SAGE-718 · program

Dalzanemdor for Parkinson'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 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.

Data current as of

Development timeline

DiscontinuedApr 2024 – Jul 2025
  1. AcquisitionSupernus Pharmaceuticals completes acquisition of Sage Therapeutics↗
  2. 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.↗
Phase 2Jul 2020 – Jun 2022
  1. 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.
  2. 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).

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 in Parkinson's disease

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)

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)

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. 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)
  3. NCT05318937 (PRECEDENT) — Phase 2 placebo-controlled study of SAGE-718 in Parkinson's disease cognitive impairment — ClinicalTrials.gov (U.S. National Library of Medicine)
  4. 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)
  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.