SAGE-718: A first in class oxysterol-based NMDA receptor positive allosteric modulator for the potential treatment of Huntington’s disease

Neuroactive steroids (NASs) like 24(S)-hydroxycholesterol [24(S)-HC], play a crucial role in maintaining homeostasis in the central nervous system (CNS). We have discovered that 24(S)-HC is a positive allosteric modulator (PAM) of the N-Methyl-D-aspartate (NMDA) receptor. NMDA receptors are glutamate-gated cation channels that play a critical role in the health and regulation of neurons, and are involved in learning, memory and neuroplasticity. Positive modulation of NMDA receptors may have potential benefit in the treatment of conditions associated with NMDA hypofunction and disorders associated with a high prevalence of anti-NMDA antibodies, as well as in disorders associated with reductions in plasma cerebrosterol, such as Huntington's disease and Alzheimer's disease.
SAGE-718 is a novel, first-in-class, oxysterol-based PAM of NMDA receptors currently in Phase 2 clinical trials for Huntington’s Disease, a devastating disease without effective therapeutic treatments. Preclinically, SAGE-718 demonstrated high potency and selectivity for NMDA receptors and in contrast with endogenous ligands, it has an optimized pharmacokinetic (PK) profile consistent with once-daily dosing. Five Phase 1 healthy volunteer studies with SAGE-718 have been completed, including SAD, MAD, and three target engagement biomarker studies. Results of an integrated analysis in healthy volunteers demonstrated SAGE-718 had effects on electrophysiological, functional neuroimaging, and cognitive measures consistent with CNS activity. The structure activity relationship efforts, preclinical data, and early clinical results of SAGE-718 will be presented.