SAGE-718

A niche, investigational oxysterol-derived neuroactive steroid that is mechanistically distinct from the GABAergic neurosteroids because it potentiates rather than inhibits neurotransmission, acting as a first-in-class NMDA receptor positive allosteric modulator.

In first-in-human Phase 1 studies, dalzanemdor was generally well tolerated, with no adverse events reported as leading to discontinuation, and it exhibited pharmacokinetics consistent with once-daily oral dosing. Because it potentiates rather than blocks NMDA receptors, its safety rationale rested on selectively correcting reduced NMDA signaling rather than broadly overactivating the receptor, a design intended to reduce the excitotoxic liability associated with direct NMDA agonists. As a purely investigational agent that did not reach approval, its long-term safety and its adverse-event profile in broad patient populations remain incompletely characterized. It should be regarded as a research compound; it is not an approved medicine and is not available as a supplement.

Dalzanemdor emerged from a Sage Therapeutics neuroactive steroid discovery program that first identified the endogenous oxysterol 24(S)-hydroxycholesterol as a positive allosteric modulator of NMDA receptors. Medicinal chemistry optimization of that natural scaffold, reported in the Journal of Medicinal Chemistry in 2022, produced SAGE-718 as a potent, high-intrinsic-activity NMDA receptor PAM with pharmacokinetics suitable for oral dosing.

The compound completed Phase 1 single-ascending-dose and multiple-ascending-dose studies in healthy participants and Huntington's disease participants, then advanced into Phase 2 trials for cognitive impairment across Huntington's disease, Parkinson's disease, and Alzheimer's disease. It received the international nonproprietary name dalzanemdor. During 2024 and 2025 the program reported that its pivotal cognition studies, including the DIMENSION study in Huntington's disease, largely failed to meet their primary endpoints, and Sage Therapeutics terminated the open-label Phase 3 PURVIEW study, effectively ending the compound's late-stage development.

Within neuropharmacology, dalzanemdor is regarded as a scientifically elegant, first-in-class proof of concept that a synthetic oxysterol could translate the endogenous NMDA-potentiating activity of 24(S)-hydroxycholesterol into an oral drug. It drew interest as a mechanistically novel approach to cognitive impairment that was distinct from cholinergic and GABAergic strategies. Its clinical reputation, however, is defined by disappointment; the broad failure of its Phase 2 cognition studies across Huntington's, Parkinson's, and Alzheimer's disease and the termination of the Phase 3 PURVIEW study have made it a frequently cited example of a compelling preclinical and target rationale that did not translate into clinical benefit. It remains a subject of interest in reviews of neuroactive steroid therapeutics and NMDA receptor hypofunction.