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Abstract Details

Using a Multimodal Biomarker Approach to Identify Functional Target Engagement of the Novel NMDA Positive Allosteric Modulator SAGE-718
Aging, Dementia, Cognitive, and Behavioral Neurology
P6 - Poster Session 6 (12:00 PM-1:00 PM)
10-009
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. 
We describe a suite of studies to demonstrate CNS target engagement of SAGE-718 in healthy volunteers. 
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.
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<0.05), but not after SAGE-718. No significant ketamine-induced changes were observed for MMN and ASSR under any condition. No serious AEs or deaths were reported. Treatment emergent AEs (TEAEs) after SAGE-718 (but before ketamine) were mild and infrequent, including headache (n=1 each study) and fatigue (n=1) in the AEP. No TEAEs resulted in discontinuation or dose reduction.
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.
Authors/Disclosures
Aaron Koenig
PRESENTER
Aaron Koenig has received personal compensation for serving as an employee of Sage Therapeutics.
Harald Murck No disclosure on file
Jason Berlin No disclosure on file
Yi Luo No disclosure on file
Sigui Li Sigui Li has received personal compensation for serving as an employee of SAGE Therapeutics.
Brandon Farley No disclosure on file
David Nguyen No disclosure on file
Irena Webster No disclosure on file
Michael Quirk Michael Quirk has received personal compensation for serving as an employee of Sage Therapeutics. Michael Quirk has received stock or an ownership interest from Sage Therapeutics.
Steve Kanes, MD, PhD (Sage Therapeutics) Dr. Kanes has received personal compensation for serving as an employee of Sage Therapeutics. Dr. Kanes has received personal compensation in the range of $0-$499 for serving as an officer or member of the Board of Directors for Verge Genomics. Dr. Kanes has received intellectual property interests from a discovery or technology relating to health care.
James Doherty, PhD (Sage Therapeutics) Dr. Doherty has received personal compensation for serving as an employee of Sage Therapeutics. Dr. Doherty has received stock or an ownership interest from Sage Therapeutics.