SAGE-718 in Parkinson's Disease Mild Cognitive Impairment: Results from the Phase 2 PARADIGM Study (Part A)
Aaron Koenig1, Jason Johannesen1, Emily Freitag1, Sigui Li1, Jennifer Petrillo1, Jeffrey Wald1, Steve Kanes1, Mike Quirk1, James Doherty1
1Sage Therapeutics, Inc.
Objective:
The ongoing Phase 2, open-label, PARADIGM Study (NCT04476017; 718-CNP-201) is evaluating SAGE-718 3 mg once daily in participants with mild cognitive impairment due to Parkinson’s disease (PD-MCI). 
Background:
There is a critical need for better therapies for patients with cognitive decline, particularly those suffering from conditions including Huntington’s disease, Parkinson’s disease, and Alzheimer’s disease. SAGE-718 is a potential first-in-class, investigational N-methyl-D-aspartate receptor positive allosteric modulator in development as a potential oral therapy for cognitive disorders. 
Design/Methods:

PD patients, aged 50-75 years, meeting PD-MCI criteria (Movement Disorders Society Task Force) and baseline Montreal Cognitive Assessment (MoCA) score of 20-25 were administered SAGE-718 3 mg tablets once daily for 14 days (Part A). The primary endpoint was safety; pharmacokinetics, cognitive performance, and motor symptoms were also evaluated.

Results:

Eleven patients were enrolled; mean (SD) age was 69.1 (6.9) years, mean (SD) MoCA baseline score was 23.8 (2.3), 100% white, 91% Hoehn and Yahr stage 2, and 82% male. Multiple domains of cognitive performance were assessed. SAGE-718 was associated with improved performance at Day 14, compared with baseline on tests of executive functioning (Multitasking, Stockings of Cambridge, Spatial Working Memory, Digital Symbol Substitution, and Two-back Test). An emerging signal suggested improved performance on tests of learning and memory (Paired Associates, Pattern Recognition, and Verbal Memory). No appreciable effect was observed on measures of simple attention/psychomotor speed. The most common adverse events (AEs) were headache, somnolence, and dizziness. No severe/serious AEs or deaths were reported, and no treatment-emergent AEs resulted in study drug discontinuation or study withdrawal. Plasma concentration data suggest a pharmacokinetic profile consistent with previous studies.

Conclusions:
These data support the emerging clinical profile of SAGE-718 in PD-MCI, suggesting improved performance on executive functioning, as well as promising signals on learning and memory. A 4-week dosing cohort (Part B) is ongoing.