Trejo L.J., Ereshefsky L., Rosipal R., Moore A., Hassman H., Owen R., Vlasuk G.

Randomized Double-Blind, Placebo Controlled Study to Evaluate NV-5138/SPN-820 (NV-5138), an mTORC1 Activator, by Quantitative EEG (QEEG) in Healthy Volunteers, Supports Target Engagement and Translational Strategy

2021 ASCP Annual Meeting, Virtual Conference, June 1-4, 2021.

Introduction: NV-5138, a direct mTORC1 activator demonstrates rapid and long-lasting 'antidepressant' effects comparable to ketamine in pre-clinical models. Ketamine and other antidepressants have been investigated for their effects on qEEG and this study was performed to understand the effects of NV-5138 in comparison with those agents as a possible valuable measurement of central pharmacological activity. qEEG may be useful to characterize the CNS impact of NV-5138 including confirmation of meaningful CNS target engagement and a dose to be carried forward to proof-of-concept.

Methods: 25 healthy male subjects were randomly assigned to a single dose of either placebo or 2400 mg NV-5138 on Day 1, and the same treatment on Day 3. Tolerability and PK were evaluated. Baseline (Day -1) and Days 1 and 3 time matched qEEGs (5 minutes each eyes closed (EC); eyes open (EO)) corresponding to 1 hour pre-dose and 1, 4, and 8 hours post-dose, were recorded. Spectral band amplitudes, frequency-derived measures, and magnitude squared coherence were assessed. Recording specs: Compumedics Grael 4k V2 EEG amplifiers, Curry 8E Software, 23 electrodes (International 10-20 system). Standard pre-processing of 2 second segments using a fast Fourier transformation and Irregular-Resampling Auto-Spectral Analysis (IRASA) to separate oscillatory and fractal components was performed (delta through gamma3 bands). Salient changes in end points for drug vs placebo on Days 1 and 3, were classified as small, medium or large, confirmed by MMRM. The pre-dose baseline time point was used as a covariate. The study was performed in accordance with all applicable requirements, including informed consent and IRB oversight.

Results: 56 subjects were screened, with a total of 25 randomized (13 placebo/12 drug). 24 subjects completed the study (1 participant withdrew consent on Day 1 (placebo). The two sequential doses of NV-5138 were well tolerated, with no incidents of death, no serious adverse events, or discontinuations due to adverse events. Dissociative effects were evaluated with the CADSS, and there were no clinically meaningful abnormalities in laboratory or physical exam parameters. The strongest changes in qEEG parameters occurred in the NV-5138 group, on both days, 1-hour post-dose (approximately at the time of NV-5138 Tmax). These assessments revealed a decrease in low-frequency EEG bands (delta and theta) and an increase in high-frequency EEG bands (gamma), while alpha bands exhibited decreased amplitudes (or desynchronization) around Tmax. At later time points alpha 1, alpha 2 and beta 1 bands increased in amplitudes, with a resultant decrease in Theta/Beta ratio and increased Alpha Slow-wave Index, linked to increasing arousal and cognitive processing and effects on mood. Salient changes observed in the fractal part of the EEG spectrum included increases in amplitudes for high beta, gamma, gamma 1, gamma 2, and gamma 3 bands (greatest change). Increased inter- and intrahemispheric coherence occurred at several specific electrode pairs, and were more prominent in the high-beta through gamma bands. Changes in qEEG in the placebo group were minimal and not related to treatment. Consistent with the increased beta through gamma band amplitudes and coherences, NV-5138 might increase perceptual and cognitive processing.

Conclusion: NV-5138 was generally safe, well tolerated. NV-5138 actively modulated neural activity as measured by qEEG band amplitudes and coherences. The pattern of electrophysiology changes on drug was consistent with desired antidepressant effects. Limitations include small sample size and use of healthy male volunteers precluding conclusions in females or in patients with depression.