Can We Treat Mood Disorders with Pharmacological Therapeutics?

Clinical treatments for neurological and mood disorders like anxiety disorder (SAD) and major depressive disorder (MDD) have failed to show consistent efficacy in treating patients. VistaGen Therapeutics is aiming to correct that. VistaGen’s compound AV-101, an NMDA receptor antagonist, is currently in clinical trials for MDD and suicidal ideation, with clinical studies for neuropathic pain and Parkinson's disease levodopa-induced dyskinesia (PDLID) on the horizon. Additionally, VistaGen’s PH94B molecule is being prepared for a Phase 3 clinical program for SAD as a first-in-class nasal spray.

We talked to VistaGen’s CEO, Shawn Singh, about the need for treatments in this area and why VistaGen thinks AV-101 and PH94B could be promising therapies.

Ruairi Mackenzie (RM): What is the “unmet need” of treating complex CNS disorders like MDD and SAD? 

Shawn Singh (SS): The current drug treatments for both MDD and SAD fall far short of effectively and safely treating the needs of millions of patients. MDD affects as many as 16 million Americans, and SAD affects as many as 22 million, yet despite multiple treatment attempts with current medications, both patient populations are left significantly underserved.

SAD creates a persistent fear of judgment, humiliation and rejection in millions of people when they are faced with a social or performance situation, like giving a speech or going on a date. SAD is serious enough to sideline careers and relationships. Despite its prevalence, there are no medications approved for as-needed, on-demand use prior to, or during, feared, anxiety-producing social situations for people with SAD.

Only antidepressant SSRIs, such as paroxetine, and SNRIs, such as venlafaxine, are FDA-approved to treat SAD. Benzodiazepines, such as lorazepam, alprazolam and diazepam, and beta blockers, such as propranolol, are prescribed, but have serious side effects, such as addiction, sedation,  cognitive impairment and/or potential cardiac safety concerns.

Based on data from clinical studies to date, we believe our PH94B nasal spray has breakthrough  potential to be an easy-to-self-administer, first-in-class neurosteroid with a novel, fast-acting mechanism of action that can be effective for treating SAD within 10 to 15 minutes. We see it as having the potential to be the first FDA-approved, on-demand, as-needed treatment for SAD. Based on clinical observations to date, it is a non-sedating, non-addictive treatment candidate without the side effects and safety concerns associated with medications currently used for SAD. We are now preparing PH94B intranasal for pivotal Phase 3 development in the U.S.

Major Depressive Disorder is a particularly intense form of depression: a chronic, pervasive feeling of utter unhappiness that impairs daily functioning. Similar to medications for SAD, current FDA-approved medications for MDD more often than not either don’t work or are very slow to work, and have considerable side effects and safety concerns. Two-thirds of patients with MDD do not respond to their first treatment with current antidepressants. Even after multiple treatment attempts with current medications, nearly one-third of patients with MDD (over 5 million Americans) experience no relief from their depression.

RM: AV-101, one of VistaGen’s marquee drugs, aims to treat MDD. It uses a mechanism of action similar to ketamine, an NMDA receptor antagonist. Why are NMDAR antagonists promising for this area of research, and how does AV-101 improve over classical NMDAR channel blockers like ketamine?

SS: Ketamine is a classic NMDA receptor antagonist – a full ion channel blocker, creating an NMDA blockade like a cork in a bottle. As we’ve seen in tests with thousands of patients over the last 10+ years, a very low intravenous dose of ketamine (about one-tenth of the dose required for anesthesia) administered in a clinical setting can generate robust and rapid antidepressant effects in patients with treatment-resistant MDD. 

AV-101 is also a NMDA receptor antagonist, but AV-101 inhibits NMDA receptor activity, while ketamine blocks it. This is a significant difference that allows AV-101 to act rapidly as an antidepressant, while side-stepping the psychological side effects associated with off-target activities of ketamine, like hallucinations and dissociation. Best of all, AV-101 is oral, creating the opportunity for it to be taken in the privacy of a patient’s own home, rather than in a required medical setting, as is the case with ketamine (both IV ketamine and intranasally administered ketamine).

RM: While current drugs for depression and anxiety can prove effective for some patients, there is often little consistency between patients. How can AV-101 improve on the reliability of other treatments? 

SS: We know that current FDA-approved antidepressants do not work on the first try in two-thirds of patients with MDD, and even after multiple tries, a full one-third of patients experience no relief from their depression. Current antidepressants target serotonin (SSRIs) or serotonin and norepinephrine (SNRIs), neurotransmitters with fundamentally different mechanistic activity from AV-101. While it is often challenging for physicians and psychiatrists to know upfront, without trial and error, which current SSRI or SNRI might be beneficial to a particular MDD patient, our goal is for AV-101 to complement all current SSRIs and SNRIs – when it is used in an adjunctive mode – without exacerbating the typical and often difficult-to-tolerate side effects of current antidepressants, as is often the case when atypical antipsychotics, such as aripiprazole, are used adjunctively with current ADTs (e.g., weight gain, tardive dyskinesia, etc.).   

Our ongoing U.S. multicenter AV-101 Phase 2 clinical trial, ELEVATE, is testing adjunctive treatment with AV-101 for MDD patients with an inadequate response to current SSRI/SNRI therapy.

RM: Could you tell us about VistaStem?

SS: VistaStem Therapeutics is a wholly owned subsidiary of VistaGen Therapeutics focused on applying proprietary stem cell technology for drug rescue and regenerative medicine (RM). VistaStem’s in-vitro human heart cell bioassay system, CardioSafe 3D™, is capable of testing for potential heart toxicity of new compounds before they are tested in animals or people. Our drug rescue program leverages CardioSafe 3D to assess and rescue new chemical entities (NCEs) with potential to become part of our CNS pipeline. We have licensed RM applications of our cardiac stem cell technology to BlueRock Therapeutics, a RM company supported by Bayer and Versant Ventures. We have not yet licensed RM applications of our blood, chrondrocyte and liver cell technology, but we may seek to do so should one or more strategic collaborative opportunities develop. 

RM: At what stage are VistaGen’s different clinical trials? What is the timescale for these trials? 

SS: Our most advanced compound is PH94B for Social Anxiety Disorder, a first-in-class nasal spray, which is being prepared for registration-enabling Phase 3 development in the U.S., which we plan to launch early next year. AV-101 is our busiest compound, currently in three clinical trials in the U.S. Two of those trials – VistaGen’s ELEVATE adjunctive treatment study and the NIH’s monotherapy study – are in Phase 2 for MDD. We expect to have data from those two studies this year.

Other notable milestones:

• Most recently, our collaborators at Baylor University began a first-step clinical study focused on U.S. veterans and suicidal ideation. The study is being conducted by Baylor and funded by the U.S. Department of Veterans Affairs.

• Additionally, VistaGen received FDA Fast Track Designation for the development of AV-101 as a non-opioid treatment for neuropathic pain, the second such FDA designation (development of AV-101 for MDD was the first). 

• Lastly, another novel, fast-acting compound in our CNS pipeline called PH10 has completed a Phase 2a proof-of-concept clinical study in MDD patients with impressive results. We are now preparing PH10 for Phase 2b development in the U.S.

Shawn Singh was speaking to Ruairi J Mackenzie, Science Writer for Technology Networks.