Addex Dipraglurant Reduces Motor Abnormalities in a Preclinical Model Relevant for Several Rare types of Dystonia
Addex Therapeutics /
Addex Dipraglurant Reduces Motor Abnormalities in a Preclinical Model Relevant
for Several Rare types of Dystonia
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Dipraglurant, a novel oral small molecule negative allosteric modulator of mGlu5
receptor, on track for Phase 2 clinical testing in the second half of 2013
Geneva, Switzerland, 29 January 2013 - Addex Therapeutics (SIX:ADXN), a leading
company pioneering allosteric modulation-based drug discovery and development,
announced positive preclinical data for its mGlu5 negative allosteric modulator
(NAM) oral small molecule, dipraglurant, in a validated rodent model of
dystonia, a spectrum of disorders, that includes several rare diseases and is
characterized by debilitating involuntary muscle contractions and body
movements. This is an area of high unmet medical need where many patients are
left inadequately treated with the current standard of care. Dipraglurant
demonstrated a robust and dose-dependent reduction in severity of a dystonia-
like attack, induced by caffeine in the tottering mouse model. These data are
consistent with earlier reported Addex findings in a Phase 2a clinical trial
measuring levodopa-induced dyskinesia in Parkinson's patients as well as a non-
human primate model of Parkinson's-related dystonia.
"The effects of dipraglurant in the mouse model are very compelling. They
provide additional support for further exploration of mGlu5 inhibitors as a
novel treatment for dystonia and also open new therapeutic avenues" said
Professor Ellen Hess at Emory University (USA) in whose laboratory the study was
performed.
The validation of the tottering mouse model in the laboratory of Professor Hess
has been funded in part by the Bachmann-Strauss Dystonia and Parkinson
Foundation. The model recapitulates key genetic and phenotypic features of so
called episodic neurological disorders, that involve aberrant calcium channel
functioning and susceptibility to neurological attacks in response to stress,
alcohol or caffeine. In the study, acute, oral administration of dipraglurant
(10, 30, 50 mg/kg) resulted in dose-dependent reductions of dystonia scores,
achieving significant reductions at the highest dose in comparison to vehicle
treatment. In a sub-group of experimental animals, dipraglurant fully blocked
the onset of dystonia. These results demonstrate the potential of mGlu5
inhibition as a novel approach for the treatment of multiple types of dystonias,
as well as other rare neurological conditions including familial hemiplegic
migraine type 1, episodic ataxia type 2, and periodic paralysis.
"We are pleased that we continue to see broad therapeutic application for
dipraglurant," said Bharatt Chowrira, CEO at Addex. "As we continue to seek a
partner to advance dipraglurant in Parkinson's levodopa-induced-dyskinesia, we
see great opportunity to take the compound forward in several rare disease
indications including certain forms of dystonias. We look forward to starting
Phase 2 clinical testing in the second half of 2013 with this potentially
important movement disorder therapeutic".
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.
mGlu5 Inhibition
There is increasingly convincing 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 Dystonia
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. There is presently no cure, and,
although many drugs are utilized to try to treat dystonia, the leading treatment
is botox injections and many patients are left with inadequate efficacy.
Dipraglurant has been shown to effectively reduce dystonia in both a clinical
study and preclinical models of Parkinson's disease levodopa-induced dyskinesia
(PD-LID). The neurophysiology of different forms of dystonia is thought to be
similar and recent preclinical data in dystonia - suggesting that dipraglurant
may also work for non-parkinsonian forms of dystonia.
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 2 clinical testing: dipraglurant (ADX48621, an mGlu5 negative
allosteric modulator or NAM) is being developed by Addex to treat Parkinson's
disease levodopa-induced dyskinesia (PD-LID) and dystonia; and ADX71149 (mGlu2
positive allosteric modulator or PAM) is being developed in collaboration with
Janssen Pharmaceuticals Inc. to treat schizophrenia and anxiety seen in patients
suffering from major depressive disorder. Addex also is advancing 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; mGlu4 PAM for MS,
Parkinson's disease, anxiety and other diseases. In addition, Addex is applying
its proprietary discovery platform to identify highly selective and potent
allosteric modulators of a number of both GPCR and non-GPCR targets that are
implicated in diseases of significant unmet medical need.
Tim Dyer
Chief Financial Officer
Addex Therapeutics
+41 22 884 15 61
PR@addextherapeutics.com
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
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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 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
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
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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
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