Evotec Announce Preliminary Findings of its Orally Active NR2B Subtype Selective NMDA Receptor Antagonist

Evotec AG has announced the preliminary findings of a double-blind, single-dose, 3-way cross-over study with its orally active NR2B subtype selective NMDA receptor antagonist, EVT 101.

The study was performed in 19 healthy young subjects and was conducted at the Centre for Neuroimaging Sciences of the Institute of Psychiatry at King’s College London using functional magnetic resonance imaging techniques (fMRI) to investigate short-term effects of two doses of EVT 101 and placebo.

The effects of the compound on cognitive endpoints, changes in local cerebral blood flow, reflecting neuronal activation or deactivation during the performance of cognitive tasks, as well as base-line regional cerebral blood flow, were explored.

All treatments were well tolerated confirming previous observations in healthy subjects.

While there was no evidence of acute improvement in cognitive function, an observation not unexpected in healthy young subjects who frequently per-form at an optimum level, the activity of a number of brain regions, known for their role as a memory retrieval network, were selectively modified during the performance of certain tasks, as assessed by analysis of the changes in local cerebral blood flow.

Analysis of the changes in basal regional cerebral blood flow indicated a selective increase in blood flow in one specific region of the cortex, an area rich in NMDA receptors which is considered to be significant for indications such as pain and depression. Basal blood flow in other brain areas was unaffected.

These findings represent the first demonstration of effects of EVT 101 on human brain function at doses that are well tolerated and predicted to be clinically relevant.

In addition, Evotec has satisfactorily completed dosing of its four week higher repeat dose study conducted in France. Encouragingly, initial findings regarding the cerebrospinal fluid (CSF) penetration of EVT 101 assessed in a subgroup receiving EVT 101 showed that the compound demonstrated penetration into the CSF at levels predicted to inhibit NR2B receptors to a significantly higher amount than memantine at its therapeutic dose in Alzheimer’s Disease.

“These data are extremely encouraging. They demonstrate EVT 101 penetrates the brain at doses that are well tolerated in man and expected to be clinically relevant, shows activity in areas relevant to pain and, importantly, modulates the activity of specific brain regions during the performance of cognitive tasks relevant to Alzheimer’s disease”, commented Dr Tim Tasker, Executive Vice President Clinical Development, Evotec AG.

Dr Mitul Mehta, academic lead for the project at the Centre for Neuro-imaging Sciences at the Institute of Psychiatry at King’s College Lon-don stated: “We have clearly visualized not only a direct, dose dependent effect of the compound on the brain but also an interaction of the drug with tasks pertinent to cognitive performance and dysfunction in Alzheimer's disease. These exciting new data also bode well for future studies in several indications of neurological and psychiatric ill health.”