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Status of the E2007 (perampanel) Development Program - Termination of Parkinson's Disease Clinical Development and Focus on Neuropathic Pain and Epilepsy Indications

Tokyo, Japan (ots/PRNewswire)

E2007 (perampanel) is a
first-in-class, orally administered, highly selective non-competitive
AMPA-type glutamate receptor antagonist, in development by Eisai
(TSE:4523) for several indications, including  Parkinson's disease,
neuropathic pain, epilepsy, multiple sclerosis and  migraine
The AMPA receptor is widely present in almost all excitatory
neuronal synapses. It is believed to play a role in a large number of
central nervous system (CNS) diseases with different underlying
pathophysiology, including neurodegenerative disorders, movement
disorders, pain and psychiatric disorders. Eisai has been pursuing
development of perampanel for several CNS indications, some of which
are currently in Phase II and Phase III. The most advanced indication
is Parkinson's disease for which Eisai has been conducting three
global Phase III studies (Studies 301, 302 and 309) with perampanel
as add-on therapy to levodopa in patients with late-stage disease.
Additionally, Eisai is preparing for global Phase III studies for
epilepsy and conducting two Phase II studies for neuropathic pain.
Following the completion of the first Phase III Study 301, we
recently completed the second Phase III Study 302, which was
primarily conducted in North America. Study 302 is a 20-week,
double-blind, placebo-controlled study comparing two doses of 2mg and
4mg of perampanel to placebo. The results, compared with placebo, did
not show a significant difference in the primary endpoint of
reduction of "off" time (time when signs and symptoms of Parkinson's
disease return as the effect of levodopa wears off). Perampanel was
generally well tolerated. After analyzing the data, Eisai has decided
to discontinue the Parkinson's disease program and not pursue
regulatory submissions for this indication. Eisai will focus
resources on two other ongoing indications, epilepsy and neuropathic
pain, both of which have different pathophysiology from that of
Parkinson's disease and robust scientific rationale.
Following the decision to terminate the Parkinson's disease
indication, Eisai has also decided to terminate the third Parkinson's
disease Phase III study (Study 309) and open label treatment
extension studies. Perampanel was generally well tolerated throughout
the program in this mostly elderly population. The decision to
terminate the Parkinson's disease program is due to lack of efficacy
over placebo seen in the recently completed two Phase III studies
only, and is not predictive of activity in the other indications
including epilepsy and neuropathic pain.
In preclinical models in Parkinson's disease, perampanel improved
the effect of levodopa, and a Phase II study suggested that
perampanel improved benefits with increasing doses. Responding to
unmet medical need, Eisai pursued development of perampanel in
Parkinson's disease as a first-in-class oral AMPA antagonist with a
non-dopaminergic mechanism, which is different from that of existing
drugs. The reason for the lack of statistical significance in
effectiveness observed in the two completed Phase III studies for
Parkinson's disease is being investigated carefully, but because the
mechanism of perampanel is different from that of dopaminergic drugs
such as levodopa and dopamine agonists, in-depth review will be
The pharmacological rationale for perampanel in Parkinson's
disease is the therapeutic augmentation of levodopa. However in
neuropathic pain and epilepsy, the rationale is to direct
parampanel's demonstrated activity as an AMPA receptor antagonist
toward inhibition of the neuronal excitability and sensitization
caused by glutamate.
Testing in various established animal models has suggested that
perampanel has a potential antiepileptic effect. The five animal
seizure models tested (maximal electroshock, 6Hz psychomotor,
pentylenetetrazole, audiogenic and kindling seizure models) suggested
that perampanel may be effective in treating epilepsy. Three Phase II
studies (Study 203, 206 and 208), which include doses to be used in
Phase III, suggest that perampanel is generally well tolerated with a
dose-dependent efficacy in patients with refractory partial seizures.
The most recently completed Phase II Study 208 evaluated maximum
tolerated dose (MTD) and safety of perampanel as adjunctive therapy
in subjects with refractory partial seizures. This was a 16-week,
placebo-controlled, dose-escalation (to a maximum of 12 mg/day),
parallel-group study conducted in Europe. Perampanel showed an
increasing trend in activity up to 12 mg/day in epilepsy patients
with refractory partial seizures. There was a 40% median seizure
reduction in the perampanel arm and a 2% median seizure increase in
the placebo arm. The responder rate, defined as a proportion of
patients with more than 50% seizure reduction,  was 40% in the
perampanel arm and 22% in the placebo arm.
Eisai is preparing to initiate global Phase III studies with
perampanel as add-on therapy in patients with refractory partial
seizures in the first quarter of fiscal year 2008. The regulatory
submission is planned for fiscal year 2012.
Several pre-clinical models have also suggested that perampanel
may be effective in treating neuropathic pain. The Phase II POC Study
227 in painful diabetic neuropathy (PDN) completed enrollment in
March and is expected to provide top-line results in September 2008.
A Phase III program will start soon afterwards, with regulatory
submission for an indication in PDN planned in fiscal year 2010. A
Phase II study in a second neuropathic pain indication, post-herpetic
neuralgia (PHN), was initiated in January 2008.
Both the Phase III programs in neuropathic pain and in epilepsy
plan to investigate a wider range of doses up to 12mg.
Perampanel has been generally well tolerated, as confirmed in the
clinical dataset of over 2,300 patients.
Eisai remains strongly committed to the further development of
perampanel, as it has the potential to be a well tolerated
first-in-class drug for neuropathic pain, epilepsy, and possibly
other CNS diseases, with a well differentiated profile of value, for
the benefit of many patients and their families.
(1) Dopaminergic Drug
Dopaminergic drugs such as levodopa and dopamine agonists act
directly at dopaminergic receptors, or improve the efficacy of
dopamine by regulating its mechanism.
(2) Non-dopaminergic Drug
Drugs that show efficacy by a mechanism other than direct effects
on the dopamine receptor or dopamine metabolism. They include the
current Parkinson's disease treatments such as anti-cholinergic
agents, NMDA inhibitors, etc.


Contacts: Corporate Communications Department, Eisai Co., Ltd., TEL:
+81-3-3817-5120; Judee Shuler, Eisai Corporation of North America,
+1-201-746-2241; Andrew Day, Eisai Europe Ltd., +44(0)208-600-7395

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