Potential for Ketamine-like Antidepressant Effects without Ketamine's CNS Side-Effects

AV-101 is an oral N-methyl-D-aspartate (NMDA) receptor glycine B (GlyB) antagonist in Phase 2 clinical development in the United States, initially as a new adjunctive treatment of MDD in patients with an inadequate response to current FDA-approved antidepressants. AV-101 has a novel mechanism of action (MOA), meaning its MOA is fundamentally different from all current FDA-approved treatments for depression. Most current FDA-approved antidepressants, commonly known as SSRIs and SNRIs, target the neurotransmitters serotonin and/or norepinephrine, respectively. If effective, SSRIs and SNRIs take many weeks to achieve therapeutic benefits. AV-101 targets glutamate, the most prevalent neurotransmitter in the brain. Similar to intravenous ketamine, an NMDA receptor antagonist which blocks activity of the NMDA receptor causing psychotomimetic side effects and safety concerns, AV-101 inhibits NMDA receptor activity and has the potential to achieve ketamine-like antidepressant effects, but with oral administration and without ketamine's side effects and safety concerns.

AV-101 may also have the potential to treat neuropathic pain, epilepsy, Parkinson's disease levodopa-induced dyskinesia, suicidal ideation and other CNS diseases and disorders where modulation of the NMDA receptors and activation of AMPA pathways may achieve therapeutic benefits.  

  • Prodrug (4-Cl-KYN), rapidly absorbed through the gut,  transported into the brain, converted into  7-Cl-KYNA, an NMDA receptor antagonist
  • Does not block NMDA receptor activity, but inhibits and modulates it through specific GlyB binding
  • Activates AMPA receptor pathway
  • Ketamine-like antidepressant effects in rodent models
  • Well-tolerated in NIH-funded Phase 1 safety studies
  • ELEVATE Phase 2 study ongoing

AV-101 Mechanism of Action Video

AV-101's Active Metabolite (7-Cl-KYNA) Does Not Block NMDA Receptor Activity; It Inhibits It

In peer-reviewed and published preclinical studies, AV-101 demonstrated the robust antidepressant-like activity of the NMDA receptor antagonist ketamine HCl, an FDA-approved anesthetic, including low dose ketamine's rapid onset and long duration of antidepressant effects, without any of ketamine's psychotomimetic and hallucinogenic side effects. In two NIH-funded randomized, double-blind, placebo-controlled Phase 1 safety studies, AV-101 was safe, well-tolerated and not associated with any drug-related severe adverse events. There were no signs of ketamine-like side effects – no sedation, hallucinations or schizophrenia-like side effects often associated with ketamine and other ion channel-blocking NMDA receptor antagonists.

AV-101's Mechanism is Fundamentally Different from All Current FDA-Approved Antidepressants and Atypical Antipsychotics