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Addex mGluR4 Allosteric Modulator Effective in Multiple Sclerosis Model - A Novel Oral Small Molecule Approach for the Treatment of Multiple Sclerosis


September 24, 2012 - Geneva

Addex Therapeutics / Addex mGluR4 AllostericModulator Effective in Multiple Sclerosis Model - ANovel Oral Small Molecule Approach for the Treatment of Multiple Sclerosis.

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Addex Therapeutics (SIX: ADXN), aleading company pioneering allosteric modulation-based drug discoveryanddevelopment, announced today achievement of a positive Proof of Conceptfor itslead metabotropic glutamate receptor 4 (mGluR4) positive allostericmodulator(PAM) compound series in a validated rodent model for multiple sclerosis(MS).MS is a chronic inflammatory demyelinating auto-immune disease thataffects thecentral nervous system (CNS), leading to serious disability.

"We are very excited that this promising Addex mGluR4 PAM series mayoffer adifferentiated approach to treating MS," said Professor UrsulaGrohmann, ofUniversity of Perugia, Italy, in whose laboratories one of thesestudies wasperformed. "These data confirm our previous observations, using anmGluR4 PAMtool compound called PHCCC, which demonstrated efficacy in the industrystandardneuroinflammation model of MS, the Relapsing-Remitting ExperimentalAllergicEncephalomyelitis (RR-EAE) model. In this study, the mGluR4 PAMworked bypromoting regulatory T-cell (Treg) formation and reversingpro-inflammatory T-cell release. Therefore, we believe that positivemodulation of mGluR4 couldpotentially stop the destruction of myelin in MS in a robust anddurablemanner."

Addex lead chemical series is a highly selective orally available mGluR4PAM andshows good pharmacokinetic properties for potential once-daily dosing.Whenadministered once a day for 3 weeks at 10, 30 and 60 mg/kg sc, AddexmGluR4 PAMdemonstrated a dose-dependent, statistically significant reduction inparalysis(clinical score) and the relapse rate in the RR-EAE model of MS inmice. Thepresentation of these data is being planned for a majorinternationalconference.

"Current MS therapies are primarily focused on reinstating motor functionafteran inflammatory attack, preventing new attacks, and preventing ortreatingdisability and symptoms, such as spasticity. In addition, most ofthesetherapies are primarily based on immunomodulatory strategies, and haveseriouscompliance-limiting side effects", noted Graham Dixon, CSO ofAddexTherapeutics. "We believe a well-tolerated, oral mGluR4 PAM wouldrepresent amajor advance in the treatment of MS because of the novel andpotentiallybroader mechanism; having the potential to not only treat symptoms, butslowdisease progression and offer neuroprotection. We are now rapidly advancingthislead series towards a clinical candidate and conducting experiments tofurtherelucidate the biological role of mGluR4 PAM in MS."

"Moving the lead compound from this series into full development in 2012clearlyillustrates our strategy of advancing innovative novel selective oralsmallmolecule drug candidates against previously "undruggable" targets" saidBharattChowrira, CEO of Addex Therapeutics. "These data along with therecentlyannounced data on the role of the mGluR4 PAMs in Parkinson'sdisease, thepositive Phase 2 data for dipraglurant in Parkinson's diseaselevodopa-induced dyskinesia, the two Phase 2 clinical trials beingconducted by our partnerJanssen, and our GABABR PAM program advancing towards an IND filing laterthisyear, demonstrate the power of Addex platform that continues togeneratemultiple, novel high value product opportunities."

About Multiple Sclerosis

Multiple sclerosis, is an idiopathic inflammatory disease of the centralnervoussystem, characterized pathologically by demyelination and subsequentaxonaldegeneration. The disease commonly presents in young adults and affectstwice asmany women as men. Common presenting symptoms include numbness, weakness,visualimpairment, loss of balance, dizziness, urinary bladder urgency,fatigue, anddepression. Approximately 2.5 million people worldwide are affectedwithprevalence ranging from 2 and 150 per 100,000, depending on thecountry andspecific population. MS takes several forms. The most common affectingaround85 per cent of everyone diagnosed with MS is relapsing remitting MS(RRMS). Itmeans that symptoms appear (a relapse), and then fade away, eitherpartially orcompletely (remitting). Secondary progressive MS (SPMS) is a stage of MSwhichcomes after RRMS in many cases. Although the pathogenesis of MS iscomplex andnot fully understood, it is believed that RRMS is characterized byrepeatedepisodes of inflammation which eventually leads to the axonaldegenerationthrough damage to, and loss of the myelin sheath characteristic of SPMS.Giventhe prominence of immune generated inflammation in MS, treatmentsfor thedisease have focused particularly on immunosuppressiveanti-inflammatory strategies. Currently approved treatments for RRMS areonly partially effectivein reducing MS relapses and in particular do not halt disabilityprogression.As these drugs alter immune function, patients can experienceserious andsometimes life threatening side effects (e.g. opportunistic infections,emergentmalignancies, alopecia, cardiotoxicity and myelosuppression). Furthermore,manyof these agents also require regular injection, or parenteral infusionswhichare uncomfortable and inconvenient for the patient.

The most significant unmet need in MS is for therapies that eitherstop orreverse neuronal damage and/or offer improved symptom relief(such asspasticity, pain, cognition). However, there is still demand for newagents fortreatment of RRMS and for therapies with improvedsafety/tolerability/sideeffect profiles. The global MS therapeutics market was valued at over $9billionin 2011 and is forecast to grow to over $12 billion by 2019.

About mGluR4

High levels of glutamate are detected in patients with relapsingremittingmultiple sclerosis. It has been suggested that glutamate mayaffectneuroinflammation via modulation of immune cells and/or neuroprotectionthroughmGluR4 signaling. Therefore, pharmacological activation of mGluR4 mayrepresenta novel therapeutic avenue addressing multiple aspects of MSpathology. ThemGluR4 belongs to the Group III mGluRs (Class C G-Protein CoupledReceptor) andis negatively coupled to adenylate cyclase via activation of theGαi/oprotein. It is expressed primarily on presynaptic terminals, functioningas anautoreceptor or heteroceptor and its activation leads todecreases inneurotransmitter release from presynaptic terminals. The mGluR4 haveuniquedistribution in key brain regions involved in multiple CNSdisorders. Inparticular, mGluR4 is abundant in striato-pallidal synapses within thebasalganglia circuitry a key area implicated in movement disorders, likeParkinson'sdisease. In the immune system mGluR4 has been found on dendritic cells(DCs).Emerging data implicate mGluR4 in multiple indications such asmultiplesclerosis, Parkinson's disease, anxiety, neuropathic and inflammatorypain,schizophrenia and diabetes.Addex Therapeutics (www.addextherapeutics.com) discovers anddevelops anemerging class of small molecule drugs, called allosteric modulators, whichhavethe potential to be more specific and confer significant therapeuticadvantagesover conventional "orthosteric" small molecule or biological drugs. TheCompanyuses its proprietary discovery platform to address receptors and otherproteinsthat are recognized as attractive targets for modulation of importantdiseaseswith unmet medical needs. The Company's two lead products are beinginvestigatedin Phase 2 clinical testing: dipraglurant (ADX48621, an mGluR5negativeallosteric modulator or NAM) is being developed by Addex to treatParkinson'sdisease levodopa-induced dyskinesia (PD-LID); and ADX71149 (mGluR2positiveallosteric modulator or PAM) is being developed by our partnerJanssenPharmaceuticals Inc. to treat schizophrenia and anxiety seen inpatientssuffering from major depressive disorder. Addex also is advancingseveralpreclinical programs including: GABABR PAM for overactive bladder andotherdisorders; mGluR4 PAM for Parkinson's, MS, anxiety and otherdiseases. Inaddition, Addex is applying its proprietary discovery platform toidentifyhighly selective and potent allosteric modulators of a number of bothGPCR andnon-GPCR targets that are implicated in diseases of significant unmetmedicalneed.

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, itsbusiness, thepotential approval of its products by regulatory authorities, orregardingpotential 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 mGluR2, mGluR4, mGluR5, GABABR or other therapeutic targetsto bematerially different from any future results, performance orachievementsexpressed or implied by such statements. There can be no guaranteethatallosteric modulators of mGluR2, mGluR4, mGluR5, GABABR or othertherapeuticstargets will be approved for sale in any market or by any regulatoryauthority.Nor can there be any guarantee that allosteric modulators of mGluR2,mGluR4,mGluR5, GABABR or other therapeutic targets will achieve any particularlevelsof revenue (if any) in the future. In particular, management'sexpectationsregarding allosteric modulators of mGluR2, mGluR4, mGluR5, GABABR orothertherapeutic targets could be affected by, among other things, unexpectedactionsby our partners, unexpected regulatory actions or delays orgovernmentregulation generally; unexpected clinical trial results, includingunexpectednew clinical data and unexpected additional analysis of existing clinicaldata;competition in general; government, industry and general publicpricingpressures; the company's ability to obtain or maintain patent orotherproprietary 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 thispressrelease as of this date and does not undertake any obligation toupdate anyforward-looking statements contained in this press release as a resultof newinformation, future events or otherwise, except as may be required byapplicablelaws.

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