Our CNS pipeline includes three differentiated new generation CNS drug candidates with potential to go beyond the current standard of care for anxiety, depression and other CNS disorders. Each of our drug candidates, PH94B, PH10 and AV-101, has a novel mechanism of action, an exceptional safety profile in all studies to date, and therapeutic potential for multiple indications in large mental health and neurology markets.
PH94B Neuroactive Nasal Spray
PH94B is an innovative investigational synthetic neuroactive pherine nasal spray with potential to treat multiple anxiety disorders without the side effects and safety concerns associated with benzodiazepines. PH94B’s rapid-onset mechanism of action is fundamentally different from benzodiazepines and all other FDA-approved anti-anxiety medications. Developed from proprietary compounds called pherines and administered at non-systemic microgram doses as an odorless nasal spray, PH94B binds to nasal chemosensory receptors which activate neural circuits in the limbic amygdala that suppress fear and anxiety. Following a highly statistically significant (p=0.002) Phase 2 study of PH94B in adults with social anxiety disorder (SAD), and a successful meeting with the U.S. Food and Drug Administration (FDA), we are currently preparing for pivotal Phase 3 development of PH94B for the acute treatment of anxiety in adults with SAD.
The FDA has granted Fast Track designation for development of PH94B for SAD, the first such designation ever granted by the FDA for a SAD drug candidate. In a manner analogous to a rescue inhaler used before an asthma attack, PH94B has potential to be used by a person with SAD before an anxiety-provoking stressor.
Based on the results of Phase 2 studies, PH94B has the potential to be the first FDA-approved acute (on-demand) treatment of anxiety for millions who suffer from SAD. In addition, PH94B has potential in postpartum anxiety, preoperative anxiety, PTSD, panic disorder, and generalized anxiety disorder.
PH10 Neuroactive Nasal Spray
PH10 is a synthetic investigational neuroactive pherine nasal spray with a novel, rapid-onset mechanism of action that is fundamentally different from all current treatments for depression. Developed from proprietary compounds called pherines and administered at microgram doses as an odorless nasal spray, PH10 binds to nasal chemosensory receptors which activate neural circuits in the brain that produce antidepressant effects. Specifically, a microgram level dose of PH10 (6.4 mcg) engages specific nasal chemosensory neurons (NCNs). NCNs activate olfactory bulb neurons (OBNs) on the base of the brain. OBNs send neural connections to neurons in the central limbic amygdala, the brain center where mood is regulated. Neurons in the limbic amygdala stimulate release of excitatory neurotransmitters (glutamate, norepinephrine) resulting in rapid-onset antidepressant effects. Systemic uptake and distribution are not required to produce rapid-onset antidepressant effects. In a small exploratory randomized, double-blind, placebo-controlled Phase 2A clinical study in major depressive disorder (MDD), at a 6.4 mcg dose, rapid-onset antidepressant effects were observed and sustained for 8 weeks (p=0.022), without psychological side effects or safety concerns associated with ketamine-based therapy.
AV-101, an Oral NMDAR Glycine Site Antagonist
AV-101 (4-Cl-KYN) belongs to a new generation of investigational medicines in neuropsychiatry and neurology known as NMDA (N-methyl-D-aspartate) glutamate receptor modulators. The NMDA receptor is a pivotal receptor in the brain and abnormal NMDA function is associated with multiple CNS diseases and disorders, including MDD, epilepsy, levodopa-induced dyskinesia, neuropathic pain and many others. AV-101 is an oral prodrug of 7-chlorokynurenic acid (7-Cl-KYNA), which binds uniquely at the glycine site of the NMDA receptor and has potential to be a new treatment for multiple CNS indications involving NMDA receptors, each with high unmet need.
Recent discoveries from successful AV-101 preclinical studies demonstrate a multi-fold concentration increase in the brain of AV-101 prodrug, and, more importantly, of 7-Cl-KYNA, AV-101's active metabolite, when AV-101 is administered adjunctively with probenecid, a safe and well-known oral anion transport inhibitor used to treat gout. This data suggest that it may be possible to increase therapeutic concentrations and duration of 7-Cl-KYNA in the brain, and thus increase NMDAR antagonism in patients when AV-101 and probenecid are combined.