Addex Partners with Viva Biotech to Advance Allosteric Modulators Targeting Adenosine 2A Receptor
March 4, 2013 - Geneva, Switzerland
Addex Therapeutics /Addex Partners with Viva Biotech to Advance Allosteric Modulators TargetingAdenosine 2A Receptor
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Partnership to demonstrate the potential to accelerate the development ofallosteric modulator-based therapeutics against GPCRs by integratingproprietaryfunctional and structural biology approaches
Geneva, Switzerland, 4 March 2013 - Addex Therapeutics (ADXN: SIX), aleadingcompany pioneering allosteric modulation-based drug discovery anddevelopment,and Viva Biotech Ltd., a leading company in structure-based drug discoverybasedin Shanghai, China, today announced they have entered into apartnership toaccelerate the advancement of oral small molecule adenosine 2A receptor(A2AR)positive allosteric modulators (PAMs) by leveraging the relativeexpertise ofeach company. The A2AR natural ligand, extracellular adenosine, islocallyproduced at the sites of inflammation and has been characterized fordecades asa "brake for inflammation." An oral small molecule compound targetingA2ARactivation, which selectively enhances the effect of highadenosineconcentration only within inflamed tissues and not in other tissues, mayhave aprofound therapeutic effect in any number of inflammatory-baseddiseasesincluding rare diseases such as sickle cell and Huntington's diseases.
"We are delighted to initiate this collaboration with Viva Biotech, aworldleader in structural biology of GPCRs," said Graham Dixon, ChiefScientificOfficer at Addex Therapeutics. "Structural biology is a key complementto ourproprietary allosteric modulation capability and increases the chancesof ussuccessfully developing novel, allosteric modulators formembrane-associated receptors. The combination of our industry leadingallosteric modulator drugdiscovery platform with Viva's cutting-edge structural biologyexpertise isexpected to facilitate the development of a selective and potent oralsmallmolecule for the activation of A2AR, a compelling new mechanism ofaction toaddress multiple inflammatory diseases, including certain rarediseaseindications with significant unmet medical needs."
Under the terms of the agreement, Viva Biotech will provide afully-integrated structural biology discovery service to Addex to deliverhigh resolution crystalstructures of A2AR in complex with positive allosteric modulators (PAMs)thatwere identified using Addex proprietary HTS technologies. Based onthisstructural information, Addex scientists will then be able to rationallydevelopnovel A2AR PAMs in a structure-guided lead optimization program. To date,Addex'A2AR PAMs constitute the first examples of chemically tractable, selective,oralsmall molecule compounds with functional activity on this important GPCRtarget.
"We are very pleased to be collaborating with Addex on this importantprogram,"said Cheney Mao, Chief Executive Officer of Viva Biotech. "Viva workswith ourcollaborators to advance novel drug targets from the ideas to identifyingnoveldrug candidates to the clinics, utilizing our broad experience in drugdiscoveryand deep expertise in G2P, G2S, GPCRs and SBDD/FBDD. With Addex, Vivabringsunique structural biology expertise and capability to thepartnership. Webelieve the combination of our capability with Addex'state-of-the-art allosteric modulator platform will accelerate thedelivery of a clinicalcandidate against this important GPCR drug target."
About Addex' novel A2AR PAMs
Addex has developed proprietary HTS technologies specificallydesigned torespond to the challenges of detecting and optimizing allostericmodulatordrugs. Using this technology, Addex has been able to identifystructurally-independent novel chemical series with drug-like propertiesand with functionalactivity at the human A2AR in recombinant cell lines as well as in a celllineendogenously expressing A2AR. In addition, these compounds have been shownto beactive in industry-standard assays (such as cAMP HTRF and GTP-gamma-Sassays)and do not compete with radioactive orthosteric ligand binding,exemplifyingtheir allosteric mechanism of action. These novel compounds areselective forA2AR, do not demonstrate any agonist activity and are only activein thepresence of adenosine binding to the active site of A2AR.
About allosteric modulators
Allosteric modulators are an emerging class of orally available smallmoleculetherapeutic agents that may offer a competitive advantage over classicaldrugs.This potential stems from their ability to offer greater selectivity andbettermodulatory control at disease mediating receptors. Most marketed drugsbindreceptors where the body's own natural molecular activators (i.e.endogenousligands) bind, specifically to a key part of each receptor called the"activesite". In short, most drugs must out-compete endogenous ligands in order tobindto the active site. By contrast, allosteric modulators arenon-competitive because they bind receptors at a different site and modifyreceptor function inthe presence of endogenous ligand binding to the active site. Because ofthis,allosteric modulators are not limited to simply turning a receptor"on" or"off", the way most conventional drugs are designed. Instead,allostericmodulators act more like a dimmer switch, offering control over theintensity ofactivation or deactivation, while allowing the body to retain itsnaturalcontrol over initiating receptor activation. One of the most attractivefeaturesof receptor activation via allosteric modulation is that thesepositiveallosteric modulators (PAMs) activate the receptor only in the presenceof thenatural ligand binding to the target receptor. In the absence of naturalligandthese PAMs do not activate the receptor. This provides an elegantregulate thereceptor activation that could translate into the development of asafertherapeutic.
Pharmacological advantages of PAMs for the activation of A2AR
Beside immune cells, A2AR engagement modulates the activity of numerouscelltypes, including various neuronal populations, platelets, smoothmuscle andendothelial cells. Thus, systemic engagement of A2AR with orthostericagonists,directed at the adenosine binding site, is known to affect severaltissues andtrigger a wide range of side effects such as hypotension andtachycardia.Extracellular adenosine is locally produced within inflamed or hypoxictissuesand is highly unstable in plasma. Therefore, in the course ofinflammatoryreactions, ligand availability regulates adenosine receptors engagementboth inspace and time. Because it preserves the natural spatial and temporalcontrolsover A2AR engagement, positive allosteric modulation provides a uniquelysuitedtherapeutic approach to address the potential of A2AR activation inchronicinflammatory diseases. By enhancing the effect of high adenosineconcentrationwithin inflamed tissues, A2AR PAM would avoid side effects thatrelate toectopic or systemic triggering of A2AR and could offer a greaterselectivityover other adenosine receptors. In particular, A2AR PAMs are expected toshowreduced 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-proteincoupledreceptor (GPCR) can, among other things, negatively regulate overreactiveimmune cells, thereby protecting tissues from collateral inflammatorydamage,The A2AR's natural ligand, extracellular adenosine, is locally producedat thesites of inflammation and has been characterized for decades as a"brake forinflammation", exerting a retro-control over inflammation. Severallines ofevidence point to a broad anti-inflammatory role of A2AR in preclinicalanimalmodels. In leukocytes, A2AR is the most abundantly expressed adenosinereceptorand activating this receptor affects a range of cellular functionsacrossdifferent immune cell types including macrophage cytokinesproduction,neutrophil migration, or T-lymphocyte activation. A2AR selective agonistsshowanti-inflammatory activity and reduce tissue damage in vivo. Conversely,A2ARselective antagonists compromise regulatory T cells function andprolonginflammation following induction of an inflammatory response. Similarly,A2AR-deficient animals show enhanced and prolonged inflammatory responses.
Several marketed anti-inflammatory drugs, including methotrexateandsulfasalazine, mediate some of their anti-inflammatory effectsthrough amechanism that promotes adenosine release and activation of A2AR. However,thesedrugs are non-specific and associated with significant sideeffects. Inaddition, there is marked variability in the degree of efficacy and sideeffectsobserved with these current drugs in the clinic. There is a need forproductsthat are selective, safe and truly disease-modifying. Therefore, an oralsmallmolecule drug targeting A2AR with a new mechanism of action such as anA2AR PAMthat is active only at the sites of inflammation, lacks any agonistactivity andpreferably is peripheral, could revolutionize and offer anattractivealternative to the existing therapeutic arsenal for the treatment of anumber ofinflammatory conditions, such as rheumatoid arthritis (RA), Crohn'sdisease andpsoriasis, as well as certain rare diseases such as , sicklecell andHuntington's disease.
About Viva Biotech
Viva Biotech (www.vivabiotech.com) is privately owned and financed byleadinginvestors in the United States. It is a well-established contractresearchorganization that provides preclinical drug discovery research servicesto thepharmaceutical industry worldwide. The core capabilities of the companyincludesits leading expertise in protein crystallography and structure baseddrugdesign, a MS based screening technology with a proprietary fragmentlibrary,GPCR target preparation and crystallization, monoclonal antibody leadgenerationand other preclinical drug discovery research capabilities such as DMPK,animaldisease models for CNS and oncology. For additional information on VivaBiotech,please contact Dr. Zengquan Wang at: Zengquan.firstname.lastname@example.org.
About Addex Therapeutics
Addex Therapeutics (www.addextherapeutics.com) is a development stagecompanyfocused on advancing innovative oral small molecules against rarediseasesutilizing its pioneering allosteric modulation-based drug discoveryplatform.The Company's two lead products are being investigated in Phase 2clinicaltesting: dipraglurant (ADX48621, an mGlu5 negative allosteric modulator orNAM)is being developed by Addex to treat Parkinson's diseaselevodopa-induced dyskinesia (PD-LID) and rare forms of dystonia; andADX71149 (mGlu2 positiveallosteric modulator or PAM) is being developed in collaboration withJanssenPharmaceuticals, Inc. to treat both schizophrenia and anxiety asseen inpatients suffering from major depressive disorder. Addex is alsoadvancingseveral preclinical programs including: GABA-BR positive allostericmodulator(PAM) for Charcot-Marie-Tooth (type 1a) disease, spasticity in patientswithmultiple sclerosis (MS), pain, overactive bladder and other disorders; andmGlu4PAM for MS, Parkinson's disease, anxiety and other diseases.Allostericmodulators are an emerging class of small molecule drugs whichhave thepotential to be more specific and confer significant therapeutic advantagesoverconventional "orthosteric" small molecule or biological drugs. The Companyusesits proprietary discovery platform to target receptors and other proteinsthatare recognized as essential for the therapeutic modulation of importantdiseaseswith unmet medical needs.
Disclaimer: The foregoing release may contain forward-looking statementsthatcan 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 regardingAddexTherapeutics, formerly known as, Addex Pharmaceuticals, its business, thepotential approval of its products by regulatory authorities, or regardingpotential future revenues from such products. Such forward-lookingstatementsreflect the current views of Addex Therapeutics regarding future events,futureeconomic performance or prospects, and, by their very nature, involveinherentrisks and uncertainties, both general and specific, whether known orunknown,and/or any other factor that may materially differ from the plans,objectives,expectations, estimates and intentions expressed or implied in suchforward-looking statements. Such may in particular cause actual resultswith allostericmodulators of mGlu2, mGlu4, mGlu5, GABA-BR or other therapeutic targets tobematerially different from any future results, performance or achievementsexpressed or implied by such statements. There can be no guarantee thatallosteric modulators of mGlu2, mGlu4, mGlu5, GABA-BR or other therapeuticstargets will be approved for sale in any market or by any regulatoryauthority.Nor can there be any guarantee that allosteric modulators of mGlu2, mGlu4,mGlu5, GABA-BR or other therapeutic targets will achieve any particularlevelsof revenue (if any) in the future. In particular, management's expectationsregarding allosteric modulators of mGlu2, mGlu4, mGlu5, GABA-BR or othertherapeutic targets could be affected by, among other things, unexpectedactionsby our partners, unexpected regulatory actions or delays or governmentregulation generally; unexpected clinical trial results, includingunexpectednew clinical data and unexpected additional analysis of existing clinicaldata;competition in general; government, industry and general public pricingpressures; the company's ability to obtain or maintain patent or otherproprietary intellectual property protection. Should one or more of theserisksor uncertainties materialize, or should underlying assumptions proveincorrect,actual results may vary materially from those anticipated, believed,estimatedor expected. Addex Therapeutics is providing the information in this pressrelease as of this date and does not undertake any obligation to update anyforward-looking statements contained in this press release as a result ofnewinformation, future events or otherwise, except as may be required byapplicablelaws.
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