Addex Therapeutics : Addex Partners with Viva Biotech to Advance Allosteric Modulators Targeting Adenosine 2A Receptor

 Addex Therapeutics : Addex Partners with Viva Biotech to Advance Allosteric
                  Modulators Targeting Adenosine 2A Receptor

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Modulators Targeting Adenosine 2A Receptor . Processed and transmitted by
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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 (SIX: ADXN), 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 

"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 

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 ( 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:

About Addex Therapeutics
Addex Therapeutics ( 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.

Tim Dyer
Chief Financial Officer
Addex Therapeutics
+41 22 884 15 61


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