Small Molecule · SAGE-718

Dalzanemdor

DiscontinuedSage Therapeutics, Inc.

Oral, first-in-class NMDA receptor positive allosteric modulator developed by Sage Therapeutics as SAGE-718 for cognitive impairment in NMDA-receptor-hypofunction disorders. A synthetic oxysterol built on the cholestane scaffold (C27H43F3O2, trifluoromethyl-substituted side chain), designed as an analog of 24(S)-hydroxycholesterol, the endogenous brain oxysterol that positively modulates NMDA receptor function. Tested in Phase 2 across three indications — cognitive impairment in Huntington's disease (DIMENSION/SURVEYOR), Alzheimer's disease (LIGHTWAVE/LUMINARY) and Parkinson's disease (PRECEDENT/PARADIGM) — and missed the primary endpoint in all three placebo-controlled studies during 2024. Sage announced it would not develop dalzanemdor further on 2024-11-20 and closed the Phase 3 open-label PURVIEW safety study. Sage was acquired by Supernus Pharmaceuticals in July 2025; no revival of dalzanemdor has been announced.

Also known as: SAGE-718, SAGE718, dalzanemdor, 1629853-48-0, (3S,8S,9S,10R,13R,14S,17R)-3,10,13-trimethyl-17-[(2R,5S)-6,6,6-trifluoro-5-hydroxy-5-methylhexan-2-yl]-1,2,4,7,8,9,11,12,14,15,16,17-dodecahydrocyclopenta[a]phenanthren-3-ol

Data current as of

Key facts

Modality
Small molecule
Chemical class
oxysterol, steroid
Chemistry
Single enantiomer
Mechanism
NMDA receptor PAM
Highest phase
Discontinued
Lead indication
Huntington's disease
Developer
Sage Therapeutics, Inc.
Trials
8 tracked · 199 sites

Mechanism of action#

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—ⓘ

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—

Development timeline#

202020212022202320242025Phase 128 Feb 2019 — phase change — First patient study in Huntington's disease: NCT03787758, a Phase 1 open-label safety/tolerability/PK study of SAGE-718 oral solution in HD patients (Part B, n=6), started per ClinicalTrials.gov.Phase 211 Jun 2024 — readout (mixed) — Phase 2 SURVEYOR topline: primary endpoint met — a statistically significant baseline difference on the HD-CAB composite between HD participants and healthy volunteers — but only a small numerical dalzanemdor-placebo difference; well tolerated, no new safety signals.29 Nov 2022 — phase change — 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.6 Jun 2022 — phase change — Placebo-controlled Phase 2 PRECEDENT study (NCT05318937) started: double-blind study of once-daily oral dalzanemdor in adults with PD-MCI; primary endpoint WAIS-IV Coding Test at Day 42; 86 enrolled.26 Jan 2022 — phase change — Phase 2 DIMENSION study (NCT05107128) started: 12-week, double-blind, placebo-controlled study of dalzanemdor in participants with cognitive impairment associated with HD; primary endpoint change from baseline in SDMT at Day 84; 189 randomized. The 28-day Phase 2 SURVEYOR study (NCT05358821) followed on 2022-05-26 and the Phase 3 open-label safety study PURVIEW (NCT05655520) on 2022-12-14 — PURVIEW is registered Phase 3 but is an open-label safety study, so it is deliberately not treated as a phase advance here.7 Dec 2020 — phase change — 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).31 Jul 2020 — phase change — Phase 2 open-label safety and tolerability study PARADIGM (NCT04476017) started in participants with Parkinson's disease mild cognitive impairment (n=18; completed 2022-03-25).Discontinued31 Jul 2025 — Acquisition — Supernus Pharmaceuticals completes acquisition of Sage Therapeutics20 Nov 2024 — readout (missed) — Phase 2 DIMENSION topline: dalzanemdor missed the primary endpoint (change from baseline in SDMT at Day 84 vs placebo; n=189) with no statistically significant or clinically meaningful secondary-endpoint differences; Sage ends all development of dalzanemdor and closes the Phase 3 open-label PURVIEW study.20 Nov 2024 — Trial terminated — Sage closes the Phase 3 open-label PURVIEW safety study after the DIMENSION miss8 Oct 2024 — readout (missed) — 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.16 Apr 2024 — readout (missed) — Phase 2 PRECEDENT topline: dalzanemdor missed the primary endpoint (WAIS-IV Coding Test score vs placebo at Day 42; n=86) in mild cognitive impairment in Parkinson's disease; Sage stops dalzanemdor development in Parkinson's.
Phase change Readout Event UpcomingHover a marker for details.
DiscontinuedApr 2024 – Jul 2025
  1. AcquisitionSupernus Pharmaceuticals completes acquisition of Sage Therapeutics↗
  2. missedPhase 2 DIMENSION topline: dalzanemdor missed the primary endpoint (change from baseline in SDMT at Day 84 vs placebo; n=189) with no statistically significant or clinically meaningful secondary-endpoint differences; Sage ends all development of dalzanemdor and closes the Phase 3 open-label PURVIEW study.Huntington's disease↗
  3. Trial terminatedSage closes the Phase 3 open-label PURVIEW safety study after the DIMENSION missHuntington's disease↗
  4. 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.Alzheimer's disease↗
  5. missedPhase 2 PRECEDENT topline: dalzanemdor missed the primary endpoint (WAIS-IV Coding Test score vs placebo at Day 42; n=86) in mild cognitive impairment in Parkinson's disease; Sage stops dalzanemdor development in Parkinson's.Parkinson's disease↗
Phase 2Jul 2020 – Jun 2024
  1. mixedPhase 2 SURVEYOR topline: primary endpoint met — a statistically significant baseline difference on the HD-CAB composite between HD participants and healthy volunteers — but only a small numerical dalzanemdor-placebo difference; well tolerated, no new safety signals.Huntington's disease↗
  2. 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.Alzheimer's disease
  3. Placebo-controlled Phase 2 PRECEDENT study (NCT05318937) started: double-blind study of once-daily oral dalzanemdor in adults with PD-MCI; primary endpoint WAIS-IV Coding Test at Day 42; 86 enrolled.Parkinson's disease
  4. Phase 2 DIMENSION study (NCT05107128) started: 12-week, double-blind, placebo-controlled study of dalzanemdor in participants with cognitive impairment associated with HD; primary endpoint change from baseline in SDMT at Day 84; 189 randomized. The 28-day Phase 2 SURVEYOR study (NCT05358821) followed on 2022-05-26 and the Phase 3 open-label safety study PURVIEW (NCT05655520) on 2022-12-14 — PURVIEW is registered Phase 3 but is an open-label safety study, so it is deliberately not treated as a phase advance here.Huntington's disease
  5. 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).Alzheimer's disease
  6. Phase 2 open-label safety and tolerability study PARADIGM (NCT04476017) started in participants with Parkinson's disease mild cognitive impairment (n=18; completed 2022-03-25).Parkinson's disease
Phase 1Feb 2019
  1. First patient study in Huntington's disease: NCT03787758, a Phase 1 open-label safety/tolerability/PK study of SAGE-718 oral solution in HD patients (Part B, n=6), started per ClinicalTrials.gov.Huntington's disease

Dalzanemdor for Huntington's disease#

DiscontinuedDiscontinuedHuntington's disease indication →

Dalzanemdor (SAGE-718) for cognitive impairment associated with Huntington's disease — Sage's lead indication for its first-in-class NMDA receptor positive allosteric modulator, and the last of the three dalzanemdor indications to fall. The 12-week, double-blind, placebo-controlled Phase 2 DIMENSION study (NCT05107128, n=189) missed its primary endpoint — change from baseline on the Symbol Digit Modalities Test (SDMT) at Day 84 — with no statistically significant or clinically meaningful differences on secondary endpoints either; dalzanemdor was generally well tolerated with no new safety signals. Announced 2024-11-20, after the Parkinson's (PRECEDENT, April 2024) and Alzheimer's (LIGHTWAVE, October 2024) programs had already been stopped, the DIMENSION miss ended the molecule: Sage stated it does not plan further development of dalzanemdor and closed the ongoing Phase 3 open-label PURVIEW safety study (NCT05655520; terminated on ClinicalTrials.gov 2025-01-20, reason 'Internal company decision'). The earlier Phase 2 SURVEYOR study (NCT05358821, n=69) had met its primary endpoint of demonstrating an HD-CAB composite difference between HD participants and healthy volunteers — an endpoint characterizing the disease rather than the drug — with only a small numerical drug-placebo difference. Sage was acquired by Supernus Pharmaceuticals on 2025-07-31; CT.gov sponsorship of all SAGE-718 records transferred to Supernus, but no revival of dalzanemdor has been announced.

Readouts

  • 2024-11-20ReportedTopline datamissedNCT05107128

    Phase 2 DIMENSION topline: dalzanemdor missed the primary endpoint (change from baseline in SDMT at Day 84 vs placebo; n=189) with no statistically significant or clinically meaningful secondary-endpoint differences; Sage ends all development of dalzanemdor and closes the Phase 3 open-label PURVIEW study. ↗

  • 2024-06-11ReportedTopline datamixedNCT05358821

    Phase 2 SURVEYOR topline: primary endpoint met — a statistically significant baseline difference on the HD-CAB composite between HD participants and healthy volunteers — but only a small numerical dalzanemdor-placebo difference; well tolerated, no new safety signals. ↗

Dalzanemdor for Alzheimer's disease#

DiscontinuedDiscontinuedAlzheimer's disease indication →

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.

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. ↗

Dalzanemdor for Parkinson's disease#

DiscontinuedDiscontinuedParkinson's disease indication →

Dalzanemdor (SAGE-718) for mild cognitive impairment in Parkinson's disease (PD-MCI) — the first of the molecule's three indications to fail. After the Phase 2 open-label safety study PARADIGM (NCT04476017, n=18, completed 2022), the double-blind, placebo-controlled Phase 2 PRECEDENT study (NCT05318937, n=86) evaluated once-daily oral dalzanemdor over 42 days in adults with PD-MCI and mild-to-moderate motor symptoms. Announced 2024-04-16: PRECEDENT did not meet its primary endpoint of a statistically significant difference versus placebo on the WAIS-IV Coding Test score at Day 42, and Sage stopped any further development of dalzanemdor for Parkinson's. CEO Barry Greene said the results were specific to PD and did not necessarily predict other neurodegenerative conditions — but the Alzheimer's (LIGHTWAVE, October 2024) and Huntington's (DIMENSION, November 2024) studies then missed as well, ending the molecule.

Readouts

  • 2024-04-16ReportedTopline datamissedNCT05318937

    Phase 2 PRECEDENT topline: dalzanemdor missed the primary endpoint (WAIS-IV Coding Test score vs placebo at Day 42; n=86) in mild cognitive impairment in Parkinson's disease; Sage stops dalzanemdor development in Parkinson's. ↗

Clinical trials#

NCT05655520Phase 3Discontinuedn=153

A Study to Evaluate the Safety and Tolerability of SAGE-718 in Participants With Huntington's Disease (PURVIEW)

Started Dec 2022· Primary completion Jan 2025· 43 sites across 4 countries

United StatesUnited KingdomAustraliaCanada

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 StatesPuerto Rico

NCT05318937Phase 2Completedn=86

A Study to Evaluate the Effects of SAGE-718 in Participants With Parkinson's Disease Cognitive Impairment (PRECEDENT)

Started Jun 2022· Primary completion Jan 2024· 38 sites across 1 country

United States

NCT05358821Phase 2Completedn=69

28-Day Study of SAGE-718 on Functioning Capacity in Participants With Huntington's Disease (SURVEYOR)

Started May 2022· Primary completion Feb 2024· 14 sites across 2 countries

United StatesCanada

NCT05107128Phase 2Completedn=189

A Study to Evaluate the Effect of SAGE-718 on Cognitive Function in Participants With Huntington's Disease (HD) (DIMENSION)

Started Jan 2022· Primary completion Sept 2024· 49 sites across 4 countries

United StatesUnited KingdomAustraliaCanada

Show all 8 trials

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

NCT04476017Phase 2Completedn=18

A Study to Evaluate the Safety and Tolerability of SAGE-718 in Participants With Parkinson's Disease Mild Cognitive Impairment (PD-MCI) (PARADIGM)

Started Jul 2020· Primary completion Mar 2022· 4 sites across 1 country

United States

NCT03787758Phase 1Completedn=6

A Study to Evaluate Safety, Tolerability, and Pharmacokinetics of SAGE-718 Oral Solution in Patients With Huntington's Disease - Part B

Started Feb 2019· Primary completion Oct 2019· 2 sites across 1 country

United States

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. NCT03787758 — Phase 1 safety/tolerability/PK of SAGE-718 oral solution in patients with Huntington's disease (Part B) — ClinicalTrials.gov (U.S. National Library of Medicine)
  3. NCT04476017 (PARADIGM) — Phase 2 open-label safety and tolerability study of SAGE-718 in Parkinson's disease mild cognitive impairment — ClinicalTrials.gov (U.S. National Library of Medicine)
  4. 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)
  5. NCT05107128 (DIMENSION) — Phase 2 study of SAGE-718 on cognitive function in participants with Huntington's disease — ClinicalTrials.gov (U.S. National Library of Medicine)
  6. NCT05318937 (PRECEDENT) — Phase 2 placebo-controlled study of SAGE-718 in Parkinson's disease cognitive impairment — ClinicalTrials.gov (U.S. National Library of Medicine)
  7. NCT05358821 (SURVEYOR) — 28-day Phase 2 study of SAGE-718 on functioning capacity in participants with Huntington's disease — ClinicalTrials.gov (U.S. National Library of Medicine)
  8. 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)
  9. NCT05655520 (PURVIEW) — Phase 3 open-label safety and tolerability study of SAGE-718 in participants with Huntington's disease (terminated 2025-01-20, internal company decision) — ClinicalTrials.gov (U.S. National Library of Medicine)
  10. Sage Therapeutics Announces Phase 2 SURVEYOR Study Reinforces Cognitive Impact of Huntington's Disease (2024-06-11) — Sage Therapeutics, Inc. (via Business Wire)
Show all 15 sources
  1. Sage Therapeutics Announces Topline Results from Phase 2 PRECEDENT Study of Dalzanemdor (SAGE-718) in the Treatment of Mild Cognitive Impairment in Parkinson's Disease (2024-04-16) — Sage Therapeutics, Inc. (via Business Wire)
  2. Sage Therapeutics Announces Topline Results from the Phase 2 DIMENSION Study of Dalzanemdor (SAGE-718) in the Treatment of Cognitive Impairment Associated with Huntington's Disease (2024-11-20) — Sage Therapeutics, Inc. (via Business Wire)
  3. 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)
  4. 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)
  5. Supernus Pharmaceuticals Completes Acquisition of Sage Therapeutics (2025-07-31) — Supernus Pharmaceuticals, Inc.