Addex mGluR4 Allosteric Modulator Effective in Multiple Sclerosis Model - A Novel Oral Small Molecule Approach for the Treatment of Multiple Sclerosis
GENEVA, Sep 24, 2012 (MARKETWIRE via COMTEX) -- Addex Therapeutics / Addex mGluR4 Allosteric Modulator Effective in Multiple Sclerosis Model - A Novel Oral Small Molecule Approach for the Treatment of Multiple Sclerosis.
Addex Therapeutics (six:ADXN), a leading company pioneering allosteric modulation-based drug discovery and development, announced today achievement of a positive Proof of Concept for its lead metabotropic glutamate receptor 4 (mGluR4) positive allosteric modulator (PAM) compound series in a validated rodent model for multiple sclerosis (MS). MS is a chronic inflammatory demyelinating auto-immune disease that affects the central nervous system (CNS), leading to serious disability.
"We are very excited that this promising Addex mGluR4 PAM series may offer a differentiated approach to treating MS," said Professor Ursula Grohmann, of University of Perugia, Italy, in whose laboratories one of these studies was performed. "These data confirm our previous observations, using an mGluR4 PAM tool compound called PHCCC, which demonstrated efficacy in the industry standard neuroinflammation model of MS, the Relapsing-Remitting Experimental Allergic Encephalomyelitis (RR-EAE) model. In this study, the mGluR4 PAM worked by promoting regulatory T-cell (Treg) formation and reversing pro-inflammatory T-cell release. Therefore, we believe that positive modulation of mGluR4 could potentially stop the destruction of myelin in MS in a robust and durable manner."
Addex lead chemical series is a highly selective orally available mGluR4 PAM and shows good pharmacokinetic properties for potential once-daily dosing. When administered once a day for 3 weeks at 10, 30 and 60 mg/kg sc, Addex mGluR4 PAM demonstrated a dose-dependent, statistically significant reduction in paralysis (clinical score) and the relapse rate in the RR-EAE model of MS in mice. The presentation of these data is being planned for a major international conference.
"Current MS therapies are primarily focused on reinstating motor function after an inflammatory attack, preventing new attacks, and preventing or treating disability and symptoms, such as spasticity. In addition, most of these therapies are primarily based on immunomodulatory strategies, and have serious compliance-limiting side effects", noted Graham Dixon, CSO of Addex Therapeutics. "We believe a well-tolerated, oral mGluR4 PAM would represent a major advance in the treatment of MS because of the novel and potentially broader mechanism; having the potential to not only treat symptoms, but slow disease progression and offer neuroprotection. We are now rapidly advancing this lead series towards a clinical candidate and conducting experiments to further elucidate the biological role of mGluR4 PAM in MS."
"Moving the lead compound from this series into full development in 2012 clearly illustrates our strategy of advancing innovative novel selective oral small molecule drug candidates against previously "undruggable" targets" said Bharatt Chowrira, CEO of Addex Therapeutics. "These data along with the recently announced data on the role of the mGluR4 PAMs in Parkinson's disease, the positive Phase 2 data for dipraglurant in Parkinson's disease levodopa-induced dyskinesia, the two Phase 2 clinical trials being conducted by our partner Janssen, and our GABABR PAM program advancing towards an IND filing later this year, demonstrate the power of Addex platform that continues to generate multiple, novel high value product opportunities."
About Multiple Sclerosis
Multiple sclerosis, is an idiopathic inflammatory disease of the central nervous system, characterized pathologically by demyelination and subsequent axonal degeneration. The disease commonly presents in young adults and affects twice as many women as men. Common presenting symptoms include numbness, weakness, visual impairment, loss of balance, dizziness, urinary bladder urgency, fatigue, and depression. Approximately 2.5 million people worldwide are affected with prevalence ranging from 2 and 150 per 100,000, depending on the country and specific population. MS takes several forms. The most common affecting around 85 per cent of everyone diagnosed with MS is relapsing remitting MS (RRMS). It means that symptoms appear (a relapse), and then fade away, either partially or completely (remitting). Secondary progressive MS (SPMS) is a stage of MS which comes after RRMS in many cases. Although the pathogenesis of MS is complex and not fully understood, it is believed that RRMS is characterized by repeated episodes of inflammation which eventually leads to the axonal degeneration through damage to, and loss of the myelin sheath characteristic of SPMS. Given the prominence of immune generated inflammation in MS, treatments for the disease have focused particularly on immunosuppressive anti-inflammatory strategies. Currently approved treatments for RRMS are only partially effective in reducing MS relapses and in particular do not halt disability progression. As these drugs alter immune function, patients can experience serious and sometimes life threatening side effects (e.g. opportunistic infections, emergent malignancies, alopecia, cardiotoxicity and myelosuppression). Furthermore, many of these agents also require regular injection, or parenteral infusions which are uncomfortable and inconvenient for the patient.
The most significant unmet need in MS is for therapies that either stop or reverse neuronal damage and/or offer improved symptom relief (such as spasticity, pain, cognition). However, there is still demand for new agents for treatment of RRMS and for therapies with improved safety/tolerability/side effect profiles. The global MS therapeutics market was valued at over $9 billion in 2011 and is forecast to grow to over $12 billion by 2019.
High levels of glutamate are detected in patients with relapsing remitting multiple sclerosis. It has been suggested that glutamate may affect neuroinflammation via modulation of immune cells and/or neuroprotection through mGluR4 signaling. Therefore, pharmacological activation of mGluR4 may represent a novel therapeutic avenue addressing multiple aspects of MS pathology. The mGluR4 belongs to the Group III mGluRs (Class C G-Protein Coupled Receptor) and is negatively coupled to adenylate cyclase via activation of the Gai/o protein. It is expressed primarily on presynaptic terminals, functioning as an autoreceptor or heteroceptor and its activation leads to decreases in neurotransmitter release from presynaptic terminals. The mGluR4 have unique distribution in key brain regions involved in multiple CNS disorders. In particular, mGluR4 is abundant in striato-pallidal synapses within the basal ganglia circuitry a key area implicated in movement disorders, like Parkinson's disease. In the immune system mGluR4 has been found on dendritic cells (DCs). Emerging data implicate mGluR4 in multiple indications such as multiple sclerosis, Parkinson's disease, anxiety, neuropathic and inflammatory pain, schizophrenia and diabetes. Addex Therapeutics ( www.addextherapeutics.com ) discovers and develops an emerging class of small molecule drugs, called allosteric modulators, 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 address receptors and other proteins that are recognized as attractive targets for modulation of important diseases with unmet medical needs. The Company's two lead products are being investigated in Phase 2 clinical testing: dipraglurant (ADX48621, an mGluR5 negative allosteric modulator or NAM) is being developed by Addex to treat Parkinson's disease levodopa-induced dyskinesia (PD-LID); and ADX71149 (mGluR2 positive allosteric modulator or PAM) is being developed by our partner Janssen Pharmaceuticals Inc. to treat schizophrenia and anxiety seen in patients suffering from major depressive disorder. Addex also is advancing several preclinical programs including: GABABR PAM for overactive bladder and other disorders; mGluR4 PAM for Parkinson's, MS, anxiety and other diseases. In addition, Addex is applying its proprietary discovery platform to identify highly selective and potent allosteric modulators of a number of both GPCR and non-GPCR targets that are implicated in diseases of significant unmet medical need.
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 mGluR2, mGluR4, mGluR5, GABABR 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 mGluR2, mGluR4, mGluR5, GABABR 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 mGluR2, mGluR4, mGluR5, GABABR 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 mGluR2, mGluR4, mGluR5, GABABR 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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