Addex Reports that Dipragluant Demonstrated Dose-Dependent mGlu5 Receptor Occupancy in a Non-Human Primate PET Study
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Addex Therapeutics /
Addex Reports that Dipragluant Demonstrated Dose-Dependent mGlu5 Receptor
Occupancy in a Non-Human Primate PET Study
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· Dose-dependent receptor occupancy correlates with plasma exposure and
links to efficacy in non-human primate model of Parkinson's Disease levodopa-
induced dyskinesia
· Data reinforces Phase 2a pharmacological profile of dipraglurant as a
potent, selective and brain penetrant mGlu5 negative allosteric modulator
· Similar receptor occupancy study in human subjects to be initiated by
July 2013
· Receptor occupancy studies supported by a $1 MM grant from the Michael
J. Fox Foundation for Parkinson's Research
· Program on track to initiate Phase 2a testing in dystonia by July 2013
Geneva, Switzerland, 2 May 2013 - Addex Therapeutics (SIX: ADXN), a leading
company pioneering allosteric modulation-based drug discovery and development
announced today that dipragluant demonstrated dose-dependent mGlu5 receptor
occupancy in a non-human primate positron emission tomography (PET) study. PET
is a non-invasive nuclear imaging technique used in drug discovery and
development for assessing specific receptor distribution in the brain and has
been proven very useful in assessing drug pharmacodynamics and receptor
occupancy. The study demonstrated the correlation between the plasma
concentration of dipraglurant and occupancy of dipraglurant on mGlu5 receptors
in the brain. The results support efficacy data as observed in a preclinical
non-human primate model of levodopa-induced dyskinesia and will be used to
inform dosing in future clinical studies. In addition, the study results
reinforce data seen in the Phase 2a trial supporting dipraglurant as a potent,
selective and brain penetrant mGlu5 negative allosteric modulator (NAM). The
study was performed by Molecular NeuroImaging (MNI) in New Haven, CT, USA and
supported by a $1 MM grant from the Michael J. Fox Foundation for Parkinson's
Research.
"The results of the study are in line with previous reports on mGlu5 receptor
occupancy studies and are consistent with the preclinical pharmacology data
gathered so far with dipraglurant," stated Gilles Tamagnan, Ph.D., Vice
President Chemistry and Translational Science at MNI. "We look forward to the
next phase of the study; investigating receptor occupancy in human volunteers
and Parkinson's patients."
The non-human primate PET study measured the mGlu5 receptor occupancy after
bolus/i.v. infusion of dipraglurant followed by administration of (18)F-FPEB, a
high-quality, high affinity, high specificity mGlu5 PET tracer. The treatment
comprised 4 different dose levels of dipraglurant (4.34, 1.52, 0.6 and 0.2
mg/kg) and two baseline PET scans. Dynamic PET images were acquired for 2 hours
and plasma samples were drawn during the PET scan and analysed for drug levels.
The results demonstrated that dipraglurant penetrates the blood-brain barrier
and dose-dependently blocks the binding of (18)F-FPEB. The dissociation constant
(K(D)) was determined to be 0.82 mg/kg and at the highest dose nearly complete
blockade of the receptor was achieved (81% RO). The receptor occupancy data
combined with the dipraglurant plasma concentration was used to analyse the
previously reported data obtained in the non-human primate model of Parkinson's
disease Levodopa induced dyskinesia (PD-LID). There was a clear and direct
relationship between mGlu5 receptor occupancy and efficacy as demonstrated by
decreasing dyskinesia in the MPTP-PD-LID model. This invaluable information
relating the receptor occupancy to the therapeutic dose is a step forward in the
understanding of the pharmacology of dipraglurant and will be translated into
dose selection for the future clinical development of dipraglurant.
"This was an important study in further understanding the pharmacology of
dipraglurant," said Graham Dixon, Ph.D., Chief Scientific Officer of Addex
Therapeutic. "These results as well as results from the PET receptor occupancy
study in humans will continue to better our understanding of how dipraglurant is
targeting mGlu5. With top line data from the dystonia trial expected by the end
of 2013, the data from all of these studies, taken as a whole, will place us in
a strong position to make data-driven decisions on the further clinical
development of dipraglurant in PD-LID, rare dystonias as well as other potential
therapeutic indications."
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 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.
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 (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 is also 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; 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 Financial Officer
Addex Therapeutics
+41 22 884 15 61
PR(at)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
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 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
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: 01.05.2013 - 07:00 Uhr
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