A PHASE IB STUDY EVALUATING SAFETY, PRELIMINARY EFFICACY, AND PUTATIVE BIOMARKERS OF NEUROPLASTICITY FOR THE NOVEL NEUROPLASTOGEN ZALSUPINDOLE (DLX-001) IN MAJOR DEPRESSIVE DISORDER

Background

Zalsupindole (DLX-001) is a novel, non-hallucinogenic, nondissociative neuroplastogen structurally inspired by 5-MeO-DMT in development for major depressive disorder (MDD). This Phase Ib study evaluated the safety, tolerability, pharmacodynamics, and preliminary antidepressant effects of zalsupindole using translational biomarkers of neuroplasticity alongside clinical outcomes.

Methods

In this dose-blinded, single-center, multiple-dose study, adults with recurrent MDD received zalsupindole under one of two dosing paradigms: once-daily dosing for 7 days (Cohort A; n=9) or intermittent dosing on Days 1 and 4 (Cohort B; n=9). Assessments included safety measures, quantitative EEG (qEEG), pharmacokinetics, standardized clinical rating scales, and the Cumulus NeuLogiq® assessment suite. In clinic treatment and assessments occurred through Day 8. Follow-up assessments occurred through Day 36 without additional treatment.

Results

All 18 participants completed the treatment period. Zalsupindole was well tolerated, with no serious adverse events or clinically meaningful changes in vital signs, ECGs, laboratory values, or physical examinations. The most common treatment-related adverse events were transient nausea and headache. As previously demonstrated in a 100+ healthy volunteer trial, no psychotomimetic, hallucinatory, or dissociative effects were observed. Further, the digital cognitive data demonstrated no evidence of acute or persistent cognitive impairment (e.g. due to sedation, dissociation or other effects). Plasma concentrations were consistent with target exposures. Clinically, rapid and sustained antidepressant effects were observed, with meaningful reductions in MADRS scores evident by Day 8 and maintained through Day 36 in both dosing cohorts. Across both cohorts, wake qEEG demonstrated zalsupindole-induced increases in absolute power of slow-wave delta and theta activity, patterns associated with cortical plasticity. Low-burden portable EEG supported replication of the acute theta finding.

Conclusions

Zalsupindole demonstrated a favorable safety and tolerability profile and consistently modulated qEEG biomarkers associated with neuroplasticity, alongside rapid and sustained reductions in depressive symptoms whether dosed daily or intermittently. Importantly, antidepressant effects were observed without evidence of psychotomimetic effects or cognitive compromise (acute or delayed). Together, these findings support the hypothesis that enhanced neuroplasticity may underlie the therapeutic effects of zalsupindole and other plastogens. A Phase II study evaluating daily and intermittent dosing paradigms versus placebo has been cleared to proceed by FDA including at-home administration.