Phase 1 Data: SNTX-2643 Blunts the Brain's Stress Response After a Single Dose

A single 3-mg dose of an investigational anxiety medication blunted the brain's response to a physiological stressor for as long as 24 hours, according to Colville Brown, MD, chief medical officer of Sensorium Therapeutics.

In an interview with Psychiatric Times, Brown shared the findings of the new phase 1 data for SNTX-2643, an investigational, state-selective serotonin transporter modulator in development as a rapid-acting treatment for social anxiety disorder (SAD) and generalized anxiety disorder (GAD). Brown told Psychiatric Times the novel agent "acts on the serotonin transporter in a way that's completely different" from standard-of-care anxiolytics.

A Drug Candidate Built on "Millennia of Human Observation"

Sensorium's approach to discovery starts with human observation rather than a preselected biological target, Brown told Psychiatric Times. SNTX-2643 is derived from kanna, a plant used traditionally for its calming effects; the company isolated its active ingredient and used precision pharmacology to develop what Brown described as a drug product suited to both SAD and GAD.

In preclinical studies, he said, the molecule showed "a potentially rapid acting preclinical profile," with a downstream protein cascade and rate of serotonin reuptake inhibition that looked different from existing anxiolytics. Brown was careful to frame those findings as preliminary: "This is in preclinical models," he said. "We have to wait for future clinical studies to really understand what that means for patients."

Phase 1 Data: Safety, Target Engagement, and a Stress Challenge

The Phase 1 study's primary objective was safety, Brown said, with secondary measures of pharmacokinetics and food effect, and exploratory work to confirm that SNTX-2643 was engaging the serotonin transporter and to gauge early pharmacodynamic effects. According to the poster presented at Psych Congress, the study enrolled 63 healthy adults—47 randomized to SNTX-2643 and 16 to placebo—across single-ascending-dose cohorts testing 1 mg, 3 mg, and 5 mg, a 25-person target-engagement cohort (a single 3-mg dose in 15 participants versus placebo in 10), and a 14-person open-label food-effect cohort. One of those paradigms, Brown said, was designed specifically to probe anxiety physiology: "We included a physiological stressor to showcase whether SNTX-2643 was able to blunt or attenuate responses to that stressor."

"The 30-second story is that SNTX-2643 was generally well tolerated," Brown said. "We saw a predictable PK profile and no significant food effect." On the pharmacodynamic measures, he said, a single 3-mg dose attenuated the brain's response to the physiological stressor at both 2 and 24 hours, with concurrent changes in autonomic measures at both time points.

Most adverse events in the study were mild and transient, Brown added, with no serious adverse events, no discontinuations due to adverse events, and no deaths. Importantly for a compound derived from a plant with psychoactive relatives, he said the study turned up no dissociation- or abuse-liability-related adverse events at any of the doses. Formal abuse-liability studies are still needed to confirm that finding, Brown noted, but he called the early signal encouraging.

Next Up: A Combined Trial for 2 Anxiety Disorders

Sensorium's next step is a phase 1b multiple-ascending-dose study, followed by a phase 2a trial that will do something Brown called uncommon in CNS drug development: enroll patients with both SAD and GAD in a single study rather than running separate trials for each. The rationale, he said, is diagnostic reality colliding with trial efficiency.

"Generalized and social anxiety disorder are often mischaracterized by even PCPs and are hard to tell apart," Brown said. "They are distinct clinical entities, however."

By pooling data across the 2 populations with Bayesian statistics, he said, Sensorium can run "a more efficient, smaller study rather than 2 large randomized double-blind control studies," an approach he linked to recent FDA guidance encouraging Bayesian and adaptive trial designs. "We think we're in line with where the agency's going," he said.

Although encouraging, Brown noted it is still early to definitely say SNTX-2643 will help patients, but he believes it is heading in the direction.

“These findings are really compelling to us,” he told Psychiatric Times. “We think we have an asset here that could potentially help those with anxiety disorders. Now we'll need to investigate that in patients in order to know that there's a differentiation there."

Dr Brown is the chief medical officer of Sensorium Therapeutics.