mGlu2 NAM for mild neurocognitive disorders

mGlu2 NAM for the treatment of mild neurocognitive disorders, or mNCD.

We are developing mGlu2 NAM as a novel orally available treatment for mNCD associated with Alzheimer’s disease, Parkinson’s disease and depressive disorders.

mNCD is a state of moderate cognitive decline leading to a lower quality-of-life, loss of autonomy and often dementia and associated psychiatric symptoms (depression, anxiety). It affects approximately 15% of the population over 60 years of age and is associated with a high societal impact, including loss of working hours, productivity, and caregiver burden. Current therapeutic approaches are not widely used due to their lack of efficacy and many side effects. With no specific therapeutic interventions available for mNCD, there is a strong medical need for new approaches that halt cognitive decline in these patients.

Glutamate is the primary excitatory neurotransmitter in the brain, and alterations in its release, receptor function, or signaling pathways can have profound effects on cognitive processes. Inhibition of ionotropic glutamate receptors (NMDA & AMPA) has been shown to impair cognition, while their activation as a strategy to enhance cognition has been hampered by challenges linked to adverse effects. The mGlu2 receptor is expressed in the brain on presynaptic nerve terminals where it modulates glutamate release, helping to maintain the balance of excitatory neurotransmission. Selective inhibition of mGlu2 receptors may therefore represent a different approach to increase glutamatergic tone, devoid of adverse effects linked to direct ionotropic receptor activation. Addex has made significant investment and progress in developing novel mGlu2 NAMs that possess high brain penetration and will selectively modulate the mGlu2 receptors only. These characteristics are significant improvements compared to traditional, orthosteric inhibitors, which are poorly selective for glutamate receptors and necessitate development of prodrugs to allow delivery to the brain, significantly increasing the cost of goods. Our program is in lead optimization and an Addex led consortium has been awarded a €4 million Eurostars grant to deliver clinical candidates to treat mild neurocognitive disorders.