Trejo L.J., Rosipal R., Moore A., Lujan B., Kosheleff A., Ereshefsky L., Owen R., Vlasuk G.

NV-5138 (or SPN-820) is a novel small molecule activator of the mechanistic target of rapamycin complex 1 (mTORC1) currently under development for use in treatment-resistant depression. This phase I study evaluated the safety, tolerability, and pharmacodynamics (as measured by quantitative electroencephalography, qEEG) of two sequential oral doses of NV-5138 in healthy adult males. Twenty- five participants were randomly assigned to double-blind treatment with a single dose of placebo or 2400 mg NV-5138 on Day 1, and a second dose of the same treatment on Day 3. The two doses of NV-5138 were safe and well tolerated, with no deaths, serious adverse events, or discontinuations due to adverse events. Spectral band amplitudes, derived frequency measures, and magnitude squared coherences were computed from qEEG recordings during resting state eyes-open and eyes-closed conditions at multiple timepoints. In the NV-5138 group only, significant changes in qEEG measures occurred at 1 hour post-dose on both days (near NV-5138 T_max), including decreases in low-frequency band amplitudes (theta) and increases in high-frequency EEG band amplitudes (high beta and gamma). These effects were mirrored by a decrease in the theta/beta ratio, a measure negatively associated with arousal and cognitive processing capability. Significantly increased high beta and gamma band coherences were also detected at several specific electrode pairs in both eyes-open and eye-closed conditions. NV-5138 actively modulated functional brain parameters consistent with positive effects on mood, cognition, and arousal. These results indicate that qEEG measures may be useful biomarkers of NV-5138 target engagement and related changes in neural activity.