Addex Partners with Viva Biotech to Advance Allosteric Modulators Targeting Adenosine 2A Receptor
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 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.email@example.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.
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