Major Depressive Disorder

Major Depressive Disorder

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 a 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. 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.

ACCORDING TO THE WORLD HEALTH ORGANIZATION (WHO), DEPRESSION IS THE LEADING CAUSE OF DISABILITY WORLDWIDE

300 million
PEOPLE WORLDWIDE
SUFFER FROM DEPRESSION1
7.1%
OF ADULTS IN THE US HAD AT LEAST
ONE MAJOR DEPRESSIVE EPISODE2

VistaGen’s Innovation:

Recent discoveries from successful AV-101 in vivo preclinical studies suggest that there is a substantial increase in brain concentrations of AV-101 and 7-Cl-KYNA when AV-101 is given together with probenecid, a drug approved by the FDA for treatment of gout which is known to block activity of certain organic ion efflux transporters in the kidney. These surprising results in the brain were first revealed in our recent preclinical studies and are consistent with well-documented clinical studies of probenecid increasing the therapeutic levels in the blood of several unrelated classes of approved drugs, including certain antibacterial, anticancer and antivirals. Many clinical studies demonstrate that probenecid is safe and well tolerated. Probenecid administered adjunctively with AV-101 in an animal model resulted in substantially increased brain concentrations of AV-101 (7-fold) and 7-Cl-KYNA (35-fold). We also recently identified that these increases in brain levels could result from blocking of some of the same transporters in the blood brain barrier that are expressed in the kidneys, which are used to regulate drug levels in the blood. This 7-Cl-KYNA efflux-blocking effect of probenecid, with the resulting increased brain levels and duration of 7-Cl-KYNA, suggests the potential impact of AV-101 with probenecid could result in far more profound therapeutic benefits for patients with MDD and other NMDAR-focused CNS diseases and disorders than was demonstrated in the Elevate Study. Nonclinical results also indicate that chronic administration of 4-Cl-KYN induces hippocampal neurogenesis, a hallmark of drugs that have antidepressive effects, and increases endogenous levels of KYNA, which also is a functional NMDAR glycine site antagonist.

The FDA has granted Fast Track designation for the development of AV-101 for treatment of MDD.

Development Status:

We are preparing to initiate a Phase 1B clinical study of AV-101 with adjunctive probenecid in the second half of 2021 to evaluate their safety in combination and potential for exploratory Phase 2A development in one or more of the CNS indications for which we have existing encouraging preclinical data with AV-101, including MDD, epilepsy, levodopa-induced dyskinesia, and neuropathic pain.