DT-101, an α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) positive allosteric modulator (PAM): Phase 1 safety, pharmacokinetic, and pharmacodynamic data in healthy volunteers

Positive allosteric modulation of the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid subtype of ionotropic glutamate receptors (AMPARs) has emerged as a promising therapeutic mechanism for psychiatric disorders, including major depressive disorder (MDD). Potentiation of AMPAR activity enhances glutamatergic signalling, promotes synaptic plasticity, and has been linked to improvements in mood and cognition in depression. However, earlier AMPAR positive allosteric modulators (PAMs) have often been limited by a narrow therapeutic index due to convulsant liability. DT-101 is a structurally novel, orally bioavailable AMPAR PAM designed to achieve a broader therapeutic index through optimised receptor modulation and a differentiated pharmacokinetic profile enabling once-daily dosing with pulsatile exposure.

This Phase 1, first-in-human (FiH), three-part study (single ascending dose [SAD], multiple ascending dose [MAD; 14 days], and a single-dose crossover for pharmacodynamic [PD] assessment) was a randomised, double-blind, placebo-controlled trial in healthy adults (ISRCTN81436702). Electroencephalography (EEG) was used for eligibility screening and safety monitoring (days 1 and 14). Primary objectives were safety and tolerability; secondary and exploratory objectives included plasma and urine pharmacokinetics (PK), cerebrospinal fluid (CSF) concentrations in one MAD cohort, and PD assessment using magnetoencephalography (MEG). The study design enabled integrated evaluation of safety, systemic and central exposure, and functional pharmacodynamic effects across dose levels and study parts.

In the crossover, participants received placebo, 9 mg, and 18 mg DT-101 in randomised order across three clinic stays separated by washout periods. MEG included both task-based paradigms (visual and auditory stimuli known to elicit gamma frequency responses) and resting-state recordings, enabling assessment of oscillatory activity reflective of excitatory/inhibitory (E/I) balance in the brain and sensitive to AMPAR-mediated modulation.

A total of 81 healthy adults participated. DT-101 was safe and well tolerated following single and multiple doses up to 36 mg once daily, with no EEG abnormalities and no clinically meaningful safety findings. DT-101 was rapidly absorbed, with approximately dose-proportional plasma exposure across SAD and MAD cohorts and a half-life consistent with once-daily pulsatile dosing. The observed half-life was in line with preclinical predictions and supports the intended dosing paradigm to optimise clinical benefit through controlled, transient receptor engagement while avoiding sustained overstimulation. CSF concentrations at steady state were comparable to unbound plasma concentrations, indicating good brain penetration. Urinary excretion was low.

MEG analyses demonstrated clear, dose-dependent modulation of cortical oscillatory activity under resting-state conditions and during visual gamma and auditory steady-state response paradigms. While there are no previously published human electrophysiological studies of responses to AMPAR PAMs, these effects are consistent with modulation of E/I balance and AMPAR potentiation, providing evidence of functional target engagement in the human brain.

DT-101 shows a favourable safety profile, mechanism-aligned pharmacokinetics, good CNS exposure, and measurable pharmacodynamic effects in healthy participants. Together, these findings support DT-101 as a differentiated AMPAR PAM and its advancement into ongoing global Phase 2 studies in MDD.

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