SAGE-718 · program
Dalzanemdor for Huntington's disease
Indications for SAGE-718: Huntington's disease · Discontinued Parkinson's disease · Discontinued Alzheimer's disease · Discontinued
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.
Development timeline
- 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.↗
- 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.↗
- 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.
- 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.
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. ↗
Clinical trials in Huntington's disease
NCT05655520Phase 3Discontinuedn=153
A Study to Evaluate the Safety and Tolerability of SAGE-718 in Participants With Huntington's Disease (PURVIEW)
NCT05358821Phase 2Completedn=69
28-Day Study of SAGE-718 on Functioning Capacity in Participants With Huntington's Disease (SURVEYOR)
NCT05107128Phase 2Completedn=189
A Study to Evaluate the Effect of SAGE-718 on Cognitive Function in Participants With Huntington's Disease (HD) (DIMENSION)
NCT03787758Phase 1Completedn=6
A Study to Evaluate Safety, Tolerability, and Pharmacokinetics of SAGE-718 Oral Solution in Patients With Huntington's Disease - Part B
Formulations
| Formulation | Route | Regimen | Pharmacokinetics |
|---|---|---|---|
| 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. | Oral | Once daily | — |
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.
| Target | Action | Affinity |
|---|---|---|
| NMDA receptorprimaryGRIN1 | PAM | —ⓘ |
← Full SAGE-718 compound page (identity, identifiers, all indications)
Sources
- 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)
- 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)
- 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)
- 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)
- 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)
- Sage Therapeutics Announces Phase 2 SURVEYOR Study Reinforces Cognitive Impact of Huntington's Disease (2024-06-11) — Sage Therapeutics, Inc. (via Business Wire)
- 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)
- 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)
- Supernus Pharmaceuticals Completes Acquisition of Sage Therapeutics (2025-07-31) — Supernus Pharmaceuticals, Inc.