GENEVA, SWITZERLAND--(Marketwire - March 04, 2013) -
Addex Therapeutics /
Addex Partners with Viva Biotech to Advance Allosteric Modulators Targeting
Adenosine 2A Receptor
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Partnership to demonstrate the potential to accelerate the development of
allosteric modulator-based therapeutics against GPCRs by integrating
proprietary
functional and structural biology approaches
Geneva, Switzerland, 4 March 2013 - Addex Therapeutics (ADXN: SIX), a
leading
company pioneering allosteric modulation-based drug discovery and
development,
and Viva Biotech Ltd., a leading company in structure-based drug discovery
based
in Shanghai, China, today announced they have entered into a
partnership to
accelerate the advancement of oral small molecule adenosine 2A receptor
(A2AR)
positive allosteric modulators (PAMs) by leveraging the relative
expertise of
each company. The A2AR natural ligand, extracellular adenosine, is
locally
produced at the sites of inflammation and has been characterized for
decades as
a "brake for inflammation." An oral small molecule compound targeting
A2AR
activation, which selectively enhances the effect of high
adenosine
concentration only within inflamed tissues and not in other tissues, may
have a
profound therapeutic effect in any number of inflammatory-based
diseases
including rare diseases such as sickle cell and Huntington's diseases.
"We are delighted to initiate this collaboration with Viva Biotech, a
world
leader in structural biology of GPCRs," said Graham Dixon, Chief
Scientific
Officer at Addex Therapeutics. "Structural biology is a key complement
to our
proprietary allosteric modulation capability and increases the chances
of us
successfully developing novel, allosteric modulators for
membrane-associated receptors. The combination of our industry leading
allosteric modulator drug
discovery platform with Viva's cutting-edge structural biology
expertise is
expected to facilitate the development of a selective and potent oral
small
molecule for the activation of A2AR, a compelling new mechanism of
action to
address multiple inflammatory diseases, including certain rare
disease
indications with significant unmet medical needs."
Under the terms of the agreement, Viva Biotech will provide a
fully-integrated structural biology discovery service to Addex to deliver
high resolution crystal
structures of A2AR in complex with positive allosteric modulators (PAMs)
that
were identified using Addex proprietary HTS technologies. Based on
this
structural information, Addex scientists will then be able to rationally
develop
novel A2AR PAMs in a structure-guided lead optimization program. To date,
Addex'
A2AR PAMs constitute the first examples of chemically tractable, selective,
oral
small molecule compounds with functional activity on this important GPCR
target.
"We are very pleased to be collaborating with Addex on this important
program,"
said Cheney Mao, Chief Executive Officer of Viva Biotech. "Viva works
with our
collaborators to advance novel drug targets from the ideas to identifying
novel
drug candidates to the clinics, utilizing our broad experience in drug
discovery
and deep expertise in G2P, G2S, GPCRs and SBDD/FBDD. With Addex, Viva
brings
unique structural biology expertise and capability to the
partnership. We
believe the combination of our capability with Addex'
state-of-the-art allosteric modulator platform will accelerate the
delivery of a clinical
candidate against this important GPCR drug target."
About Addex' novel A2AR PAMs
Addex has developed proprietary HTS technologies specifically
designed to
respond to the challenges of detecting and optimizing allosteric
modulator
drugs. Using this technology, Addex has been able to identify
structurally-independent novel chemical series with drug-like properties
and with functional
activity at the human A2AR in recombinant cell lines as well as in a cell
line
endogenously expressing A2AR. In addition, these compounds have been shown
to be
active in industry-standard assays (such as cAMP HTRF and GTP-gamma-S
assays)
and do not compete with radioactive orthosteric ligand binding,
exemplifying
their allosteric mechanism of action. These novel compounds are
selective for
A2AR, do not demonstrate any agonist activity and are only active
in the
presence of adenosine binding to the active site of A2AR.
About allosteric modulators
Allosteric modulators are an emerging class of orally available small
molecule
therapeutic agents that may offer a competitive advantage over classical
drugs.
This potential stems from their ability to offer greater selectivity and
better
modulatory control at disease mediating receptors. Most marketed drugs
bind
receptors where the body's own natural molecular activators (i.e.
endogenous
ligands) bind, specifically to a key part of each receptor called the
"active
site". In short, most drugs must out-compete endogenous ligands in order to
bind
to the active site. By contrast, allosteric modulators are
non-competitive because they bind receptors at a different site and modify
receptor function in
the presence of endogenous ligand binding to the active site. Because of
this,
allosteric modulators are not limited to simply turning a receptor
"on" or
"off", the way most conventional drugs are designed. Instead,
allosteric
modulators act more like a dimmer switch, offering control over the
intensity of
activation or deactivation, while allowing the body to retain its
natural
control over initiating receptor activation. One of the most attractive
features
of receptor activation via allosteric modulation is that these
positive
allosteric modulators (PAMs) activate the receptor only in the presence
of the
natural ligand binding to the target receptor. In the absence of natural
ligand
these PAMs do not activate the receptor. This provides an elegant
regulate the
receptor activation that could translate into the development of a
safer
therapeutic.
Pharmacological advantages of PAMs for the activation of A2AR
Beside immune cells, A2AR engagement modulates the activity of numerous
cell
types, including various neuronal populations, platelets, smooth
muscle and
endothelial cells. Thus, systemic engagement of A2AR with orthosteric
agonists,
directed at the adenosine binding site, is known to affect several
tissues and
trigger a wide range of side effects such as hypotension and
tachycardia.
Extracellular adenosine is locally produced within inflamed or hypoxic
tissues
and is highly unstable in plasma. Therefore, in the course of
inflammatory
reactions, ligand availability regulates adenosine receptors engagement
both in
space and time. Because it preserves the natural spatial and temporal
controls
over A2AR engagement, positive allosteric modulation provides a uniquely
suited
therapeutic approach to address the potential of A2AR activation in
chronic
inflammatory diseases. By enhancing the effect of high adenosine
concentration
within inflamed tissues, A2AR PAM would avoid side effects that
relate to
ectopic or systemic triggering of A2AR and could offer a greater
selectivity
over other adenosine receptors. In particular, A2AR PAMs are expected to
show
reduced impact on hypotension and tachycardia than straight agonists.
About A2AR in inflammatory conditions
Adenosine 2A receptor (A2AR or ADORA2A), a Family A class of G-protein
coupled
receptor (GPCR) can, among other things, negatively regulate over
reactive
immune cells, thereby protecting tissues from collateral inflammatory
damage,
The A2AR's natural ligand, extracellular adenosine, is locally produced
at the
sites of inflammation and has been characterized for decades as a
"brake for
inflammation", exerting a retro-control over inflammation. Several
lines of
evidence point to a broad anti-inflammatory role of A2AR in preclinical
animal
models. In leukocytes, A2AR is the most abundantly expressed adenosine
receptor
and activating this receptor affects a range of cellular functions
across
different immune cell types including macrophage cytokines
production,
neutrophil migration, or T-lymphocyte activation. A2AR selective agonists
show
anti-inflammatory activity and reduce tissue damage in vivo. Conversely,
A2AR
selective antagonists compromise regulatory T cells function and
prolong
inflammation following induction of an inflammatory response. Similarly,
A2AR-deficient animals show enhanced and prolonged inflammatory responses.
Several marketed anti-inflammatory drugs, including methotrexate
and
sulfasalazine, mediate some of their anti-inflammatory effects
through a
mechanism that promotes adenosine release and activation of A2AR. However,
these
drugs are non-specific and associated with significant side
effects. In
addition, there is marked variability in the degree of efficacy and side
effects
observed with these current drugs in the clinic. There is a need for
products
that are selective, safe and truly disease-modifying. Therefore, an oral
small
molecule drug targeting A2AR with a new mechanism of action such as an
A2AR PAM
that is active only at the sites of inflammation, lacks any agonist
activity and
preferably is peripheral, could revolutionize and offer an
attractive
alternative to the existing therapeutic arsenal for the treatment of a
number of
inflammatory conditions, such as rheumatoid arthritis (RA), Crohn's
disease and
psoriasis, as well as certain rare diseases such as , sickle
cell and
Huntington's disease.
About Viva Biotech
Viva Biotech (www.vivabiotech.com) is privately owned and financed by
leading
investors in the United States. It is a well-established contract
research
organization that provides preclinical drug discovery research services
to the
pharmaceutical industry worldwide. The core capabilities of the company
includes
its leading expertise in protein crystallography and structure based
drug
design, a MS based screening technology with a proprietary fragment
library,
GPCR target preparation and crystallization, monoclonal antibody lead
generation
and other preclinical drug discovery research capabilities such as DMPK,
animal
disease models for CNS and oncology. For additional information on Viva
Biotech,
please contact Dr. Zengquan Wang at: Zengquan.wang@vivabiotech.com.
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 (ADX48621, 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.
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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