DT-101 – A NOVEL ALPHA-AMINO-3-HYDROXY-5-METHYL-4-ISOXAZOLE RECEPTOR (AMPAR) POSITIVE ALLOSTERIC MODULATOR DEMONSTRATES FAVORABLE TOLERABILITY AND FUNCTIONAL BIOMARKERS IN PHASE 1 HEALTHY VOLUNTEER TRIAL

Positive allosteric modulators (PAMs) of the α-amino-3-hydroxy-5-methyl-4isoxazole subtype of ionotropic glutamate receptor (AMPAR) enhance glutamatergic signaling and synaptic plasticity, but the clinical development of earlier compounds have been constrained by suboptimal pharmacokinetics and limited therapeutic index (TI). DT-101 is a next-generation, structurally novel, orally bioavailable AMPAR PAM designed to achieve much broader TI through optimized receptor modulation. Importantly, DT-101 has a differentiated pharmacokinetic profile enabling once-a-day pulsatile dosing that is optimal for engaging synaptic plasticity mechanisms. A Phase 1 randomized, double-blind, placebocontrolled trial was conducted with single-ascending dose (SAD) and multiple-ascending dose (MAD) in healthy adult volunteers. The primary objectives were safety and tolerability of DT-101. Secondary and exploratory objectives included the plasma pharmacokinetics (PK) of DT-101 as well as measurements of cerebrospinal fluid (CSF) drug concentration. A separate cohort of healthy volunteers was used to assess the pharmacodynamic responses to single doses of DT-101 using magnetoencephalography (MEG), a method previously shown to be sensitive to modulators of excitatory/inhibitory tone in the brain. DT-101 was considered safe and well tolerated, with no dose-limiting toxicities or clinically meaningful safety findings. DT-101 achieved its predefined target PK profile, demonstrating doseproportional exposure and favorable half-life supportive of once-daily dosing. DT-101 concentration in CSF was equivalent to unbound plasma concentration, consistent with good exposure into the CNS. MEG analyses demonstrated a clear DT-101-mediated modulation of cortical oscillatory activity and network dynamics consistent with AMPA receptor potentiation, providing direct evidence of functional DT-101 effects in the brain. MEG effects correlated with plasma exposure, enabling data-driven refinement of Phase 2 dose selection. In summary, DT-101 exhibits a favorable safety profile with target-aligned PK, confirmed CSF exposure, and sensitive MEG-based demonstration of functional glutamatergic modulation. These Phase 1 findings supported advancement of DT-101 into a large, global Phase 2 trial in major depressive disorder (MDD).