Evenamide met study objectives of good
tolerability, safety, and preliminary evidence of efficacy as an
add-on therapy for the treatment of schizophrenia
Unique mechanism: glutamate modulation and
voltage-gated sodium channel blockade
Newron Pharmaceuticals S.p.A. (“Newron”), a biopharmaceutical
company focused on the development of novel therapies for patients
with diseases of the central nervous system (CNS) and pain, today
presented detailed results of a Phase IIa study with its unique
sodium channel blocker, Evenamide (NW-3509), in patients with
schizophrenia. The new chemical entity is orally available and
specifically targets voltage-gated sodium channels by a unique
mechanism of action.
The results were presented at the 16th International Congress on
Schizophrenia Research, 24-28 March 2017, in San Diego.
Ravi Anand, M.D., Newron’s Chief Medical Officer, stated:
“Evenamide uniquely combines voltage-gated sodium channel blockade
with attenuation of glutamate release. The results of this first
study in patients with schizophrenia confirm preclinical data,
which indicated that Evenamide might provide significant evidence
of efficacy as an add-on to the most commonly prescribed
atypical antipsychotics in patients with chronic
schizophrenia, without effect on any of the over 130
neurotransmitters, enzymes, or transporters targeted by most
antipsychotics.”
Dr. Anand continued: “The patients in this study, who were
showing signs of worsening symptoms of psychosis while on doses of
antipsychotics they had responded to in the recent past, benefited
on all efficacy measures evaluated. The onset of improvement
occurred early in treatment. Evenamide was not associated with any
increase in extrapyramidal, sexual, endocrine, cardiac, laboratory
or metabolic side effects caused by the use of antipsychotics. The
addition of Evenamide to patients showing a worsening of their
symptoms while on their current atypical antipsychotic was not only
well-tolerated, but showed a consistent pattern of benefit on all
efficacy measures assessed. These preliminary results warrant
further investigation in larger and longer trials in patients with
more severe symptoms.”
The four-week, Phase IIa, double-blind, placebo-controlled,
randomized, multi-national study was designed to investigate the
tolerability, safety and preliminary evidence of efficacy of
Evenamide as an add-on treatment in 89 patients with a DSM-5
diagnosis of schizophrenia. Patients included in the study were
primarily male (86%) and 19 to 60 years of age, with a mean
baseline PANSS total score of 62.9 ± 7.4, and were experiencing
break-through psychotic symptoms while on stable and adequate doses
of risperidone (mean dose: 4.2 ± 2.0 mg/day; n=70) or aripiprazole
(mean dose: 19.7 ± 7.0 mg/day; n=19), the atypical antipsychotics
to which they had responded previously. The study was conducted in
two U.S (n=61) and three Indian (n=28) study centers, and enrolled
patients with schizophrenia with a mean duration of illness of
approximately 18 years and an average of three hospitalizations.
Patients were randomized to receive twice daily Evenamide (15-25
mg) or placebo, in addition to their current antipsychotic.
The study protocol, including doses and study design, was
finalized with FDA input and guidance, and received approval from
the Drug Controller General of India (DCGI), as well as the
institutional review board (IRB) at each center.
The results of the study indicate that patients treated with
Evenamide showed improvement on the symptoms of schizophrenia
assessed by the Positive and Negative Syndrome Scale (PANSS). The
mean (SD) change from baseline at Day 28 for the PANSS total score
was greater for Evenamide [-5.1 (9.67)] than for placebo [-3.7
(9.65)]. For the PANSS Positive Symptoms sub-scale, a statistically
significant/near significant improvement from baseline (mean
baseline score: 14.8 ± 2.8) to Day 28 for Evenamide, compared to
placebo [LS mean difference (SE)], was noted in the ANCOVA-LOCF
[-1.28 (0.632), p=0.046], ANCOVA-OC [-1.48 (0.641), p=0.024], and
MMRM [-1.19 (0.643), p=0.068] analyses. Numerically greater
improvement with Evenamide was also observed for patients’
functioning, assessed by the Strauss-Carpenter Level of Functioning
scale, and severity of illness (Clinical Global Impression of
Severity), compared to their standard antipsychotic alone. In
addition, a global assessment of change from baseline in the
patient’s overall condition (Clinical Global Impression of Change),
performed by a clinician, showed a greater proportion of
Evenamide-treated patients rated as improved (54%), compared to
placebo (36%). An additional analysis demonstrated that the
proportion of patients who showed improvement on the PANSS Positive
sub-scale at Day 28 was significantly greater (p=0.0043; Fisher’s
exact chi-square test) for the Evenamide group (74.5%) compared to
the placebo group (43.6%).
Evenamide in the range of 15-25 mg bid (30-50 mg/day) was well
tolerated. The most frequent (>5% of patients in any group)
adverse events (AEs) (Evenamide vs. placebo) were somnolence [8
(16.0%) vs. 5 (12.8%)], insomnia [5 (10.0% vs. 1 (2.6%)], overdose
[3 (6.0%) vs. 1 (2.6%)], dry mouth [3 (6.0%) vs. 2 (5.1%)],
headache [3 (6.0%) vs 0], and cold sweat/hyperhidrosis [2 (4.0%)
vs. 0]. The incidence of ‘respiratory, thoracic and mediastinal
disorders’ was higher for placebo [1 (2.0%) vs. 3 (7.7%)]. Most AEs
were of mild severity [Evenamide, 58 of 69 (84%); placebo, 30 of 34
(88%)]; 9 of 69 (13%) AEs for Evenamide and 4 of 34 (12%) for
placebo were assessed as moderate.
Two patients in the Evenamide group discontinued treatment due
to AEs: seizure (n=1) and atrial fibrillation (n=1). The
proportions of patients with clinically notable abnormalities in
vital signs or laboratory values were very low and were similar in
the Evenamide and placebo groups. The proportion of patients with
clinically significant ECG abnormalities was low and similar
between groups, and there was no evidence of effects on QTc.
Assessment of extrapyramidal symptoms (EPS) using the
Extrapyramidal Symptoms Rating Scale did not reveal any
treatment-emergent EPS with Evenamide treatment.
About schizophreniaSchizophrenia is a long-term mental
health condition that causes a range of different psychological
symptoms. It is one of the most common serious mental health
conditions. About 1 in 100 people will experience schizophrenia in
their lifetime, with many continuing to lead normal lives.
Schizophrenia is most often diagnosed between the ages of 15 and
35. Men and women are affected equally. There is no single test for
schizophrenia. It is most often diagnosed after an assessment by a
mental health care professional, such as a psychiatrist. It is
important to diagnose schizophrenia as early as possible, as the
chances of recovery improve the earlier it is treated.
Schizophrenia is often described in terms of positive and negative
(or deficit) symptoms. Positive symptoms are those that most
individuals do not normally experience but are present in people
with schizophrenia. They can include delusions, disordered thoughts
and speech, and tactile, auditory, visual, olfactory and gustatory
hallucinations, typically regarded as manifestations of psychosis.
Hallucinations are also typically related to the content of the
delusional theme. Positive symptoms generally respond well to
medication. Negative symptoms are deficits of normal emotional
responses or of other thought processes, and are less responsive to
medication.
About Evenamide (NW-3509)Evenamide is an orally available
new chemical entity that specifically targets voltage-gated sodium
channels. The compound modulates sustained repetitive firing,
without inducing impairment of normal neuronal excitability.
Evenamide normalizes glutamate release induced by aberrant sodium
channel activity. The potential benefits of the compound have been
demonstrated in numerous preclinical models predictive of efficacy
in psychiatric diseases, including models of psychosis such as
amphetamine-induced hyperactivity, sensorimotor gating and
information processing deficits (pre-pulse inhibition impairment
induced by different stimuli), mania and depression. Efficacy of
Evenamide has also been demonstrated in models of aggression and
compulsive behavior, as well as in short- and long-term memory
tests. Sub-threshold doses of the compound increased the activity
of inactive doses of both typical and atypical antipsychotics in
models of schizophrenia, psychosis and mania. Moreover, given its
neuronal stabilization properties, Evenamide may reduce relapses
and prevent or treat episodes of psychosis due to established
super-sensitivity psychosis (SSP) induced by antipsychotics. As it
is devoid of the risk of drug-induced movement disorders or weight
gain, Evenamide can be given in combination for extended periods of
time.
About Newron PharmaceuticalsNewron (SIX: NWRN) is a
biopharmaceutical company focused on the development of novel
therapies for patients with diseases of the Central Nervous System
(CNS) and pain. The Company is headquartered in Bresso near Milan,
Italy. Xadago® (safinamide) has received marketing
authorization for the treatment of Parkinson’s disease in the
European Union, Switzerland and the USA, and is commercialized by
Newron’s Partner Zambon. US WorldMeds holds the commercialization
rights in the USA. Meiji Seika has the rights to develop and
commercialize the compound in Japan and other key Asian
territories. In addition to Xadago® for Parkinson’s disease, Newron
has a strong pipeline of promising treatments for rare disease
patients at various stages of clinical development, including
sarizotan for patients with Rett syndrome and ralfinamide for
patients with specific rare pain indications. Newron is also
developing Evenamide as the potential first add-on therapy for the
treatment of patients with positive symptoms of schizophrenia.
www.newron.com
Important NoticesThis document contains forward-looking
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ability to develop and expand its business, successfully complete
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future collaborations for the development and commercialisation of
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(2) the market for drugs to treat CNS diseases and pain conditions,
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MediaNewronStefan Weber, +39 02 6103 46
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