induction,
predicted
GMR
was
1.5‐fold
value,
meeting
acceptance
criteria.
Hence,
appropriate
evaluating
DDIs
inhibitors
inducers
not
evaluated
in
studies;
low/not
clinically
relevant
(<50%
impact
exposure).
Furthermore,
no
significant
following
coadministration
sensitive
CYP2C8,
CYP2C9,
CYP2C19,
CYP3A4,
P‐glycoprotein
substrates.
Seminars in Neurology,
Journal Year:
2025,
Volume and Issue:
45(02), P. 287 - 297
Published: April 1, 2025
Abstract
Since
the
first
antiseizure
medication
(ASM)
was
introduced
in
1857,
more
than
30
medications
have
been
approved
by
United
States
Food
and
Drug
Administration
(FDA)
for
treatment
of
epilepsy.
However,
limitations
efficacy
tolerability
led
to
one-third
patients
suffering
from
uncontrolled
seizures.
Recent
advances
genetics,
disease
modeling,
high-throughput
target-based
phenotype-based
screening,
study
design,
identification
novel
mechanisms
action
or
routes
delivery
resulted
200
therapeutics
currently
under
development
epilepsy
pipeline.
This
discusses
near-to-market
drugs
advanced
clinical
development,
with
select
earlier
stages.
Background
regarding
mechanisms,
animal
studies,
pharmacokinetics,
pharmacodynamics,
efficacy,
tolerability,
safety
data
are
provided
each
drug
when
available.