Drug developers have successfully tackled general anxiety with a number of innovations. But social anxiety disorder, which can trigger debilitating fear, self-consciousness or nervousness during social interactions, has proved to be a tougher puzzle to solve.
Several older antidepressants, including two SSRIs, are FDA-approved specifically for social anxiety disorder, but newer options have been elusive. That hasn’t stopped researchers from trying in recent years. And now, one of pharma’s biggest players has entered the arena.
In July, Eli Lilly struck a deal to acquire AtaiBeckley for about $2.8 billion upfront. AtaiBeckley is developing one of the social anxiety space’s leading contenders. Currently dubbed EMP-01, the novel oral formulation of R-MDMA scored a win in February when AtaiBeckley announced positive results from an exploratory phase 2a trial.
But Lilly is stepping into a space beset by two notable late-stage failures.
Vistagen’s fasedienol failed to meet both its primary and secondary endpoints in a phase 3 study, the company announced in June. And last year, Neuphoria Therapeutics scrapped its social anxiety disorder program when its candidate also failed to meet its primary and secondary endpoints.
Still, newer drugs like psychedelics could have a unique advantage in treating social anxiety disorder.
“I would not say we are at the end of our rope on developing drugs for social anxiety disorder or for any anxiety spectrum disorder for that matter,” said Bruce Leuchter, a neuropsychiatrist and president and CEO of Neurvati Neurosciences and GRIN Therapeutics.
That’s partly due to the unmet need. About 30 million U.S. adults are affected by social anxiety disorder, but only about half receive treatment. Among patients who access care, around half don’t adequately respond to first-line therapies, according to AtaiBeckley.
“It's a big indication,” Leuchter said. “You've got a lot of unmet need, and you've got limited therapeutic options. You might be able to have some impact on these patients, but you're certainly not having the kind of impact that the patient wants and that the physician wants.”
And the time is right for researchers to make a breakthrough. Clinical trials for psychiatric drugs are often “imperfect” because they rely on rating how clinical trial participants feel and behave, rather than biomarkers or other concrete biological indicators, Leuchter said. Efforts to understand how psychiatric drugs actually work biologically using tools like neuroimaging, rather than relying on clinical presentation alone, could help improve drug development in the space.
“What's happening inside the brain when they're exposed to [a] drug and how do we understand that? Couple it with: What we're seeing clinically? Would that get us more efficacy and a greater response rate?” Leuchter said. “The broader psychiatric space is making a real concerted effort to [understand] these things.”
Failed studies, not failed drugs
Vistagen’s phase 3 social anxiety disorder failure may illustrate the common psychiatry phenomenon of “failed studies, not failed drugs,” Leuchter said.
Vistagen put study subjects in simulated public speaking scenarios to assess whether fasedienol could treat acute social anxiety disorder on an as-needed basis. The study’s primary endpoint was a self-reporting tool called the Subjective Units of Distress Scale.
But zeroing in on improvement in certain situations “can make it difficult to have a particular endpoint serve as a referendum for whether or not you're actually impacting the chronic underlying condition,” Leuchter said.
Vistagen also recently reported that its candidate did show some efficacy signals and that it plans to meet with the FDA to discuss a potential registrational pathway involving a future phase 3 trial using the Liebowitz Social Anxiety Scale as the primary endpoint.
“They're contemplating an approach to assessing efficacy that exists beyond the narrow circumstance of social engagement or public speaking and trying to move more broadly into assessing some of the symptoms that may get at social anxiety disorder outside of a discrete public speaking experience,” Leuchter said.
Momentum for psychedelics
Momentum in the psychedelic space around psychiatric treatments is being driven by the “almost mind-blowing” effects of the drugs, Leuchter said.
“The impact that they're having is material,” he said. “So you're not squinting to see separation between a placebo and an actively treated patient because the effect size is so large.”
He likens psychiatric treatments to turning up the volume dial on a stereo. While some psychiatric mechanisms of action turn the dial up to five, psychedelics seem to crank the dial to 10.
“It may matter less which diagnosis you're targeting,” he said. “It may matter more that you're just turning the volume up.”
Understanding the underlying biology of psychiatric drug development comes into play with psychedelics, too, since “the potency of these drugs on neurobiological, neurophysiological function” could drive their effectiveness, Leuchter said.
Rather than using the blanket term “psychedelics,” Leuchter prefers to talk about them with more medical terms such as neuroplastogens, which increase neurite outgrowth and have neuroplastic potential, or entactogens, which nonselectively release serotonin, dopamine and norepinephrine into the brain. AtaiBeckley’s EMP-01, an oral version of R-MDMA, is an entactogen.
While EMP-01’s phase 2a trial measured safety and tolerability as primary endpoints, the company said preliminary efficacy results were also encouraging.
“It may be that MDMA derivatives are able to move the needle more effectively across psychiatric conditions,” Leuchter said.
