VLS-01 for Treatment-Resistant Depression: Positive Phase1B Results

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atai Life Sciences recently announced positive preliminary results from the phase 1b trial of VLS-01, an oral transmucosal film formulation of N,N-dimethyltryptamine (DMT) that is applied to the buccal surface and is designed to aid in the treatment of patients with treatment-resistant depression (TRD).¹ VLS-01 induces a short psychedelic experience, and allows for a total in-clinic treatment of 2-hours with peak plasma concentration reached within 30 to 45 minutes and subjective psychedelic effects generally resolved within 90 to 120 minutes—eliminating the need for intravenous (IV) administration.

“We’re delighted with the positive results from the VLS-01 phase 1b study, which further support its potential as a promising therapeutic option for the 100 million people worldwide suffering from TRD,” said Srinivas Rao, MD, PhD, co-chief executive officer and cofounder of atai.

Investigators sought to evaluate the relative safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of VLS-01 compared with IV DMT. The single center, open-label study enrolled 17 healthy participants, who each received 1 dose of IV DMT followed by 3 different doses of VLS-01 buccal film [20 mg (N=8), 60 mg (N=6), 120 mg (N=14), or 160 mg (N=16)] with a 28-day washout window between administrations.

“Our proprietary oral transmucosal formulation of DMT, VLS-01, is designed to induce a short psychedelic effect to allow for scalability and broad patient access. VLS-01 is expected to fit into an established interventional psychiatry treatment paradigm of 2 hours in the clinic and is anticipated to offer a more patient and physician-friendly experience compared to intravenous administration,” said Florian Brand, atai co-founder and chief executive officer, in an earlier news release.²

Peak plasma concentrations were dose-proportional and comparable between the higher VLS-01 buccal film doses (120 mg and 160 mg) and the 30 mg IV DMT dose. Dose-dependent and robust subjective effects were seen in both the 120 mg and 160 mg doses.

In the 120 mg dose cohort, 13 of 14 participants achieved Subjective Intensity Rating Scale scores greater than 7 out of 10, subjective effects were fully resolved by 120 minutes, and participants reported that their experience was ‘psychologically meaningful’ with ‘increased levels of self-reflection.’

In terms of safety profile, VLS-01 was well tolerated with all adverse events being mild or moderate, and most resolving on the day of dosing. The most common treatment-emergent adverse events (TEAEs) were headache, dissociation, euphoric mood, and nausea. No TEAEs of vomiting or local irritation were noted at doses of 120 mg or lower, except for 1 subject out of 14 (7%) who reported nausea at the 120 mg dose. There were no observed adverse events related to blood pressure, heart rate, or suicidality.

Based on these positive phase 1b results, atai intends to initiate a randomized, double-blind, placebo-controlled phase 2 study (NCT06524830) to assess the safety, efficacy, and durability of repeated doses of VLS-01 in patients with TRD.

“In this trial, the 120 mg dose was found to strike a balance between psychedelic effect intensity and safety as well as tolerability. These encouraging findings, if replicated in phase 2, suggest that VLS-01 could become a best-in-class treatment for TRD, one that offers a well-tolerated, convenient oral dosing and a short psychedelic experience that fits into the two-hour in-clinic commercial paradigm established within interventional psychiatry. These phase 1b results lay a strong foundation for our phase 2 trial in patients with TRD, which is set to begin around year-end,” said Rao.

According to atai’s plans, the phase 2 trial will consist of 2 treatment periods. In the first, approximately 142 patients will be randomized 1:1 to receive a 120 mg dose of VLS-01 buccal film or placebo on day 1, followed by a second dose of the same intervention at week 2. The primary endpoint is the change from baseline in Montgomery-Asberg Depression Rating Scale (MADRS) total score at week 4. The last double-blind assessment visit will be at week 14. This first treatment period will provide 12 weeks of durability data for 2 doses of VLS-01.

The second treatment period starts at week 14 and will explore the response to 2 different dose levels of VLS-01. Patients will be randomized 1:1 to receive a third dose of either 60 mg or 120 mg of VLS-01. Final safety and efficacy assessment will be conducted 2 weeks following the administration of the third dose.

References

1. atai Life Sciences announces positive preliminary results from phase 1b trial of VLS-01 (buccal film DMT). News release. August 13, 2024. https://ir.atai.life/news-releases/news-release-details/atai-life-sciences-announces-positive-preliminary-results-phase

2. O’Brien E. First participant dosed in phase 1b trial of VLS-01 for TRD. Psychiatric Times. March 5, 2024. https://www.psychiatrictimes.com/view/first-participant-dosed-in-phase-1b-trial-of-vls-01-for-trd