PLAN-LES-OUATES GENEVA, SWITZERLAND--(Marketwire - March 21, 2012) -
Addex Therapeutics /
Addex Reports Positive Top Line Phase IIa Data for Dipraglurant in
Parkinson's
Disease Levodopa-Induced Dyskinesia (PD-LID)
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* All key objectives achieved
* Safety and tolerability demonstrated
* Statistically significant reduction in dyskinesia severity
* Effective dose identified
Geneva, Switzerland, 21 March 2012 - Addex Therapeutics (SIX: ADXN), a
leading
company pioneering allosteric modulation-based drug discovery and
development,
announced today positive top line data from a Phase IIa clinical
study of
dipraglurant in Parkinson's disease (PD) patients suffering from
debilitating
levodopa-induced dyskinesia (LID). The data show that dipraglurant
met the
primary objective of the study by exhibiting a good safety and
tolerability
profile. Dipraglurant also demonstrated statistically significant
reduction in
LID severity with both 50mg and 100mg doses. Dipraglurant appears to
reduce
dystonia severity in addition to chorea, the two major LID components. A
full
analysis of the data will be presented at a scientific forum in 2012.
Dipraglurant is an oral, small molecule allosteric modulator that
inhibits
selectively the metabotropic glutamate receptor 5 (mGluR5), a Class C G-
Protein
Coupled Receptor (GPCR), with potential to be used in combination with
levodopa
or dopamine agonists or as a standalone treatment for PD-LID, PD-related
motor
symptoms, non-motor symptoms of PD and other movement disorders.
The Coordinating Investigator of the dipraglurant study, Olivier
Rascol, MD,
PhD, Professor of Clinical Pharmacology at the Toulouse University
Hospital, and
one of the world's leading experts on treating Parkinson's disease
commented:
"There is no drug approved for the treatment of PD-LID and dipraglurant
is an
exciting new approach. The study was successful in achieving the
primary
objective of good safety and tolerability. In addition, these proof of
concept
data are promising and warrant further investigation of
dipraglurant in
Parkinson's disease."
In this double-blind, placebo-controlled study conducted in the US and
Europe,
the primary objective was to demonstrate safety and tolerability in
PD-LID
patients. In addition, the trial was designed to evaluate exploratory
efficacy
as a secondary objective. Efficacy was measured using the modified
Abnormal
Involuntary Movement Scale (mAIMS), patient diaries documenting
"off-time"
(impaired voluntary movement), "on-time" (with or without dyskinesia) and
sleep.
Additional endpoints include the Unified Parkinson's Disease Rating
Scale
(UPDRS), the Clinician & Patient Global Impression of Change (CGIC &
PGIC), and
an evaluation of the patients' mood using the Hospital Anxiety &
Depression
Score. The trial was supported by a grant from The Michael J. Fox
Foundation for
Parkinson's Research.
"Dyskinesia is a top priority for our Foundation because of its
significant
negative impact on patients' quality of life," said Todd Sherer, PhD, CEO
of The
Michael J. Fox Foundation. "A successful treatment for PD-LID will
change the
way Parkinson's disease is treated by enabling physicians to use
levodopa
earlier and more effectively. To this end, since 2006, we have been
funding
research on mGluR5 inhibition as one of the most promising potential
treatments
for LID. We are proud to have been involved in funding this
trial of
dipraglurant by Addex, which is at the forefront of this effort."
A total of 76 male and female patients (dipraglurant, n = 52; placebo, n =
24)
with moderate or severe PD-LID were randomized into the study. Patients
followed
a dose-titration regimen, receiving 50mg doses from Day 1 to Day 14 and
then
100mg from Day 14 until Day 28. This first-in-patients study met its
primary
objective of demonstrating safety and tolerability in patients with PD.
There
were no significant changes in any safety monitoring parameters
and, in
particular, no changes in liver function tests were seen in either
treatment
group. Both the 50mg and 100mg dose levels were well tolerated. The
incidence of
adverse events was similar in both active and placebo groups
(88.5% for
dipraglurant versus 75% for placebo). Typical mGluR5-type adverse
events
(vertigo, visual disturbance, feeling drunk) were seen in less than
10% of
patients in the dipraglurant group but were not severe or dose limiting.
Exploratory efficacy data showed an anti-dyskinetic effect on observer
evaluated
mAIMS and in patient reported diary data. Both the 50mg and 100mg
doses of
dipraglurant showed a statistically significant reduction in LID. Peak
mAIMS was
significantly reduced on Day 1 (50mg; p = 0.042) and on Day 14 (100mg;
p =
0.038). The targeted magnitude of effect of either a 30% reduction in mAIMS
or a
20% separation from placebo was achieved on Days 1, 14 and 28. The
magnitude of
reduction in mAIMs was maintained for dipraglurant on Day 28 (100mg),
but not
statistically significant due to an increase in placebo response on that
day.
Similar results were seen for the area under the curve (AUC) mAIMS
evaluation in
the total 3 hour post levodopa dosing period, with about a 30% reduction
in the
dipraglurant group at Days 14 and 28, which was statistically significant
at Day
14 (p = 0.042). In a subset of patients with levodopa-induced
dystonia,
dipraglurant appears to have reduced dystonia severity. The UPDRS
Part III
(motor scores) performed during mAIMS evaluation, indicated that
dipraglurant
did not interfere with levodopa efficacy.
Patient-reported, diary data supported the objective, observer-reported
mAIMS
data, with an increase in daily on-time without dyskinesia up to twice
that of
placebo; i.e. dipraglurant patients had as much as 70 minutes more
on-time
without dyskinesia than placebo patients. Furthermore, during Week 4,
patients
reported a reduction in daily off-time of 50 minutes, suggesting an
effect on
parkinsonian motor symptoms in addition to the observed reductions in
LID.
Patients and clinicians tended to favor dipraglurant treatment for
dyskinesia
with a higher percentage reporting improvement for the dipraglurant
group, as
measured by the PGIC and CGIC.
"These data for dipraglurant are positive and we are pleased to
have
demonstrated robust proof of concept," said Charlotte Keywood, MD, Chief
Medical
Officer of Addex. "Both dipraglurant doses had a good safety and
tolerability
profile and demonstrated efficacy. The increase in on-time without
dyskinesia,
combined with the decrease in off-time observed during week 4, is
encouraging,
and warrants further evaluation. It's particularly promising that
the
significant reduction in dyskinesia severity on the mAIMS was mirrored
by a
reduction in patient reported dyskinesia time and that both
clinicians and
patients favoured dipraglurant over placebo."
A successful treatment for PD-LID would change the way Parkinson's
disease is
treated, by enabling physicians to use the most effective drug for
Parkinson's
disease - levodopa - earlier and more aggressively, according to market
research
carried out by Datamonitor for Addex. In addition, based on robust
preclinical
data, potential label expansions for dipraglurant include: PD motor
symptoms
and/or non-motor symptoms, like co-morbid anxiety and depression, as
well as
non-parkinsonian dystonias.
"Addex is leading the effort in developing this potential breakthrough
therapy,
which could change the treatment paradigm for Parkinson's disease,"
said Dr.
Bharatt Chowrira, CEO of Addex. "With these promising positive data in
hand, we
intend to seek a partner to progress dipraglurant to the market as
rapidly as
possible."
While dipraglurant has broad potential for treating Parkinson's and
other
diseases, the most direct path to market is treatment of PD-LID. No
drug is
approved for PD-LID and LID has been identified by the regulatory
authorities,
patient advocacy groups, such as The Michael J. Fox Foundation, and key
opinion
leaders as a very important unmet medical need. The potential market
opportunity
for dipraglurant in Parkinson's disease is well in excess of $1
billion,
according to Datamonitor. Potential label expansions could more than
double the
peak sales potential for dipraglurant.
Dyskinesia & PD
PD is a chronic, progressive neurological disorder that affects one in
100
people over the age 60 but as young as 18. Approximately 7.5 million
people
worldwide are suffering from this neurodegenerative disorder. The most
commonly
administered drug to treat Parkinson's symptoms is levodopa (also
called L-dopa), which helps restore levels of dopamine, a chemical
messenger in the
brain. Following prolonged use, approximately 80 percent of patients
treated
with levodopa will develop uncontrollable movements, i.e. dyskinesias, a
major
source of disability in their lives.
To learn about dyskinesia, listen to this podcast featuring Dr.
Sherer and
produced by The Michael J. Fox Foundation for Parkinson's Research or
find
additional information on PD at the Foundation's website.
mGluR5 inhibition
There is increasingly convincing evidence that mGluR5 inhibition may
be a
valuable new strategy for treating Parkinson's disease. Recent
clinical and
preclinical research show that mGluR5 inhibition alleviates PD-LID.
Clinical and
preclinical evidence suggest that mGluR5 inhibition also may have an
effect on
parkinsonian motor symptoms. mGluR5 is found in regions of the brain
considered
to be key control points in the neuronal movement circuits affected by
abnormal
signaling by the neurotransmitter glutamate in PD. Perturbations in
glutamate
signaling (along with disruptions in dopaminergic signaling) are believed
to be
an underlying cause of movement disorders like Parkinson's disease. As
such,
inhibiting mGluR5 could act to re-establish normal movement via a
non-dopaminergic mechanism. Separately, preclinical findings also
suggest that
mGluR5 inhibitors may be neuroprotective and may, therefore, hold
potential as
disease modifying agents that can slow or prevent progression of PD. The
mGluR5
inhibition mechanism also has achieved validation for other
indications
including, anxiety, depression, pain and Fragile X syndrome.
A webcast and conference call will be held tomorrow at 16:00 CET
(15:00
GMT/11:00 ET) tomorrow, March 22, 2012. To participate, please listen
to the
webcast or call one of the following telephone numbers. RSVP is not
necessary.
Dial-in numbers: +41 91 610 56 00 (Europe)
+44 203 059 58 62 (UK)
+1 866 291 4166 (USA)
The live webcast, webcast replay and transcript, will be available at
www.addextherapeutics.com.
Addex Therapeutics (www.addextherapeutics.com) discovers and
develops an
emerging class of small molecule drugs, called allosteric modulators, which
have
the potential to be more specific and confer significant therapeutic
advantages
over conventional "orthosteric" small molecule or biological drugs. The
Company
uses its proprietary discovery platform to address receptors and other
proteins
that are recognized as attractive targets for modulation of important
diseases
with unmet medical needs. The Company's two lead products are being
investigated
in Phase II clinical testing: dipraglurant (ADX48621, an mGluR5
negative
allosteric modulator or NAM) is being developed by Addex to treat
Parkinson's
disease levodopa-induced dyskinesia (PD-LID); and ADX71149 (mGluR2
positive
allosteric modulator or PAM) is being developed by our partner
Janssen
Pharmaceuticals Inc. to treat schizophrenia. Addex also is advancing
several
preclinical programs including: GABA-BR PAM for pain, overactive
bladder and
other disorders; mGluR4 PAM for Parkinson's, anxiety and other diseases;
GLP1R
PAM for type 2 diabetes; mGluR2 NAM for treating Alzheimer's
disease and
depression; and FSHR/LHR NAM for sex hormone dependent tumors &
reproductive
system disorders. In addition, Addex has discovery programs to
identify
allosteric modulators of: receptor tyrosine kinase (RTK) superfamily,
including
TrkB PAM for treating neurodegenerative diseases (e.g. Alzheimer's,
Parkinson's
and Huntington's diseases); and TNF receptor superfamily, including
TNFR1 NAM
for inflammation (e.g. rheumatoid arthritis) and other diseases.
Disclaimer: The foregoing release may contain forward-looking statements
that
can be identified by terminology such as "not approvable", "continue",
"believes", "believe", "will", "remained open to exploring", "would",
"could",
or similar expressions, or by express or implied discussions regarding
Addex
Therapeutics, formerly known as, Addex Pharmaceuticals, its business, the
potential approval of its products by regulatory authorities, or regarding
potential future revenues from such products. Such forward-looking
statements
reflect the current views of Addex Therapeutics regarding future events,
future
economic performance or prospects, and, by their very nature, involve
inherent
risks and uncertainties, both general and specific, whether known or
unknown,
and/or any other factor that may materially differ from the plans,
objectives,
expectations, estimates and intentions expressed or implied in such
forward-looking statements. Such may in particular cause actual results
with allosteric
modulators of mGluR2, mGluR4, mGluR5, GABABR, FSHR/LHR, GLP1R, TNFR1, RTK,
TrkB
or other therapeutic targets to be materially different from any future
results,
performance or achievements expressed or implied by such statements. There
can
be no guarantee that allosteric modulators of mGluR2, mGluR4, mGluR5,
GABABR,
FSHR/LHR, GLP1R, TNFR1, RTK, TrkB or other therapeutics targets will be
approved
for sale in any market or by any regulatory authority. Nor can there be any
guarantee that allosteric modulators of mGluR2, mGluR4, mGluR5, GABABR,
FSHR/LHR, GLP1R, TNFR1, RTK, TrkB or other therapeutic targets will
achieve
any particular levels of revenue (if any) in the future. In particular,
management's expectations regarding allosteric modulators of mGluR2,
mGluR4,
mGluR5, GABABR, FSHR/LHR, GLP1R, TNFR1, RTK, TrkB or other therapeutic
targets
could be affected by, among other things, unexpected actions by our
partners,
unexpected regulatory actions or delays or government regulation generally;
unexpected clinical trial results, including unexpected new clinical data
and
unexpected additional analysis of existing clinical data; competition in
general; government, industry and general public pricing pressures; the
company's ability to obtain or maintain patent or other proprietary
intellectual
property protection. Should one or more of these risks or uncertainties
materialize, or should underlying assumptions prove incorrect, actual
results
may vary materially from those anticipated, believed, estimated or
expected.
Addex Therapeutics is providing the information in this press release as of
this
date and does not undertake any obligation to update any forward-looking
statements contained in this press release as a result of new information,
future events or otherwise, except as may be required by applicable laws.
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