Addex Therapeutics (SIX: ADXN), a leading company pioneering allosteric modulation-based drug discovery and development, announced today publication of a study demonstrating the potential therapeutic effect of ADX71149 (JNJ-40411813), a selective metabotropic glutamate type 2 (mGlu2) receptor positive allosteric modulator (PAM), in severe panic disorders and post-traumatic stress disorder (PTSD). Data published in the leading peer-reviewed journal, Molecular Psychiatry, shows that a panic-prone state leads to specific reduction in mGluR2 function within the amygdala network in the brain and facilitates the fear response, suggesting treatment with an mGluR2 PAM, such as ADX71149, could provide an effective alternative in these difficult to treat disorders. ADX71149 is licensed to Janseen Pharmaceuticals Inc., and is currently being prepared for a Phase 2 study in patients with epilepsy.
“This excellent research by Dr Shekhar and his co-authors at Indiana University School of Medicine supports the potential of ADX71149 in additional, difficult to treat psychiatric disorders. We have hypothesized for some time on the multifaceted effects that the fear response has on certain areas of the brain but are now able to pinpoint specific molecular changes in the amygdala network, an area of the brain integrally involved in fear and generating a panic response,” commented Robert Lütjens, co-head of discovery at Addex. “We continue to study the role our allosteric modulators play in all types of neurological disorders and believe our approach could lead to safer and potentially more effective treatments.”
In the publication, the researchers show that optogenetic stimulation of the amygdala region enhances acquisition, delays the extinction of conditioned fear, and strengthens long-term fear memories. Using electrophysiological approaches on amygdala slices taken from panic-prone rats, an increase in the excitability of principal neurons in the amygdala was observed. Pretreatment with the selective mGluR2 PAM, JNJ-42153605, reduced the frequency of spontaneous excitatory postsynaptic potentials and significantly reduced glutamate release within the amygdala region.Treating panic-prone rats with the ADX71149 resulted in prevention of sodium lactate-induced panic responses and normalized conditioned fear extinction deficits. These findings led the researchers to re-analyze the results from a Phase 2 clinical study that evaluated ADX71149 as an adjunctive treatment for major depressive disorder (MDD) with significant anxiety symptoms. The post-hoc analysis shows that a subset of patients with panic disorder symptoms and treated with ADX71149 demonstrated remission of their panic symptom scores.
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 medications for the treatment of anxiety, schizophrenia, epilepsy 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.