EVT 101 and 103: Orally Active NR2_B Selective NMDA Antagonists for Alzheimer's Disease and | or Neuropathic Pain

Receptor subtype selectivity promises to avoid the side effects associated with non-selective NMDA antagonists

Status:
EVT 101:Phase II entry expected in H2 2008
EVT 103: Phase I ready

NMDA subtype expression pattern in the brain

EVT 101 has potential in the treatment of Alzheimer's disease and Neuropathic pain. It is a highly potent and selective antagonist of NR2_B subunit containing NMDA receptors. In preclinical models, the compound has potent beneficial effects and an improved side effect profile compared to non-selective NMDA receptor antagonists and has good oral bioavailability and in vivo pharmacokinetics.

EVT 101 has successfully completed a single and multiple ascending dose trial in a total of 90 healthy subjects, both young and elderly. In all subjects EVT 101 was well absorbed, achieved good exposure levels, and was very well tolerated with no significant adverse events. In both the young and elderly subjects, the compound had a good pharmacokinetic profile, with an eleven hour half-life consistent with once or twice daily oral dosing. The good tolerability of EVT 101 is significant given the unfavorable side-effect profile of non-selective NMDA antagonists.

Evotec has completed two additional Phase Ib studies with EVT 101. The first study was a single dose fMRI brain imaging study in health subjects which explored the effects of the compound on cognitive endpoints and on changes in local cerebral blood flow, reflecting neuronal activation or deactivation. Results from this study showed that 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. 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.

Evotec is currently planning Phase II studies of EVT 101 in both Alzheimer's disease and Neuropathic Pain.

In addition, Evotec has satisfactorily completed dosing in its four week higher repeat dose study. 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. Full results from this study are expected by the end of Q2 2008.

Evotec is currently planning Phase II studies of EVT 101 in Alzheimer's disease and/or Neuropathic Pain to commence in H2 2008.

The follow up compound EVT 103 is also an orally active, highly potent subtype specific NMDA NR2_B receptor antagonist which has successfully competed preclinical studies required for Phase I entry.

For the latest press release announcing successful completion Phase Ib Brain imaging fMRI study with EVT 101 (28th March 2008) click here