Donello J., Burgdorf J., Bertelsen K., Leonardo Trejo L.J., Rosipal R., Moskal J., Burch R., Shekhar A.

Background: Major depressive disorder (MDD) is a common disabling and potentially life-threatening condition estimated to affect > 300 million people worldwide. Glutamatergic mediated plasticity and modulation of NMDA receptor activity have been employed in developing rapid-acting treatments for MDD. GATE-251 (also known as AGN-251751) is a NMDA receptor modulator that binds to a unique site on the receptor. In animals, zelquistinel has oral bioavailability greater than 90%, and provides eficacy in several animal models of depressive-like behavior. This Phase 1 first-in-man study evaluated safety, pharmacokinetics and GATE-251 as well as EEG measures of NMDAR activation in healthy volunteers.
Methods: This double-blind, randomized, placebo-controlled study evaluated healthy male or female subjects aged 18-55 years, with supine heart rate of 50-100 bpm who used no other drugs for at least 14 days prior to this study and were negative in drug of abuse screens. Part A of the study evaluated safety, plasma pharmacokinetics and EEG following single fasting doses of 100 microg, 1 mg, 3 mg, 10 mg, 25 mg, or 50 mg GATE-251 as an oral solution, compared to a water placebo (randomization 6:2 drug: placebo). A separate group studied a 1 mg dose in female subjects. Part B evaluated safety and CSF pharmacokinetics of single doses of 1 mg or 10 mg fasted and 1 mg fed (N= 5, 3, 3) in subjects with indwelling lumbar catheters. Part C evaluated plasma PK in fasted male subjects compared to subjects who received a high-fat breakfast (N= 5, 3).
Results: Safety: In this study no serious adverse events were reported, nor were any clinically significant changes in plasma chemistry, hematology or urinalysis observed. No subjects experienced clinically significant changes in vital signs or ECG. There were no treatment emergent psychotomimetic symptoms (as measured by changes in C-SSRS, BPRS + or CADSS) from predose baseline to end of study. Treatment-related adverse events (TRAEs) were few: in Part A (N= 14 placebo, N= 42 GATE-251) there were no TRAEs in the placebo group and 1 in the 1 mg GATE-251 group: headache. In Part B (N= 4 placebo, N= 12 GATE-251), there were no TRAEs in the placebo group and 2 in the 10 mg group: 1 lumbar puncture syndrome, 1 disturbance in attention. In Part C (N= 0 placebo, N= 6 GATE-251), there were no TRAEs.
Pharmacokinetics: In Part A, GATE-251 exhibited rapid absorption and dose-related increases in exposure assessed as Cmax or AUC. T1/2 was similar across doses at 0.5 hr, and was not different in male vs female subjects. In Part B, transport into the CSF was significant, with a Tmax of 4 h. Too few sampling times prevented calculation of T1/2 in CSF. A high fat meal slowed absorption of GATE-251 compared to fasted, with reduced Cmax exposure, although AUC exposure was not affected.
EEG: GATE-251 increased resting alpha EEG power, indicative of effective central modulation and enhanced NMDAR activation. While Gate-251 induced alpha power showed an inverted U-shaped dose response relationship at higher doses, doses that optimally enhanced alpha EEG demonstrated CSF drug concentration that corresponded to concentrations that enhance NMDAR activity in vitro.
Conclusions: GATE-251 was well-tolerated oral NMDA modulator with few treatment-related AEs. There was no evidence of psychotomimetic effects over the dose range evaluated. GATE-251 was rapidly absorbed into the plasma and exposure was dose-related. No gender-associated differences were observed. In plasma, AUC exposure was not affected by a high fat meal whereas in CSF AUC exposure appeared to be enhanced. The CSF levels achieved within this dose range were robust and corresponded the concentrations necessary to modulate NMDA receptors in vitro. Translational pharmacodynamics of qEEG/ERPs and the plasma/CSF pharmacokinetics demonstrate that the assessed doses meet and/or exceed drug concentrations that are predicted to be maximally efficacious in humans.