AV-101 for MDD - Mechanism of Action
Based on evidence of effectiveness of the NMDA (N-methyl-d-aspartate) receptor antagonist ketamine, the glutamatergic system plays a key role in mood disorders. We believe that specific ways of targeting the NMDA subtype glutamate receptor can produce a new generation of NMDA receptor antagonists with better safety and tolerability for the treatment of major depressive disorder (MDD). In peer-reviewed, published preclinical studies supported by the U.S. National Institute of Mental Health (NIMH), part of the U.S. National Institutes of Health (NIH), AV-101 (4-Cl-KYN), distinct from fluoxetine (an SSRI) and similar to ketamine (an NMDA receptor antagonist), (A) demonstrated rapid, dose-dependent and persistent antidepressant-like effects following a single treatment, (B) was not associated with the rewarding and psychotomimetic effects of ketamine and (C) did not induce locomotor sensitization or stereotypical behaviors. While AV-101’s mechanism of action is similar to intravenous and intranasal ketamine in that they all reduce NMDA receptor function, ketamine creates a blockade of the ion channel on the NMDA receptors and AV-101 antagonizes the glycine binding site on the NMDA receptor, giving it the potential to produce fast-acting antidepressant effects without the side effects associated with ketamine. In two NIH-funded randomized, double-blind, placebo-controlled Phase 1 safety studies in healthy individuals, 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, such as sedation, hallucinations or schizophrenia-like side effects which are often associated with ketamine and other ion channel-blocking NMDA receptor antagonists.
PH94B for SAD - Mechanism of Action
Intranasal PH94B is a first-in-class neuroactive steroid (a "pherine") that engages nasal chemosensory receptors which, in turn, trigger rapid activation of the limbic system areas of the brain associated with social anxiety disorder (SAD). This mechanism of pharmacological action, the rapid onset of efficacy, and the excellent safety and tolerability profile shown in clinical trials make PH94B an excellent product candidate for PRN (as-needed) treatment for individuals with SAD.
PH10 for MDD - Mechanism of Action
PH10 is also a first-in-class neuroactive steroid (a pherine) administered as a nasal spray that binds locally on nasal chemosensory receptors and triggers responses in the hypothalamus, amygdala, prefrontal cortex and hippocampus. It is believed to initiate nerve impulses that follow defined pathways to directly affect brain function. Similar to PH94B, PH10 does not circulate systemically in the blood. In a small exploratory Phase 2a study in individuals with MDD, PH10 showed a large, rapid-onset antidepressant effect, without psychological side effects or safety concerns.