Addex Therapeutics, a leading company pioneering allosteric modulation-based drug discovery and development, announced that ADX71149, a metabotropic glutamate receptor type 2 (mGluR2) positive allosteric modulator (PAM), demonstrated synergistic efficacy with levetiracetam (a globally commercialised 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."
Epilepsy is one of the most common serious neurological disorders affecting about 65 million people globally (Thurman et al. 2011). It affects 1 per cent of the population by age 20 and 3 per cent 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 per cent) after two unprovoked seizures, occurring over the next 10 years; (3) diagnosis of an epilepsy syndrome. 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. SV2A ligands include levetiracetam, which is an antiepileptic drug commercialised under trademark Keppra, approved in Europe and USA as a monotherapy or add-on therapy in patients diagnosed with epilepsy.
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 commercialise 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.