Chronic treatment with Addex Dipraglurant Rescues Impairment of Long-Term Synaptic Plasticity in a Validated Preclinical Model of Primary Generalized Torsion Dystonia 1
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Addex Therapeutics /
Chronic treatment with Addex Dipraglurant Rescues Impairment of Long-Term
Synaptic Plasticity in a Validated Preclinical Model of Primary Generalized
Torsion Dystonia 1
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Geneva, Switzerland, 4 September 2013 - Addex Therapeutics (SIX: ADXN), a
leading company pioneering allosteric modulation-based drug discovery and
development announced today additional positive preclinical data for its mGlu5
negative allosteric modulator (NAM) oral small molecule, dipraglurant, in a
validated model for primary generalized torsion dystonia 1 (DYT1), a common and
severe genetic form of dystonia, caused by a mutation in the TOR1A gene encoding
the torsin A protein. In the study, that is part of an ongoing collaboration
with Professor Antonio Pisani, University of Rome Tor Vergata and Fondazione
Santa Lucia, chronic treatment with dipraglurant (50 mg/kg i.p. for 8 days)
partially restored long-term depression and synaptic de-potentiation which are
impaired in the DYT1 mutant mice over expressing the human mutant TOR1A gene.
These data together with previously reported results obtained with dipraglurant
in in vitro and in in vivo preclinical behavioral models, as well as
observations made in the Phase 2a study of dipraglurant in Parkinson's disease
patients, further support the hypothesis that inhibition of mGlu5 could be
beneficial in counteracting the abnormal electrophysiological function observed
in dystonia. In keeping with the Company's rare disease development strategy,
Addex plans to initiate a Phase 2a study with dipraglurant in a rare dystonia.
"These findings in the DYT1 mutant mice over expressing the human mutant TOR1A
gene are very promising," stated Professor Antonio Pisani, University of Rome
Tor Vergata and Fondazione Santa Lucia, and principal investigator on the study.
"These results are consistent with previous observations obtained with mGlu5
tool compounds and provide additional support for further exploration of
dipraglurant in preclinical and clinical studies of dystonia."
"We are pleased to continue to build positive data to support developing
dipraglurant in dystonia and our collaboration with Professor Pisani, is a great
example of how we continue to advance our portfolio in a capital efficient
manner." said Tim Dyer, CEO at Addex.
About Dystonia and DYT1
Dystonia is a movement disorder that causes the muscles to contract and spasm
involuntarily, according to the Dystonia Medical Research Foundation. The
involuntary muscle contractions force the body into repetitive and often
twisting movements as well as awkward, irregular postures. There are
approximately 13 forms of dystonia, and dozens of diseases and conditions
include dystonia as a major symptom. Dystonia may affect a single body area or
be generalized throughout multiple muscle groups. Dystonia affects men, women,
and children of all ages and backgrounds. Estimates suggest that no less than
300,000 people in North America are affected. Dystonia causes varying degrees of
disability and pain, from mild to severe. Early-onset primary dystonia (DYT1) is
the most common form of hereditary primary dystonia. Usually first symptoms
occur in the limbs and dystonia generalizes within a few years of onset. Onset
can be during adolescence and early adulthood. DYT1 is caused by mutations in
the TOR1A gene, a gene that encodes the protein torsin A. Torsin A is widely
expressed in human tissues, particularly in neurons where mutations in TOR1A
selectively alter normal functioning. One of the characteristics of DYT1
dystonia is significant impairment of plasticity in the striatum where a close
functional link between mGlu5 receptors, adenosine (A2A) and dopamine (D2)
receptors has been shown. It has been observed that defective D2 receptor
function in striatal neurons could be blocked by antagonizing A2A receptors
which in turn were able to restore alterations in synaptic plasticity. On the
basis of a close interplay with D2 and A2A receptors, mGlu5 receptor antagonism
has the potential to contribute to the restoration of plasticity deficits as
observed in mutant animals. Preliminary data demonstrated that an mGlu5 receptor
antagonist, MPEP, was able to restore physiological levels of long-term
potentiation. mGlu5 receptor inhibition with an allosteric modulator could
potentially be a novel approach in the pharmacological treatment of dystonia, as
an attractive alternative to anticholinergics. Anticholinergics have significant
compliance-limiting side effects such as dry mouth, cognitive impairment,
changes in blood pressure, pulse rate or ECG, constipation, dizziness and
somnolence. Consequently, there is a significant unmet medical need for a safe
and effective oral small molecule for the treatment of these dystonias.
About Dipraglurant
Dipraglurant is an oral, small molecule allosteric modulator that inhibits
selectively the metabotropic glutamate receptor 5 (mGlu5), 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 Parkinson's disease
levodopa-induced dyskinesia (PD-LID), motor and non-motor symptoms of
Parkinson's disease and other movement disorders. Data from a recent Phase 2a
show that dipraglurant met the primary objective of the study by exhibiting a
good safety and tolerability profile. Dipraglurant also demonstrated a
statistically significant reduction in LID severity with both 50 and 100 mg
doses. Dipraglurant appears to reduce dystonia severity in addition to chorea,
the two major LID components. In a 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.
About mGlu5 Inhibition
There is an increasing body of evidence that mGlu5 inhibition may be a valuable
new strategy for treating a number of important diseases and conditions, such as
Parkinson's disease, Parkinson's disease levodopa-induced dyskinesia (PD-LID),
anxiety, depression, pain, tardive dyskinesia, dystonia, addiction, autism and
Fragile X syndrome. With regards to Parkinson's disease, recent clinical and
preclinical evidence suggest that mGlu5 inhibition may have an effect on
parkinsonian motor symptoms as well as dyskinesia. MGlu5 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 Parkinson's
disease. 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 mGlu5 could act to re-
establish normal movement via a non-dopaminergic mechanism. Separately,
preclinical findings also suggest that mGlu5 inhibitors may be neuroprotective
and may, therefore, hold potential as disease modifying agents that can slow or
prevent progression of Parkinson's disease.
About Addex Therapeutics
Addex Therapeutics (www.addextherapeutics.com) is a development stage company
focused on advancing innovative oral small molecules against rare diseases
utilizing its pioneering allosteric modulation-based drug discovery platform.
The Company's two lead products are being investigated in Phase 2 clinical
testing: dipraglurant (an mGlu5 negative allosteric modulator or NAM) is being
developed by Addex to treat Parkinson's disease levodopa-induced dyskinesia (PD-
LID) and rare forms of dystonia; and ADX71149 (mGlu2 positive allosteric
modulator or PAM) is being developed in collaboration with Janssen
Pharmaceuticals, Inc., to treat both schizophrenia and anxiety as seen in
patients suffering from major depressive disorder. Addex also has several
preclinical programs including: GABA-BR positive allosteric modulator (PAM) for
Charcot-Marie-Tooth (type 1a) disease, spasticity in patients with multiple
sclerosis (MS), pain, overactive bladder and other disorders; and mGlu4 PAM for
MS, Parkinson's disease, anxiety and other diseases. Allosteric modulators are
an emerging class of small molecule drugs 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 target receptors and other proteins that are
recognized as essential for the therapeutic modulation of important diseases
with unmet medical needs.
Tim Dyer
Chief Executive Officer
Addex Therapeutics
+41 22 884 1561
PR(at)addextherapeutics.com
Disclaimer: The foregoing release may contain forward-looking statements that
can be identified by terminology such as "seek", "not pursue", "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, 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 factors may in particular cause actual results
with allosteric modulators of mGlu2, mGlu4, mGlu5, GABA-BR 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 Addex Therapeutics will complete the restructuring and reduction of its
liabilities or any financing nor that allosteric modulators of mGlu2, mGlu4,
mGlu5, GABA-BR 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 mGlu2, mGlu4, mGlu5, GABA-BR 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 mGlu2,
mGlu4, mGlu5, GABA-BR 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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Source: Addex Therapeutics via Thomson Reuters ONE
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Datum: 04.09.2013 - 07:00 Uhr
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