Addex’s ADX71149 Anti-Epileptic Effect Highlighted in Scientific Journal, Epilepsia
Geneva, Switzerland, 27 February 2017 – Addex Therapeutics (SIX: ADXN) announced today the publication of a study demonstrating the anti-epileptic effects of ADX71149, a metabotropic glutamate receptor subtype 2 (mGlu2) positive allosteric modulator (PAM), given alone or in combination with the globally marketed antiseizure drug levetiracetam (LEV) in a preclinical model of epilepsy. These data, published in Epilepsia, the peer-reviewed journal of the international league against epilepsy (http://onlinelibrary.wiley.com/doi/10.1111/epi.13659/abstract), support the potential utility of ADX71149 to address treatment-resistant epilepsy.
“These studies performed by our collaborator Janssen Pharmaceuticals, Inc. suggest there is a positive pharmacodynamic relationship or strong synergistic effect for ADX71149 and LEV when given in combination,” said Robert Lütjens, Head of Discovery of Addex. “If this effect can be translated in the clinic, it will strongly support a rational polypharmacy concept in the treatment of epilepsy patients.”
The publication summarizes the effects obtained when the mGlu2 receptor is activated using an agonist or PAM, such as ADX71149, in the 6Hz psychomotor seizure test, considered to be the most relevant model of pharmacoresistant limbic seizures. In particular, the data show that while seizures are reduced when mGlu2-acting compounds are administered alone, their combination with LEV result in a potent reduction of doses required to produce full efficacy, which is important because higher doses of LEV are associated with dose-limiting side effects, such as aggression, nervousness/anxiety, somnolence and fatigue. In this study, a fixed dose of ADX71149 was seen to increase the potency of LEV, leading to an approximate 35-fold increase in its potency. Conversely, using a fixed dose of LEV with varying doses of ADX71149 resulted in an approximate 14-fold increase in ADX71149 potency.
“The Janssen team has conducted outstanding research with mGlu2 PAMs and continue to validate the potential of ADX71149 in epilepsy,” commented Tim Dyer, CEO of Addex. “Treatment-resistant epilepsy remains a high unmet medical need, with new avenues of treatment urgently needed. We are continuing to explore with Janssen how best to move ADX71149 into a Phase 2a proof of concept study.”
About Epilepsy and Levetiracetam (LEV): 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. It also 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 more than 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.
Addex Therapeutics (www.addextherapeutics.com) is a biopharmaceutical company focused on the development of novel, orally available, small molecule allosteric modulators for neurological disorders. 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's 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. Addex's lead drug candidate, dipraglurant (mGluR5 negative allosteric modulator or NAM) has successfully completed a Phase 2a POC in Parkinson's disease levodopa-induced dyskinesia (PD-LID), and is being prepared to enter registration trials for PD-LID with support from the Michael J. Fox Foundation for Parkinson's Research (MJFF). In parallel, dipraglurant's therapeutic use in dystonia is being investigated with support from the Dystonia Medical Research Foundation (DMRF). Addex's second clinical program, ADX71149 (mGluR2 positive allosteric modulator or PAM) is being developed in collaboration with Janssen Pharmaceuticals, Inc for epilepsy. In addition, ADX71441 (GABAB receptor PAM) has received regulatory approval to start Phase 1 and is being investigated for its therapeutic use in Charcot-Marie-Tooth Type 1A disease (CMT1A), cocaine and alcohol use disorder and nicotine dependence. Discovery programs include mGluR4PAM, mGluR7NAM, TrkBPAM and mGluR3NAM & PAM.
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