Addex Announces Positive Data with ADX71441 in a Pre-Clinical Transgenic Model of Charcot-Marie-Tooth 1A Disease
January 7, 2013 - Geneva
Addex Therapeutics /Addex Announces Positive Data with ADX71441 in a Pre-Clinical TransgenicModelof Charcot-Marie-Tooth 1A Disease. Processed and transmitted by Thomson Reuters ONE.The issuer is solely responsible for the content of this announcement.
ADX71441, a novel oral small molecule positive allosteric modulator, ontrackfor Phase 1 clinical testing in the first half of 2013
Addex Therapeutics (SIX: ADXN), a leadingcompany pioneering allosteric modulation-based drug discovery anddevelopment,announced today achievement of a positive Proof of Concept for its leadGABA-Breceptor (GABA-BR) positive allosteric modulator (PAM) compound, ADX71441,in avalidated pre-clinical model of Charcot-Marie-Tooth 1A (CMT1A). CMT1A is arare(1:5,000) hereditary motor and sensory demyelinating peripheral neuropathy(alsoknown as Hereditary Motor and Sensory Neuropathy, HMSN) which is caused byanintrachromosomal duplication and consecutive toxic overexpression of thePMP22gene on chromosome 17. CMT1A is one of the most common inherited peripheralnerve-related disorders which is passed down through families in anautosomaldominant fashion. CMT1A disease becomes evident in young adulthood andslowlyprogresses with distally pronounced muscle weakness and numbness. Pain canrangefrom mild to severe. The disease can be highly debilitating with wheelchair-boundness and is often accompanied by severe cases of neurologicalpain. Thereis no known cure for this incapacitating disease.
"We are very excited about the promising results obtained with the AddexGABA-BRPAM candidate" said Professor Michael Sereda, of the Max-PlanckInstitute ofExperimental Medicine, Göttingen, Germany, in whose laboratories thestudy wasperformed. "Current CMT1A therapies are primarily symptomaticsuch asphysiotherapy and only focus on the manifestations of the disease,while thedata obtained with the Addex compound seem to suggest that positivemodulationof GABA-B receptor could lower toxic PMP22 overexpression and potentiallydelaythe progression of the disease and offer a unique therapeuticopportunity forCMT1A patients".
ADX71441 is a potent, selective, orally available small molecule that isbrainpenetrant and shows good pharmacokinetic properties for once-daily dosing.AddexGABA-BR PAM was studied in the transgenic CMT rat model which has 1.6-foldPMP22overexpression (mRNA level) and exhibits clinical abnormalities, such asreducednerve conduction velocity and lower grip strength that mimic findings inCMT1Apatients. Nine week oral therapy of ADX71441 in CMT rats (5 weeks everyotherday at 10 mg/kg followed by 4 weeks at 5 mg/kg every day) down regulatedPMP22mRNA, reduced the amount of hypo-myelinated axons and increased compoundmuscleaction potentials in peripheral nerves when compared to vehicletreated CMTrats. It also prevented grip strength loss in CMT rats compared to wildtyperats.
"These data confirm previous observations obtained using a GABA-BRagonist andthe GABAB1-/- mice (knock-out mice), which identified the importance ofGABA-BRin the inhibition of the proliferation and in the reduction of thesynthesis ofspecific myelin proteins, in particular PMP22" noted Sonia Poli, VP NonClinicalDevelopment at Addex. "These and other data further reinforce the centralroleof GABA-BR in a broad range of important diseases and conditions,includingspasticity, Fragile X, autism, pain, anxiety, obsessive-compulsivedisorder,overactive bladder and alcohol binge drinking".
"We are rapidly advancing ADX71441 into clinical development. Phase 1clinicaltesting with this compound is planned for the first half of this year,initiallyfor the treatment of spasticity associated with multiple sclerosis (MS)"saidGraham Dixon, CSO at Addex. "These data are very encouraging as theyindicatethat the compound may also have a therapeutic benefit in treatment ofpatientswith this debilitating rare disease."
CMT1A is a rare hereditary motor and sensory neuropathy (HMSN) whichcausesdemyelination of the peripheral nerves with a consequence ofseverely anduniformly reduced nerve conduction velocities and consecutive axonalloss. Thedisease leads to damage or destruction to the myelin sheath coveringaroundnerve fibers. Nerves that stimulate movement, the motor nerves, aremostseverely affected. The nerves in the legs are affected first and mostseverely.Similar symptoms may appear in the arms and hands, which may include aclaw-likehand. The disease is highly invalidating with cases of accompanyingneurologicalpain and muscle loss. A combination of lower motor neuron-type motordeficitsand sensory symptoms are observed: paresis and muscle atrophy develops,withareflexia. The chronic nature of the motor neuropathy will result infootdeformity, hammertoes, very high-arched feet, loss of lower leg muscle,whichleads to skinny calves, numbness in the foot or leg, "steppage" gait(feet hitthe floor hard when walking), foot drop (inability to hold foothorizontal) andweakness of the hips, legs, or feet. Involvement of the hands may followas thedisease progresses. Signs of sensory system dysfunction are common(70%) andinclude loss of vibration and joint position sense followed by decreasedpainand temperature sensation. Onset of the disease is between age 5 and 25years,with a prevalence of 1 in 5,000. Charcot-Marie-Tooth is one of the mostcommoninherited nerve-related disorders passed down through families in anautosomaldominant fashion. Charcot-Marie-Tooth disease slowly gets worse. Someparts ofthe body may become numb, and pain can range from mild to severe.Eventually thedisease may cause disability. There are no known cures for thisdebilitatingcondition. Duplication of a chromosome 17 fragment harbouring PMP22 (=CMT1A)represents 43% of the total CMT cases, whereas the yield ofduplicationdetection rises to 70% in CMT1. PMP22 is an essential component ofmyelinexpressed in all myelinated fibers in the PNS and is produced by Schwanncells.While PMP22 represents only 2-5% of the amount of peripheral myelinprotein inrodents and humans, it is necessary for stabilizing compact myelin.However,PMP22 is not only an essential constituent of myelin, but too much or toolittleof the protein causes neuropathy, possibly by disturbing Schwann cellgrowth anddifferentiation.
Activation of gamma-aminobutyric acid subtype B (GABA-B) receptor, aFamily Cclass of GPCR, is clinically & commercially validated. Generic GABA-Breceptoragonist, baclofen, is marketed for spasticity and some spinal cordinjuries, andused for OAB, but is not commonly used due to severe side effects of thedrugand rapid clearance. Orthosteric GABA-B receptor agonists have alsoshownclinical validation in gastroesophageal reflux disease (GERD). Addex'GABA-Breceptor PAMs have shown efficacy in multiple preclinical modelsincluding:CMT1A, OAB, pain, osteoarthritis pain and anxiety.
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 mGlu5negativeallosteric modulator or NAM) is being developed by Addex to treatParkinson'sdisease levodopa-induced dyskinesia (PD-LID); and ADX71149 (mGlu2positiveallosteric modulator or PAM) is being developed in collaboration withJanssenPharmaceuticals Inc. to treat schizophrenia and anxiety seen inpatientssuffering from major depressive disorder. Addex also is advancingseveralpreclinical programs including: GABA-BR PAM for spasticity in MS, OAB andotherdisorders; mGlu4 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 mGlu2, mGlu4, mGlu5, GABA-BR or other therapeutic targetsto bematerially different from any future results, performance orachievementsexpressed or implied by such statements. There can be no guaranteethatallosteric modulators of mGlu2, mGlu4, mGlu5, GABA-BR or othertherapeuticstargets 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'sexpectationsregarding allosteric modulators of mGlu2, mGlu4, mGlu5, GABA-BR 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.
This announcement is distributed by Thomson Reuters on behalf ofThomson Reuters clients. The owner of this announcement warrants that:
(i) the releases contained herein are protected by copyright and other applicable laws; and
(ii) they are solely responsible for the content, accuracy and originality of the information contained therein.
Source: Addex Therapeutics via Thomson Reuters ONE
Chief Financial Officer
+41 22 884 15 61