Using a Multimodal Biomarker Approach to Identify Functional Target Engagement of the Novel NMDA Positive Allosteric Modulator SAGE-718 (1944)

Objective: We describe a suite of studies to demonstrate CNS target engagement of SAGE-718 in healthy volunteers. Background: NMDA-receptor-hypoactivity has been linked to many clinical phenomena, including cognitive dysfunction. Potential treatments may involve enhancement of NMDA-receptor-related neurotransmission. SAGE-718 is an oral positive allosteric modulator of the NMDA-receptor. Design/Methods: Two experimental paradigms, based on single-administration of SAGE-718 (3mg oral solution) vs. placebo in a randomized cross-over design, were performed. First, subjects underwent MRI approximately 6.5hrs after SAGE-718 or placebo to obtain a baseline. Ketamine (0.25mg/kg IV infusion) was administered over 60mins starting ~7hrs after SAGE-718 or placebo dosing, during which fMRI-derived changes of blood oxygenation level (BOLD) response and functional connectivity between regions of interest were recorded (n=13). Second experiment, electrophysiological parameters were assessed ~6hrs after SAGE-718 or placebo and ~1hr before ketamine and again during the 60min ketamine infusion. Ketamine-induced changes in single click auditory evoked potential (AEP, N100-P200), mismatch negativity (MMN), and auditory steady state response (ASSR) (n=18) were measured. Safety was assessed by adverse event reporting and standard clinical assessments. Results: Ketamine-induced-BOLD changes were broad, including increased activity in posterior brain regions and decreased activity in anterior brain regions. SAGE-718 attenuated ketamine-induced-BOLD alterations independent of directionality. N100-P200 was significantly reduced by ketamine under placebo conditions (p Conclusions: In healthy volunteers, SAGE-718 modulated the effects of ketamine on regional and global measures of resting brain activity, suggesting functional target engagement of the NMDA-receptor. These findings suggest further investigation of SAGE-718 for conditions characterized by relative NMDA-hypofunction is warranted. Disclosure: Dr. Koenig has nothing to disclose. Dr. Murck has nothing to disclose. Dr. Berlin has nothing to disclose. Dr. Luo has nothing to disclose. Dr. Li has nothing to disclose. Dr. Farley has nothing to disclose. Dr. Nguyen has nothing to disclose. Dr. Webster has nothing to disclose. Dr. Quirk has nothing to disclose. Dr. Kanes has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Sage Therapeutics, Inc.. I am an employee and shareholder in Sage Therapeutics. I am an employee and shareholder in Sage Therapeutics.