Major Depressive Disorder
A Global Public Health Concern
Depression is a serious medical illness and a global public health concern that can occur at any time over a person's life. While most people will experience depressed mood at some point during their lifetime, major depressive disorder (MDD) is different. MDD is the chronic, pervasive feeling of utter unhappiness and suffering, which impairs daily functioning. Symptoms of MDD include diminished pleasure in activities, changes in appetite that result in weight changes, insomnia or oversleeping, psychomotor agitation, loss of energy or increased fatigue, feelings of worthlessness or inappropriate guilt, difficulty thinking, concentrating or making decisions, and thoughts of death or suicide and attempts at suicide. Close to 800,000 people die due to suicide every year, and it is the second leading cause of death in individuals 15-29 years old. For many people, depression cannot be controlled for any length of time without treatment. Currently available FDA-approved medications available in the multi-billion-dollar global antidepressant market often fall far short of satisfying the unmet medical needs of millions suffering from the debilitating effects of depression.
1World Health Organization. Preventing suicide: a global imperative. Available at: http://www.who.int/mental_health/suicideprevention/world_report_2014/en/
Shortcomings of Currently Available Antidepressants (SSRIs and SNRIs)
While current FDA-approved antidepressants are widely used, about two-thirds of patients with MDD do not respond to their initial antidepressant treatment. Inadequate response to current antidepressants is among the key reasons MDD is one of the leading public health concerns in the United States, creating a significant unmet medical need for new agents with fundamentally different mechanisms of action.
ELEVATE is our ongoing Phase 2 clinical trial designed to evaluate the efficacy and safety of adjunctive use of oral AV-101 for MDD in patients with an inadequate response to standard antidepressant therapy with either an FDA-approved SSRI or SNRI. We are developing AV-101, initially, as a new generation adjunctive treatment to replace the widespread use of atypical antipsychotics, such as aripiprazole, for tens of millions of patients with MDD worldwide suffering from an inadequate response to standard SSRIs and SNRIs.
Paradigm-shifting clinical studies performed by Dr. Carlos Zarate, Jr. and others at the U.S. National Institute of Mental Health (NIMH)2, Yale University and several other academic research centers have demonstrated that, when given intravenously, a single low dose intravenous infusion of the NMDA receptor antagonist ketamine can produce robust and rapid antidepressant effects in patients with treatment-resistant MDD. AV-101's mechanism of action is functionally similar to ketamine in that both are NMDA receptor antagonists. However, ketamine is a classic channel-blocking NMDA receptor antagonist. AV-101 is a NMDA receptor GlyB antagonist that inhibits NMDA receptor function rather than blocking it. We believe this difference (modulating NMDA receptor activity rather than blocking it), together with the activation of AMPA receptor pathways, can potentially bypass the adverse side effects that occur with ketamine while still achieving fast-acting ketamine-like antidepressant effects.
In peer-reviewed, published preclinical studies supported by the NIMH3, AV-101, dinstinct from fluoxetine (an SSRI) and similar to ketamine (an NMDA receptor antagonist):
- demonstrated rapid, dose-dependent and persistent antidepressant-like effects following a single treatment;
- was not associated with the rewarding and psychotomimetic effects of ketamine; and
- 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.4 In addition, there were no signs of side effects, such as sedation, hallucinations or schizophrenia-like side effects often associated with ketamine and other ion channel-blocking NMDA receptor antagonists.