Phase 1b Trial Signals Benefit of VLS-01 for Treatment-Resistant Depression

Credit: Nik Shuliahin/Unsplash

Positive preliminary Phase 1b results demonstrated the potential benefit of VLS-01, a proprietary oral transmucosal film formulation of N,N-dimethyltryptamine (DMT) applied to the buccal surface, for mental health disorders, including treatment-resistant depression.¹

Announced by Atai Life Sciences on August 13, 2024, VLS-01 induced a short psychedelic experience that typically resolved within 90–120 minutes. The company’s proprietary buccal film formulation was designed to achieve a short psychedelic experience within the established two-hour in-clinic patient visit.

“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 treatment-resistant depression,” said Srinivas Rao, MD, PhD, co-chief executive officer and co-founder, Atai Life Sciences.

The Phase 1b trial measured the relative safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of VLS-01 compared with intravenous (IV) DMT. A total of 17 healthy participants received a single IV DMT dose, 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).

Upon analysis, VLS–01 achieved peak plasma concentrations within 30–45 minutes. Higher VLS-01 buccal film doses (120 mg and 160 mg) displayed dose-proportional and comparable effects to the 30 mg IV DMT dose.

Meanwhile, in the 120 mg dose cohort, 13 of 14 individuals achieved Subjective Intensity Rating Scale (SIRS) scores greater than 7 out of 10. Subjective effects reported in SIRS were fully resolved by the 120-minute mark.

According to the release, participants in the trial reported the experience to be “‘psychologically meaningful’ ‘with increased levels of self-reflection’”

Safety data revealed a well-tolerated profile – all adverse events were classified as mild or moderate and most resolved on the day of dosing. Headache, disassociation, euphoric mood, and nausea were the most common treatment-emergent adverse events (TEAEs).

Based on these positive data, Atai announced plans to initiate a randomized, double-blind, placebo-controlled Phase 2 study. The study will evaluate the safety, efficacy, and durability of the response of repeated VLS-01 doses in patients with treatment-resistant depression (TRD), across two treatment periods.

In the first treatment period, 142 individuals will be randomized 1:1 to a 120 mg VLS-01 buccal film or placebo on Day 1, and receive a second intervention dose at Week 2. The primary endpoint will be the change from Baseline in Montgomery-Asberg Depression Rating Scale (MADRS) total score at Week 4, with a final double-blind assessment visit at Week 14.

The second treatment period will begin at Week 14, with individuals assigned 1:1 to receive a third dose of 60 mg or 120 mg VLS-01 and a final safety and efficacy assessment two weeks after administration. Atai announced its plan to initiate the Phase 2 trial by the end of 2024, with topline data anticipated at the end of 2025.

“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,” Rao added.

In related psychedelic news, the US Food and Drug Administration (FDA) recently issued a Complete Response Letter (CRL) for midomafetamine (MDMA) capsules for the treatment of posttraumatic stress disorder (PTSD).²

The decision on MDMA-assisted therapy came after considerable negative feedback from the FDA’s Psychopharmacologic Drugs Advisory Committee (PDAC). In June 2024, the PDAC voted 2 to 9 against MDMA-assisted therapy for PTSD, citing concerns about safety, cardiovascular risks, and issues related to functional unblinding in trial settings.

“If the FDA were to delay its approval or even decide to reject it, it would be a setback for the field,” Casey A. Paleos, MD, chief medical officer of InnerMost PBC, told HCPLive before the decision.³ “However, the data on its efficacy are too strong and convincing for that to be likely. I believe it's now a question of when, not if, and under what circumstances.”

References

1. _{Atai Life Sciences N.V. Atai Life Sciences announces positive preliminary results from phase 1B trial of VLS-01 (buccal film DMT). GlobeNewswire News Room. August 13, 2024. Accessed August 13, 2024. https://www.globenewswire.com/news-release/2024/08/13/2929035/0/en/atai-Life-Sciences-Announces-Positive-Preliminary-Results-from-Phase-1b-Trial-of-VLS-01-Buccal-Film-DMT.html.}
2. _{Derman C. FDA rejects application for MDMA-Assisted therapy in PTSD, calls for additional trial. HCP Live. August 9, 2024. Accessed August 13, 2024. https://www.hcplive.com/view/fda-rejects-application-for-mdma-assisted-therapy-in-ptsd-calls-for-additional-trial.}
3. _{Casey Paleos M. Casey Paleos, MD: Interpreting Trial Data and safety for MDMA-Assisted therapy in PTSD. HCP Live. August 7, 2024. Accessed August 13, 2024. https://www.hcplive.com/view/casey-paleos-md-interpreting-trial-data-and-safety-for-mdma-assisted-therapy-in-ptsd.}