Michael Liebowitz, MD: The History of Social Anxiety Disorder and Fasedienol

Earlier this month, biopharmaceutical company Vistagen announced non-peer-reviewed phase 3 trial results showing investigative nasal spray fasedienol was associated with significant improvement in clinical social anxiety scoring among patients with social anxiety disorder (SAD).¹

The preliminary data from PALISADE-2 showed patients receiving the first-in-class pherine nasal spray prior to a staged, anxiety-inducing public speaking event reported significantly improved Subjective Units of Distress Scale (SUDS) scores versus placebo. Analysis of patient-reported outcomes additionally showed significant improved measures of anxiety among the fasedienol arm versus placebo.

The company is continuing to develop this novel agent that very well may serve as the first treatment indicated by the US Food and Drug Administration (FDA) to treat SAD, a condition that has historically been poorly understood and even less adequately address in drug development.

In an interview with HCPLive, Michael Liebowitz, MD, director and founder of the Anxiety Disorders Clinic at New York State Psychiatric Institute, discussed his pioneering role in clinically defining SAD a half-century ago, as well as his involvement with the development of fasedienol. As recently as the 1980s, Liebowitz explained, anxiety was a “monolithic category” in psychiatry.

Liebowitz’s colleague Donald F. Klein, MD, was one of the first persons to break anxiety up with the identification of panic disorder as its own entity, based on phenomenology and treatment-response characteristics. Liebowitz and colleagues then carved out SAD, which as recently as the DSM-3 had limited the definition to include performance anxiety or avoidant personality disorder.

“And we established that there was what we wound up calling a generalized form of social anxiety: people who were not just terrified of public speaking, but who had difficulties talking to colleagues, going to parties, meeting strangers—almost all interpersonal relations were terrifying because they felt evaluated, scrutinized and judged,” Liebowitz said.

Patients were identified as either highly anxious or become quite avoidant, with their condition greatly impacting academic, vocational and social life. “And it could really start in the teens, with precursors that you could see in childhood, all the way back to very anxious infants who were scared of novelty,” Liebowitz said.

The Liebowitz Social Anxiety Scale (LSAS) was developed to help inform and support pharmacologic strategies for a clinically diagnosed condition, rather than a mood disorder. While early-generation psychiatric treatments such as selective serotonin or serontonin and norepinephrine reuptake inhibitors (SSRIs, SNRIs) and cognitive behavioral therapy (CBT) were available as treatments for patients as recently as the 1980s, little came for patients with SAD afterward.

“That’s kind of where the field froze, for the last 10 – 15 years,” Liebowitz said. Available SSRIs and SSNRIs are beneficial but may take 8 weeks to work, with dosage requirements sometimes higher than they are for depression. CBT is “rigorous for addressing anxiety,” Liebowitz explained, as it continually introduces stressors during care. Beta blockers, anecdotally, may benefit anxiety-inducing situations. But none are wholly beneficial for the specific parameters for SAD.

Liebowitz and colleagues began working with Ferring in the mid-2000s to consider a rapid-acting nasal spray agent that may benefit psychiatric illnesses. Liebowitz was the one who recommended its possible use for SAD.

At phase 2, fasedienol was assessed in 2 study settings: a staged public speaking event and a real-world crossover assessment in patients undergoing socially- or performance-challenging events. Both showed significant benefit, Liebowitz explains, as treatment was associated with as significant benefit on LAS improvement in 2 weeks as had been observed over 12 weeks with SSRIs. Ferring then partnered with Vistagen for late-stage assessments.

“We’ve really replicated the phase 2 results,” Liebowitz said. “There’s been a lower placebo response rate than we had in phase 2, and a lower overall drug response rate, but still twice the magnitude and a lot of clinical significance. And that’s going to be a huge help in finishing up the phase 3 program to see if we can get this drug on the market for patients to use.”

References

1. ^{Kunzmann K. Nasal Spray Fasedienol Provides Rapid Social Anxiety Benefit in Phase 3 Trial. HCPLive. Published August 8, 2023. https://www.hcplive.com/view/nasal-spray-fasedienol-rapid-social-anxiety-benefit-phase-3-trial}