CEO Shawn Singh explains how his company hopes to change the treatment landscape for depression with an alternative to ketamine

What is your background and current role?

I joined VistaGen’s Board of Directors in 2000, while serving as managing principal of Cato BioVentures, one of VistaGen’s largest long-term, healthcare-focused institutional investors. I joined VistaGen as chief executive officer in August 2009. I have over 25 years of experience working with private and public biotechnology, medical device and pharmaceutical companies, as well as a venture capital firm and profitable contract research and development organisation, serving in numerous senior management roles.

What is the history of VistaGen as a company?

VistaGen Therapeutics is a clinical-stage biopharmaceutical company focused on developing and commercialising new-generation medicines for depression, pain, suicidal ideation and other neuropsychiatry and central nervous system (CNS) diseases and disorders with high unmet need.

VistaGen also has a wholly owned subsidiary, VistaStem Therapeutics, focused on using stem cell technology for CNS pipeline expanding-drug rescue and regenerative medicine involving blood, cartilage, heart and liver cells.

What is the current depression treatment landscape like?

Mental health is one of the biggest issues in the world today – over 300 million people worldwide suffer from depression. What’s more, two-thirds of patients with depression do not respond to their initial antidepressant drug treatment.

Most current antidepressants target primarily the neurotransmitters serotonin (drugs known as SSRIs) and/or norepinephrine (drugs knowns as SNRIs) in the brain. Off-label intravenous (IV) administration of low dose ketamine (a long-ago FDA-approved anasthetic frequently used worldwide as such) in a medical setting has emerged as a new generation treatment alternative for treatment-resistant depression, with fast-acting antidepressant efficacy through targeting the NMDA receptor, the most prevalent neurotransmitter in the brain, instead of serotonin and/or norepinephrine. Although not believed to be a long-term solution due to IV administration as well as its psychological side effects (patients’ out-of-body experiences, hallucinations) and safety concerns (e.g. blood pressure/heart rate spikes), successful use of IV ketamine catalysed R&D around new generation antidepressants focused on NMDA receptor modulation, such as VistaGen’s oral AV-101, focused on producing ketamine-like antidepressant effects, without ketamine-like psychological side effects and safety concerns, and without requiring administration in a clinical setting.

The bottom line is that people who are suffering from mental illness need real hope and a comprehensive plan for their healthcare, including access to better mental health assessment and high-quality care, with better follow-up, broad-based support across the board, and, importantly, fundamentally different treatment options.

Tell us about AV-101 – what unmet needs is it trying to address?

AV-101 is a new generation drug candidate for depression (and other CNS disorders) in Phase 2 clinical development. VistaGen acquired Artemis Neuroscience, and its licence to AV-101, originally from the University of Maryland.

AV-101 is mechanistically similar to ketamine (both are NMDA receptor antagonists), but they are chemically different, acting differently on the NMDA receptor and are expected to be administered fundamentally differently. Ketamine blocks the ion channel of the NMDA receptor like a cork in a bottle, leading to its unwanted side effects and safety concerns.

In contrast, AV-101 acts more specifically on NMDA receptors, inhibiting (not blocking) NMDA receptor activity through focused binding on the glycine binding (GlyB) site of the NMDA receptor, functioning on the NMDA receptor like a finely-tuned thermostat to down regulate its activity without blocking it. AV-101’s NMDA receptor inhibition or modulation, as compared to ketamine’s NMDA receptor blockade, is believed to explain AV-101’s ketamine-like antidepressant effects without causing ketamine-like psychological side effects or other safety concerns.

Also, importantly, AV-101 is oral and intended to be suitable for convenient at home use rather than administration in a clinical setting similar to IV, intranasal ketamine and rapastinel, another NMDA receptor modulator acquired by Allergan after Phase 2 development for $571 million in cash on signing and over $1 billion in potential future milestone payments.  This means AV-101 has potential for fast-onset ketamine-like antidepressant benefits, without ketamine’s well-known psychological side effects and safety concerns, plus at-home use convenience for patients.

By contrast to new generation antidepressants, current FDA-approved antidepressants, the SSRIs and SNRIs – which are not always effective – not only have significant side effects, but also take many weeks to achieve therapeutic benefits and often times require multiple dosing adjustments, wash-out periods and persistent trial and error before achieving adequate antidepressant effects. Inadequate response to current antidepressants is VistaGen’s initial therapeutic and commercial focus for AV-101 and is among the key reasons that MDD is a leading public health concern.

What are the biggest remaining patient needs in depression that need to be addressed?

We need to treat depression like a disease that can be addressed and treated, and remove the stigma and shame that come with asking for help for those who are living with depression. Once the ‘mental health’ piece comes into play, people often pull back with apprehension – patients, family members, friends, co-workers. That has to change. Additionally, there are different factors that play into a person’s mental health – from family and relationships to jobs and genetics. We need to consider all of these aspects when coming up with a comprehensive game plan, one that also factors in potential for suicidal thoughts and behaviours.

We must also be open to new, disruptive treatments and approaches to mental health conditions. The existing options just don’t cut it – they fall far short of the unmet need; for example, the ‘rinse and repeat’ approach with current SSRIs, SNRIs and adjunctive atypical antipsychotics is just not working for millions of people.

New, disruptive treatments in the CNS space, especially those involving ketamine and ketamine-like drugs, could help people who have depression considerably, and by extension those in their support network.

Lastly, we need to start having real, meaningful, two-way conversations. As a society, we need to talk more about how untreated depression and other neuropsychiatric and mental conditions affect people in both the short- and long-term. Early intervention is key, and we must ask, listen and follow-up much more than we are used to doing today.

What is the future of depression treatment likely to look like?

New hope for millions of patients with depression is on the near-term horizon. The new generation of drug treatment alternatives for depression are likely to be faster-acting, more effective in treatment-resistant and inadequate response populations, and, ideally, as safe or safer than current medicines, with at-home use convenience and fewer side effects.