>> VistGen's AV-101 is an NMDA receptor modulator. Its mechanism allows it to have ketamine-like efficacy and fast onset of action <<
No, AV-101 hits NMDA and AMPA, while Ketamine hits NMDA and opioid receptors. Even Ketamine doesn't have Ketamine-like efficacy when the opioid receptor is blocked by naltrexone. The key to Ketamine's remarkable fast onset is it's mysterious (and unique?) activity at the opioid receptor. For another drug to get ultra fast onset will almost certainly require similar opioid receptor activity.
The obvious way to get another fast acting antidepressant is to make a minor tweak to the structure of Ketamine. Spravato works because it is the mirror image isomer of Ketamine, and thus retains at least some of Ketamine's activity at the opioid receptor.
Dosing AV-101 for only 2 weeks is the other flaw in VTGN's clinical strategy. If AV-101 relies on AMPA to improve depression symptoms via stimulating neurogenesis, this is not something that will happen in a few days or weeks. You'll likely need at least 4 weeks of dosing, and 8 would be better.
The way things stand, Elevate trial may fail and they still won't know what they have with AV-101, other than it doesn't have fast onset. It might still be a good antidepressant after long term dosing but this won't be revealed by Elevate since it only doses for 2 weeks.
So the problems here are two-fold -
1) AV-101 doesn't hit the opioid receptor (which is the key to fast onset), and
2) AV-101 relies on AMPA activation to stimulate neurogenesis (growth of new neurons), a process that takes longer than 2 weeks.
While the odds here are low, I'm hoping that AV-101 succeeds since there are millions of patients who could use a new/better treatment option.
