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Abstract Details

Cognitive Performance After Repeated Administration of the NMDA Positive Allosteric Modulator SAGE-718 in Healthy Volunteers
Aging, Dementia, and Behavioral Neurology
P12 - Poster Session 12 (12:00 PM-1:00 PM)
10-003
Here, we describe the effects of 10-day repeated-exposure of SAGE-718 on a cognitive battery in healthy volunteers. 
NMDA-receptor hypoactivity has been linked to a range of 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.
Forty subjects were randomized (1:1) to multiple doses of SAGE-718 (n=19) or placebo (n=21) in a double-blinded manner. Computerized testing measured performance on key cognitive domains: verbal learning (International Shopping List Test), memory (International Shopping List Test–Delayed Recall), executive function (Groton Maze Learning Test), emotional cognition (Social Emotional Cognition Test), psychomotor function (Detection Test), attention (Identification Test), working memory (One Back Test), higher-order working memory (Two Back Test), inhibition (Stop Signal Reaction Test), and paired associated learning (Continuous Paired Associate Learning Test). A mixed-effect regression model analysis was then applied. Safety was assessed by adverse event reporting and standard clinical assessments. 
Statistically significant improvements were observed in the Two-Back Test at days 2, 4 and 8 (p<0.05) and the Groton Maze Test at day 6 (p<0.05) compared to placebo. A dose-response relationship was observed for the Two-Back Test, with Cmax positively correlated with an increase in change from baseline performance (p=0.02). A similar trend was observed for the Groton Maze Test (Cmax vs change from baseline, p=0.06). No serious adverse events or deaths were reported. The most frequent treatment emergent adverse events (TEAEs) were mild and numerically similar to placebo (SAGE-718, n=6 (31.6%); placebo, n=7 (33.3%)). No TEAEs resulted in discontinuation or dose reduction. 

In healthy volunteers, SAGE-718 was generally well tolerated and exhibited greater improvement on tests of higher-order working memory and complex problem solving compared to placebo. These findings suggest further investigation of SAGE-718 is warranted for conditions characterized by NMDA hypofunction, particularly those manifesting with executive deficits.
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
No disclosure on file
No disclosure on file
No disclosure on file
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.