Addex ADX71149 Demonstrates Synergistic Efficacy with Levetiracetam in Preclinical Models of Epilepsy
Geneva, Switzerland, 23 September 2015 – Addex Therapeutics (SIX: ADXN), a leading company pioneering allosteric modulation-based drug discovery and development, announced today that ADX71149, a metabotropic glutamate receptor type 2 (mGluR2) positive allosteric modulator (PAM), demonstrated synergistic efficacy with levetiracetam (a globally commercialized antiepileptic drug) in preclinical models of epilepsy. ADX71149 has been extensively profiled, by Addex Partner, Janssen Pharmaceuticals Inc., in preclinical models of epilepsy showing efficacy both stand alone and in combination with SV2A ligands including levetiracetam. These data are included in patent application number WO2015110435.
In the 6 Hz psychomotor seizure test, ADX71149 given subcutaneously showed robust protection with ED50 determined to be 12.2 mg/kg and 21 mg/kg at 32 mA and 44 mA, respectively. In combination studies with varying doses of levetiracetam, a fixed dose of ADX71149 increased the potency of levetiracetam leading to an approximate 35-fold shift in its ED50. Conversely, using a fixed dose of levetiracetam with varying doses of ADX71149, levetiracetam increased the potency of ADX71149, leading to an approximate 14-fold shift in its ED50, suggesting a positive pharmacodynamic relationship or strong synergistic effect for the two molecules when given in combination.
“The 6Hz psychomotor seizure test is the most relevant model of pharmacoresistant limbic seizures and the effect observed supports a theory that modulation of presynaptic calcium channels through SV2a and control of glutamate release through activation of mGlu2 receptors are two important and potentially synergistic mechanisms in epilepsy” commented Sonia Poli, CSO at Addex. “This finding supports the clinical evaluation of ADX71149 in combination with SV2A ligands in forms of epilepsy which are resistant to standard treatments”
“The Janssen team has done an outstanding job characterizing ADX71149 in this new research area”, commented Tim Dyer, CEO at Addex. “Based on the new data, we are working with our partner on how we can move ADX71149 into a Phase IIa proof of concept study.”
About Epilepsy and Levetiracetam
Epilepsy is one of the most common serious neurological disorders affecting about 65 million people globally (Thurman et al. 2011). It affects 1% of the population by age 20 and 3% of the population by age 75 (Holmes et al. 2008). Epilepsy describes a condition in which a person has recurrent seizures due to a chronic, underlying process. Epilepsy refers to a clinical phenomenon rather than a single disease entity, since there are many forms and causes of epilepsy. Epilepsy is a disease of the brain defined by any of the following conditions: (1) At least two unprovoked (or reflex) seizures occurring >24 h apart; (2) one unprovoked (or reflex) seizure and a probability of further seizures similar to the general recurrence risk (at least 60%) after two unprovoked seizures, occurring over the next 10 years; (3) diagnosis of an epilepsy syndrome (Fisher et al. 2014). The synaptic vesicle protein 2A (SV2A) has been identified as a broad spectrum anticonvulsant target in models of partial and generalized epilepsy, and studies in animal models and human tissue suggest that changes in the expression of SV2A are implicated in epilepsy (Mendoza-Torreblanca et al. 2013; Kaminski et al. 2012). SV2A ligands include levetiracetam (Lynch et al. 2004), which is an antiepileptic drug commercialized under trademark Keppra®, approved in Europe and USA as a monotherapy or add-on therapy in patients diagnosed with epilepsy.
About ADX71149 and the Addex / Janssen Agreement
ADX71149 is a novel, first-in-class potent, oral, small molecule positive allosteric modulator (PAM) of metabotropic glutamate receptor 2 (mGluR2), a Family C class of G Protein Coupled Receptor (GPCR). The development of ADX71149 is part of a worldwide research collaboration and license agreement between Addex and Janssen Pharmaceuticals, Inc. to discover, develop and commercialize a novel mGluR2 PAM medication for the treatment of anxiety, schizophrenia and other undisclosed indications. Under the terms of the agreement, Addex is eligible for up to a total of €112 million in milestone payments based on potential development and regulatory achievements. In addition, Addex is eligible for low double-digit royalties on sales of any mGluR2 PAM medication developed under the agreement.
About Addex Therapeutics
Addex Therapeutics (www.addextherapeutics.com) is a biopharmaceutical company focused on the development of novel, orally available, small molecule allosteric modulators for neurological disorders. Addex lead drug candidate, dipraglurant (mGluR5 negative allosteric modulator or NAM) has successfully completed a Phase IIa POC in Parkinson’s disease levodopa-induced dyskinesia (PD-LID), and is being prepared to enter Phase IIb for PD-LID. In parallel, dipraglurant’s therapeutic use in dystonia and treatment resistant depression is being investigated. Addex second clinical program, ADX71149 (mGluR2 positive allosteric modulator or PAM) is being developed in collaboration with Janssen Pharmaceuticals, Inc. Addex also has several preclinical programs including: ADX71441 (GABAB receptor PAM) which has received regulatory approval to start Phase I and is being investigated for therapeutic use in Charcot-Marie-Tooth (Type 1A) disease, alcohol use disorder and nicotine dependence; mGluR4PAM for drug abuse and dependence, Parkinson’s disease and other neurodegenerative diseases; mGluR2NAM for treatment resistant depression and cognitive deficits; mGluR7NAM for psychosomatic disorders, TrkBPAM for neurodegenerative disorders; and GLP1PAM for type 2 diabetes. 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. Addex allosteric modulator drug discovery platform targets receptors and other proteins that are recognized as essential for therapeutic intervention – the Addex pipeline was generated from this pioneering allosteric modulator drug discovery platform.
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