Background

SAGE-718 is a derivative of the endogenous steroid 24(S)-hydroxycholesterol. It is a positive allosteric modulator of the NMDA receptor, whose activity induces long-term potentiation of synapses, and thus is essential for learning and memory. SAGE-718 is being developed to treat cognitive dysfunction in people with neurodegenerative diseases.

The role of 24(S)-hydroxycholesterol in brain function, and in neurodegenerative diseases, is complex and controversial. It is the most abundant cholesterol metabolite in the brain. Some studies, but not all, suggest its levels decrease with aging and in AD. It has been reported to have both beneficial and detrimental effects on neuronal function, survival, and amyloid or tau pathology (reviewed by Gamba et al., 2021). Work from SAGE and other labs reported decreases in plasma 24(S)-hydroxycholesterol in patients with Huntington’s disease, which correlated with more severe cognitive symptoms (2019 ACNP poster M-147; see also Leoni et al., 2008). This metabolite is also reported to be decreased in people with PD (e.g. Di Natale et al., 2018; Huang et al., 2019), though that finding is not universal (e.g. Bjorkhem et al., 2018).

Company scientists published on NMDA receptor modulatory activity of 24(S)-hydroxycholesterol and several synthetic drug-like derivatives. The derivatives enhanced NMDA receptor-mediated LTP in hippocampal slices, and reversed behavioral and cognitive deficits in mice and rats treated with NMDA receptor channel blockers (Paul et al., 2013). The structure and synthesis of SAGE-718 was subsequently disclosed (Hill et al., 2022). It was shown to potentiate NMDA receptor activity, and rescue NMDA receptor hypofunction in preclinical models. SAGE-718 did not produce seizures or neurotoxicity in animals (Beckley et al., 2024).

Findings

In 2018 and 2019, Sage conducted Phase 1 studies in healthy volunteers to assess safety and pharmacodynamics. The latter was measured by SAGE-718's ability to reverse the synaptic effects of a low dose of the NMDA blocker ketamine using electrophysiology and MRI spectroscopy. According to results presented at the 2020 AD/PD conference, single doses of the drug normalized ketamine-induced changes in synaptic activity and neurotransmitter levels. In a multi-dosing study, endpoints included cognitive testing. In that study, 11 days of SAGE-718 improved performance on more difficult CogState tests of working memory and executive function, compared to placebo. On simpler tasks, treatment and placebo groups performed equally well. In another Phase 1 study of six people with Huntington’s disease, two weeks of SAGE-718 improved working memory (Apr 2020 news).

In September 2020, SAGE began Phase 2 in Parkinson’s patients with mild cognitive impairment. In an open-label study, 18 participants took 3 mg tablets once daily for two or four weeks. Primary outcomes were adverse events; other safety outcomes included vital signs, lab assessments, ECG, and suicidal ideation. The study finished in March 2022, and some results were presented at the AD/PD meeting that year. According to news sources, the patients treated for two weeks showed significant improvements in measures of executive function. The benefits were maintained for one month, with no serious side effects reported (news). This study used no placebo control.

In February 2021, another Phase 2 open-label study, called LUMINARY, began evaluating safety and efficacy of 3 mg daily of SAGE-718 in 26 people with MCI and mild dementia due to Alzheimer’s disease. The two-week trial also included a cognitive battery and functional assessments, and was completed in September 2021. According to data presented at the March 2022 American Academy of Neurology meeting, patients improved their executive performance and learning and memory after two weeks of treatment, compared to baseline. The company reported a 2.3-point improvement on the MoCA, and gains in daily function on the Clinical Global Impression of Change and Amsterdam Instrumental Activities of Daily Living Questionnaire. There was no placebo group for comparison. Eight mild or moderate treatment-emergent adverse events in seven patients were reported, but not identified. There were no serious adverse events or deaths (press release).

In September 2021, the FDA granted SAGE-718 fast track designation for Huntington’s disease (news).

In February 2022, the company began DIMENSION, a placebo-controlled Phase 2 trial in Huntington’s patients with mild to moderate cognitive impairment. The study is recruiting 178 participants to test a regimen of 1.2 mg daily for one month, followed by two months at 0.9 mg, against primary outcome of change from baseline in the Huntington's Disease Cognitive Assessment Battery (HD-CAB). The trial, at sites in the U.S., Canada, Australia, and the U.K., is expected to finish in December 2024. An open-label extension is planned.

In June 2022, the company began another Phase 2 study in early stage Huntington's patients, of whom 40 will take 1.2 mg SAGE-718 or placebo daily for four weeks, with a primary outcome of the HD-CAB composite. This trial also includes a comparison group of 40 healthy adults who will receive no treatment but will complete the cognitive assessments (May 2022 investor presentation).

Also in May 2022, a Phase 2 placebo-controlled study began for MCI due to Parkinson’s disease. It planned to enroll 76 people, to take 1.2 mg SAGE-718 per day in softgel capsules for six weeks. The primary outcome is change from baseline on the Wechsler Adult Intelligence Scale-IV Coding Test (WAIS-IV), which measures processing speed. The secondary outcomes relate to adverse events. The study finished in February 2024.

In December 2022, the company began a placebo-controlled Phase 2 trial for Alzheimer’s. It will enroll 150 people with mild cognitive impairment to mild dementia due to AD, for a course of six weeks of 1.2 mg SAGE-718 daily, then six weeks of 0.9 mg. The primary outcome is change from baseline in the WAIS-IV; secondary outcomes are adverse events and study withdrawals. The trial is running at 35 sites in the U.S and one in Puerto Rico until December 2024.

Also in December 2022, an open-label safety and tolerability trial began for patients with Huntington’s. It will include up to 300 patients, either rollovers from previous studies or new volunteers. Treatment will last for one year, and outcomes are adverse events, withdrawals, changes in vital and other safety signs, and suicidality. This trial will end in December 2025.

On April 17, 2024, Sage announced that the Phase 2 Parkinson’s trial had missed its primary endpoint, and that the company was stopping development of SAGE-718 for PD (press release). Results from the ongoing Phase 2 trials in AD and HD are expected in mid- to late 2024.

For details on SAGE-718 trials, see clinicaltrials.gov