THE USE OF MAGNETOENCEPHALOGRAPHY (MEG) IN A FIRST-IN-HUMAN TRIAL TO DEMONSTRATE THE FUNCTIONAL CONSEQUENCES OF TARGET ENGAGEMENT BY DT-101, A NOVEL AMPA RECEPTOR POSITIVE ALLOSTERIC MODULATOR

Development of new drugs for neuropsychiatric disorders is limited by the lack of objective biomarkers that can demonstrate central nervous system engagement and inform early clinical decision-making. In this work, we integrated magnetoencephalography (MEG) into a first-in-human (FiH) clinical trial of DT-101, a novel AMPA receptor (AMPAR) positive allosteric modulator (PAM), to assess its utility as a pharmacodynamic biomarker. To our knowledge, this represents the first incorporation of MEG into a FiH trial, and the findings informed dose selection and supported progression to Phase 2 evaluation in major depressive disorder (MDD). MEG provides millisecond temporal resolution and relatively high spatial resolution, and directly measures neural activity, making it well suited to detect pharmacologically induced changes in brain function. MEG was incorporated using two complementary FiH study designs: integration within a Multiple Ascending Dose (MAD) to assess effects after repeated dosing, and a standalone double-blind crossover to enable within-participant comparisons across single doses. Comparable drug-related effects were observed across both designs. Healthy volunteers completed ~1-hour MEG sessions beginning around Tmax. In the MAD study, three dose cohorts (18:6 DT-101:placebo) were assessed on dosing Day 12 (±1 day). In the crossover study (n=19), participants received placebo, low-dose, and high-dose DT-101 in randomised treatment periods with washout. MEG paradigms included eyes-open resting state, auditory mismatch negativity (MMN), auditory steady-state response (ASSR), and high-contrast visual gratings to elicit gamma oscillations. Resting-state data were analysed using whole-brain beamforming across eight frequency bands (total range 1–100 Hz), with dose effects assessed using linear mixed-effects models. DT-101 produced dose-related changes across frequency bands, characterised by reduced activity at lower frequencies, consistent with effects opposite to those previously reported for the AMPAR antagonist perampanel1. Visual grating stimulation elicited expected occipital gamma responses, with beamforming revealing DT-101 dose-dependent increases in stimulus-induced occipital activity over a broad range of frequencies up to gamma. In the auditory paradigms, DT-101 increased 40-Hz ASSR power without affecting inter-trial coherence, and no drug-related effects were observed with MMN. DT-101 was well tolerated, with cerebrospinal fluid concentrations comparable to plasma levels. Together, these findings demonstrate target-relevant neurophysiological effects and illustrate how MEG can provide informative pharmacodynamic evidence in early-phase psychopharmacology studies. MEG may therefore represent a valuable tool to support dose selection and translational decision-making in psychiatric drug development.