wileyonlinelibrary.com/journal/ane Acta Neurol Scand. 2018;137:376–377.
© 2018 John Wiley & Sons A/S.
Published by John Wiley & Sons Ltd
Adjunctive perampanel for partial- onset seizures
Perampanel, a selective, non- competitive, AMPA receptor antagonist,
is approved in >50 countries for adjunctive treatment of partial- onset
seizures (POS), with or without secondarily generalized seizures, and
for primary generalized tonic- clonic seizures in patients with epilepsy
aged ≥12 years. In the United States, perampanel was recently ap-
proved for monotherapy use for POS in patients with epilepsy aged
Approvals for POS were based on three randomized,
double- blind, placebo- controlled phase III studies (Studies 304, 305,
and 306), in which adjunctive perampanel 4- 12 mg/d reduced the
frequency of POS compared with placebo.
Study 335 (NCT01618695), a randomized, double- blind, placebo-
controlled phase III trial, evaluated the efficacy, safety, and tolerability
of adjunctive perampanel (4- 12 mg/d) in an Asia- Pacific population
with refractory POS. This study provided an opportunity to explore
regional similarities and differences compared with the predominantly
Caucasian populations who had participated in Studies 304, 305, and
Efficacy and safety outcomes from Study 335 were similar
to the previous phase III studies, supporting a consistent profile for
perampanel across different populations with POS.
In Studies 304 and 305, perampanel 12 mg/d did not appear to
offer additional efficacy benefits compared with 8 mg/d,
log- linear relationship between perampanel exposure and efficacy.
Therefore, Study 335 explored the perampanel dose- response rela-
tionship stratified by use of concomitant enzyme- inducing antiepilep-
tic drugs (EIAEDs), which are known to reduce perampanel exposure.
Study 335 demonstrated a magnitude of efficacy that was similar to
the previous phase III studies for the 8 mg/d dose but greater for the
12 mg/d dose.
The ceiling effect observed in Studies 304 and 305
may be attributable to an imbalance in the number of patients taking
EIAEDs across the perampanel dose groups or due to efficacy outcomes
being confounded by patients not achieving and remaining on their
target randomized dose.
For example, a greater tolerability in Study
335 may have enabled patients to achieve and remain on their target
randomized dose, as discontinuation rates due to treatment- emergent
adverse events in patients receiving perampanel 12 mg/d were lower
in Study 335 (13.9%) than in Studies 304 (19.4%
) and 305 (19.0%
In Study 335, adjunctive perampanel 4 mg/d was not associated
with significant reductions in seizure frequency compared with pla-
cebo, whereas this dose was significant in Study 306.
This may be
due to a more refractory population in Study 335, as highlighted by the
greater proportion of patients taking three concomitant AEDs at base-
line, or it may reflect the higher proportion of patients in Study 335
taking EIAEDs. In keeping with this, and for those patients in Study
335 who received perampanel 4 mg/d and were only taking concomi-
tant non- EIAEDs, there was a similar reduction in seizure frequency to
that observed in a previous analysis.
Furthermore and in real- world
clinical practice where the dose of perampanel can be titrated accord-
ing to individual clinical needs, it has been shown that some patients
do respond favorably to lower doses of perampanel, including the
4 mg/d dose.
As the design of Study 335 was similar to Studies 304, 305, and 306,
data could be pooled to explore the pharmacokinetics (PK) and pharma-
codynamics (PD) of perampanel in patients with POS. The population
PK analysis also included data from a phase II cognition study involv-
ing adolescent patients (aged ≥12 to ≤17 years) with POS.
these analyses demonstrated no effect of a variety of intrinsic factors
on perampanel exposure and further clarified that concomitant EIAED
use may require administration of a higher perampanel dose depend-
ing upon patient tolerability and within the approved dose range. Such
clarification will guide clinicians when integrating perampanel into their
clinical practice and demonstrate that PK parameters and covariates
are similar between adult and adolescent patients.
Whilst consistent with previous analyses,
these two articles pro-
vide a complementary perspective on the activity of adjunctive per-
ampanel in patients with refractory POS across a broad dose range
(4- 12 mg/d). Furthermore, data from Study 335 provide additional ef-
ficacy, safety, and PK data for adjunctive perampanel in patients with
POS by increasing the relative weight of previously underrepresented
Editorial support, under the direction of the author, was carried out by
Rebecca Furmston of Complete Medical Communications and funded
by Eisai Inc. Study 335 was funded by Eisai Co., Ltd.; the PK/PD analy-
ses, as well as the additional studies included in these, were funded
by Eisai Inc.
CONFLICTS OF INTEREST
Bernhard J. Steinhoff has received speaker’s honoraria from Desitin,
Eisai, GW Pharmaceuticals, Novartis, and UCB. He has acted as a paid
consultant for Actelion, B. Braun, Eisai, Shire, and UCB.
B. J. Steinhoff http://orcid.org/0000-0001-5995-5862
B. J. Steinhoff
Kork Epilepsy Center, Kehl-Kork, Germany