Pushing Late-Stage Treatments Forward in the Clinic

Disruption of everyday life as a result of the COVID-19 pandemic, civil unrest, and negative influence of social media have caused a number of anxiety-provoking stressors to skyrocket this year. Consequently, prescriptions of potentially addictive anti-anxiety drugs called benzodiazepines have increased amongst Americans. Shawn Singh, Chief Executive Officer of VistaGen Therapeutics, discusses the company's ongoing efforts to treat and help manage the anxiety symptoms related to these triggers and the anxiety-related disorders they provoke, initially in subjects suffering from Social Anxiety Disorder (SAD), and the FDA’s consensus on the design of their pivotal Phase III study of PH94B, a neuroactive nasal spray, for acute treatment of anxiety in adults with SAD.

MA: As a result of COVID-19, clinical trials across the board have experienced delays in both operations and patient recruitment. How will VistaGen tackle these challenges?=

Shawn Singh

Shawn Singh: The highly statistically significant (p = 0.002) published Phase II study of PH94B in SAD, with Dr. Michael Liebowitz, creator of the Liebowitz Social Anxiety Scale, or LSAS, as principal investigator, involved anxiety-provoking public speaking challenges (preparing for and delivering a short speech) conducted in a clinical setting before impartial audiences.

Our consensus with the FDA supports using the same design in our pivotal Phase III study of PH94B for the acute treatmet of anxiety in adults with SAD. We are developing PH94B as an acute, as-needed (PRN) nasal spray that a person can take when the anxiety-provoking stressor is predictable and, within just 10 to 15 minutes, get relief from those symptoms.

As we move into Phase III, while there is no timeline for where we will be in the context of this pandemic, there are specific guidelines from the FDA and certain considerations for sponsors regarding ongoing and planned studies that will need to be followed. Fortunately for us, due to our consensus with FDA on our study design for Phase III, we do not need subjects to go out into the real world and experience a diverse range of anxiety-provoking stressors and then report back to us on their experiences. Alternatively, our study will be driven by a standard anxiety-provoking trigger (preparing for and delivering a short speech to a small audience) and conducted in a clinical setting over a brief time period (3 to 4 visits over about 4 weeks), potentially involving a telemedicine component. Clinical trial sites across the country are making things as safe as possible for staffs and study subjects. There are far fewer subjects in waiting rooms these days, which allows for social distancing.

While some may be hesitant to visit a clinical site, particularly right now, we believe many subjects will be eager to obtain some mental health services under these conditions—especially for SAD, an anxiety disorder affecting about 20 million Americans, even before the pandemic.

Now more than ever, patients around the world need new medications that go beyond the standard of care for anxiety, depression, and suicidal ideation. For patients who have a debilitating mental health condition, our goal with PH94B for SAD, as well as for several other anxiety disorders, is to develop and offer an innovative, life-changing treatment that goes beyond the current standard of care and allows patients to manage their anxiety to the point where they are able to live their lives as the ideal version of themselves—a crucial driver for everything we do.

MA: The last time that we spoke with VistaGen, the Company had just completed its Pilot Phase III study for PH94B. Recently, VistaGen announced a positive meeting with the U.S. FDA on critical aspects of the Company's upcoming pivotal Phase 3 clinical study of PH94B. Can you elaborate on this consensus?

SS: We reached consensus with the FDA on all key aspects of our pivotal Phase III study of PH94B for acute treatment of anxiety in adults with SAD. VistaGen and the FDA are now aligned on the pivotal study design. When we are on the other side of what we hope will be successful efficacy and safety outcomes in our Phase III studies, we are confident the studies will support our NDA submission. Our initial goal for PH94B is for it to be the first FDA-approved, rapid-onset, PRN acute treatment of anxiety for adults with social anxiety disorder.

The efficiencies associated with having the same challenge for all subjects in the study—that being only a single public speaking challenge—after randomization are significant. The duration of each subject’s involvement in the study will be very manageable and the relatively modest cost of the Phase III study, along with the study size due to lower potential statistical variances due to the standard laboratory-simulated challenges and assessment, are notable. Based on our statistical plan submitted to the FDA, we do not need the study to be as large as previously envisioned; our enrollment target is 182 completed subjects. This is an efficient number, even with potential COVID-19-related impacts on clinical trial recruitment and execution. We anticipate that the study will be conducted at 12 to 15 sites in North America. We estimate that enrollment of 182 completed subjects should be doable by screening about 400 potential subjects. Those who do not qualify for the pivotal study may advance into our safety study, which we plan to conduct in parallel.

MA: How does VistaGen plan to further evaluate efficacy, safety, and quality for its Phase III trial compared to the currently available treatments? What data are you generating from your trial that would make it stand out compared to other therapies on the market for the treatment of SAD?

SS: There is absolutely nothing on the market today that is FDA-approved for the acute treatment of anxiety in adults with SAD. The only FDA-approved drugs for the treatment of SAD are antidepressants, which take weeks to deliver a therapeutics benefit, if at all, a long onset period that we believe many SAD patients find inadequate. In addition, the side effects of antidepressants often are experienced almost right out of the gate.

With PH94B, we are not focused on developing an alternative to the antidepressants approved by the FDA for SAD. Rather, we are focused on creating a better treatment alternative to benzodiazepines, or “benzos,” which are frequently prescribed off-label and used—especially in the midst of the COVID-19 pandemic—for SAD and other anxiety-related indications.

PH94B's key features distinguish it, and are majorly different, from the benzos currently being used. In studies to date, PH94B is a drug that works rapidly like a benzo, but does not require systemic uptake and distribution to achieve its anti-anxiety benefits and does not cause the many challenging side effects and safety concerns of benzos-sedation, cognition and memory impairment, and risk of misuse or abuse. In our opinion, that makes PH94B a total game-changer for acute treatment of SAD and potentially many other anxiety disorders. We have received the FDA’s first ever Fast Track designation for development of PH94B for SAD.

MA: How is VistaGen set to potentially achieve both time- and cost-efficiency in the clinic for this study based on the FDA's feedback?

SS: Our consensus with the FDA reduced the required number of primary efficacy endpoints in the study to a single efficacy endpoint using the Subjective Units of Distress Scale (SUDS), reduced the required number of clinical patient visits significantly during the study, thereby, considerably reducing the overall size of the study, while still maintaining appropriate statistical power, and eliminating potential data variability related to diverse anxiety-provoking experiences by having the single laboratory-simulated public speaking challenge used in the key Phase II study remain the same and be used for our pivotal Phase III studies. 

Moe Alsumidaie, MBA, MSF, is a thought leader and expert in the application of business analytics toward clinical trials, and Editorial Advisory Board member for and regular contributor to Applied Clinical Trials.