SAGE-718 · program

Dalzanemdor for Alzheimer's disease

DiscontinuedDiscontinuedSage Therapeutics, Inc.

Indications for SAGE-718: Huntington's disease · Discontinued Parkinson's disease · Discontinued Alzheimer's disease · Discontinued

Dalzanemdor (SAGE-718) for mild cognitive impairment and mild dementia due to Alzheimer's disease. After the Phase 2a open-label safety study LUMINARY (NCT04602624, n=26, completed 2021), the 12-week, randomized, double-blind, placebo-controlled Phase 2 LIGHTWAVE study (NCT05619692, n=174) evaluated dalzanemdor in participants with MCI or mild dementia due to AD. Announced 2024-10-08: LIGHTWAVE did not demonstrate a statistically significant difference versus placebo on the primary outcome, the WAIS-IV Coding Test score at Day 84, and Sage stated it does not plan further clinical development of dalzanemdor in AD. This was the second of dalzanemdor's three 2024 failures — Parkinson's (PRECEDENT) had been stopped in April 2024, and the Huntington's miss (DIMENSION, November 2024) then ended the molecule entirely.

Data current as of

Development timeline

DiscontinuedOct 2024 – Jul 2025
  1. AcquisitionSupernus Pharmaceuticals completes acquisition of Sage Therapeutics↗
  2. missedPhase 2 LIGHTWAVE topline: dalzanemdor missed the primary endpoint (WAIS-IV Coding Test score vs placebo at Day 84; n=174) in mild cognitive impairment and mild dementia due to Alzheimer's disease; Sage ends dalzanemdor development in AD.↗
Phase 2Dec 2020 – Nov 2022
  1. Placebo-controlled Phase 2 LIGHTWAVE study (NCT05619692) started: 12-week, randomized, double-blind study of once-daily dalzanemdor in MCI or mild dementia due to AD; primary endpoint WAIS-IV Coding Test at Day 84; 174 enrolled.
  2. Phase 2a open-label safety and tolerability study LUMINARY (NCT04602624) started in participants with MCI or mild dementia due to AD (n=26; completed 2021-09-28).

Readouts

  • 2024-10-08ReportedTopline datamissedNCT05619692

    Phase 2 LIGHTWAVE topline: dalzanemdor missed the primary endpoint (WAIS-IV Coding Test score vs placebo at Day 84; n=174) in mild cognitive impairment and mild dementia due to Alzheimer's disease; Sage ends dalzanemdor development in AD. ↗

Clinical trials in Alzheimer's disease

NCT05619692Phase 2Completedn=174

A Study to Evaluate the Effects of SAGE-718 in Participants With Mild Cognitive Impairment or Mild Dementia Due to Alzheimer's Disease (LIGHTWAVE)

Started Nov 2022· Primary completion Jun 2024· 📍 39 sites across 2 countries (United States, Puerto Rico)

NCT04602624Phase 2Completedn=26

A Study to Evaluate the Safety and Tolerability of SAGE-718 in Participants With Mild Cognitive Impairment or Mild Dementia Due to Alzheimer's Disease (LUMINARY)

Started Dec 2020· Primary completion Sept 2021· 📍 10 sites across 1 country (United States)

Formulations

FormulationRouteRegimenPharmacokinetics
Dalzanemdor oral capsule (once daily)
Oral capsules taken once daily in the morning for 42 days in the Phase 2 PRECEDENT study (per coverage of the 2024-04-16 topline release). Milligram dose strengths were not stated in the cited press releases and are left uncited.
OralOnce daily—

Mechanism of action (compound-wide)

First-in-class oral positive allosteric modulator (PAM) of the NMDA-type glutamate receptor. Dalzanemdor is a synthetic oxysterol modeled on 24(S)-hydroxycholesterol, the major brain cholesterol metabolite and an endogenous positive allosteric modulator of NMDA receptors acting at an oxysterol site distinct from the glycine and glutamate co-agonist sites. The therapeutic hypothesis was that enhancing NMDA receptor function would improve the executive/cognitive deficits of disorders characterized by NMDA receptor hypofunction — Huntington's disease, Alzheimer's disease and Parkinson's disease cognitive impairment. Target engagement was supported in Phase 1 by attenuation of ketamine (NMDA-antagonist) challenge effects in healthy volunteers. The hypothesis failed clinically: all three placebo-controlled Phase 2 studies (PRECEDENT, LIGHTWAVE, DIMENSION) missed their primary cognitive endpoints in 2024.

TargetActionAffinity
NMDA receptorprimaryGRIN1PAM—ⓘ

← Full SAGE-718 compound page (identity, identifiers, all indications)

Sources

  1. Dalzanemdor (SAGE-718) fails to improve cognition in Phase 2 trial — PRECEDENT coverage (announcement date, once-daily oral capsule dosing, 42-day duration, CEO statement) — Parkinson's News Today (BioNews)
  2. NCT04602624 (LUMINARY) — Phase 2 open-label safety and tolerability study of SAGE-718 in MCI or mild dementia due to Alzheimer's disease — ClinicalTrials.gov (U.S. National Library of Medicine)
  3. NCT05619692 (LIGHTWAVE) — Phase 2 placebo-controlled study of SAGE-718 in MCI or mild dementia due to Alzheimer's disease — ClinicalTrials.gov (U.S. National Library of Medicine)
  4. Sage Therapeutics Announces Topline Results from the Phase 2 LIGHTWAVE Study of Dalzanemdor (SAGE-718) in the Treatment of Mild Cognitive Impairment and Mild Dementia in Alzheimer's Disease (2024-10-08) — Sage Therapeutics, Inc. (via Business Wire)
  5. SAGE-718 — Alzforum Therapeutics entry (oxysterol NMDA receptor positive allosteric modulator, 24(S)-hydroxycholesterol analog; development history across HD/AD/PD) — Alzforum (FBRI / Biomedical Research Forum)
  6. Supernus Pharmaceuticals Completes Acquisition of Sage Therapeutics (2025-07-31) — Supernus Pharmaceuticals, Inc.