DT-101, an α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor positive allosteric modulator, gave target-relevant magnetoencephalographic responses in healthy adults in first in human trial

DT‑101 is a novel positive allosteric modulator of the α‑amino‑3‑hydroxy‑5‑methyl‑4‑isoxazolepropionic acid receptor (AMPAR), developed to enhance excitatory glutamatergic signalling, thereby supporting synaptic plasticity and having potential antidepressant benefit. Major depressive disorder has a huge unmet clinical need, but drug development for neuropsychiatric disorders is associated with high attrition rates, with many compounds failing in late‑stage trials despite promising preclinical and early clinical data. A key contributor to this failure is the lack of translational biomarkers that can characterise functional brain effects early in drug development. Magnetoencephalography (MEG) allows non‑invasive, highly sensitive assessment of drug‑related changes in human brain activity, particularly suited for high frequency cortical oscillations. Here, MEG was integrated into a first‑in‑human (FiH) healthy volunteer clinical trial, and demonstrated mechanistically relevant brain effects that supported and informed further clinical development.

This was a Phase 1, FiH, three-part (single- and multiple-ascending dose (MAD), and single dose crossover), randomised, double-blind, placebo-controlled trial to assess the safety, tolerability, pharmacokinetics, and exploratory pharmacodynamics of DT-101 in healthy participants (ISRCTN81436702). MEG was incorporated into both the MAD and the single dose crossover. MEG data was collected on a CTF-275 system, and structural T1-weighted MRI scans were collected for each participant. MEG sessions started at approximately Tmax and lasted around 60 minutes with four paradigms: resting state (eyes open); auditory mismatch field (MMF); auditory steady state response (ASSR; 40 Hz click trains); “visual gamma” (stationary and moving high-contrast gratings that elicit sustained increases in gamma oscillations in visual cortex[1,2]). MEG data were co-registered to MRI scans and processed as appropriate for each paradigm. Data is reported here for the crossover where participants (n=19) received single doses of placebo, 9 mg, and 18 mg DT-101 in randomised order separated by washout periods.

The amplitude and frequency of oscillations elicited by the visual gamma stimulus have been shown to be sensitive to the excitatory/inhibitory cortical balance[3], thus making this paradigm of key relevance to the AMPA PAM mechanism of DT-101. Visual gamma data were analysed using FieldTrip’s LCMV beamforming in the broadband gamma 40-90Hz frequency range. Further beamforming of the amplitude changes between DT-101 and placebo sessions were performed in posterior source space in frequency bands from theta to gamma. The grating stimuli induced sustained increases in gamma activity in early visual cortex, with further analysis showing DT-101 dose-dependent increases in activity across frequency bands.

DT‑101 at 18 mg significantly increased 40‑Hz ASSR power and showed a trend to increasing inter‑trial coherence, while no DT-101‑related effects were observed on MMF. Resting‑state MEG revealed common areas of DT-101-related changes between doses.

MEG demonstrated target‑relevant brain engagement by DT‑101 in healthy volunteers and supported and informed dose selection and progression to Phase 2 studies in MDD. While broad adoption of MEG in clinical trials is limited by scarcity of facilities, the superior sensitivity of MEG, especially for high frequency oscillations, enables the most comprehensive probe of electrophysiological drug responses in humans.

References

1. Swettenham JB, Muthukumaraswamy SD, Singh KD. 2009. Spectral Properties of Induced and Evoked Gamma Oscillations in Human Early Visual Cortex to Moving and Stationary Stimuli, J Neurophysiol 102: 1241–1253
2. Muthukumaraswamy SD, Singh KD, Swettenham JB, Jones DK. 2010. Visual gamma oscillations and evoked responses: Variability, repeatability and structural MRI correlates, NeuroImage, 49, 3349-3357
3. Shaw AD, Moran RJ, Muthukumaraswamy SD, Brealy J, Linden DE, Friston KJ, Singh KD. 2017. Neurophysiologically-informed markers of individual variability and pharmacological manipulation of human cortical gamma, NeuroImage, 161, 19-31