#AAN2022 – SAGE-718 May Help With Cognitive Function in Alzheimer’s

Lindsey Shapiro, PhD avatar

by Lindsey Shapiro, PhD |

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SAGE-718 | Alzheimer's News Today | illustration for AAN Annual meeting

Treatment with the investigational candidate SAGE-718 was generally well-tolerated and associated with cognitive improvements in people with Alzheimer’s disease, according to preliminary results from the LUMINARY Phase 2 clinical trial.

The therapy’s developer, Sage Therapeutics, presented these findings in a talk, titled “SAGE-718 in Patients With Mild Cognitive Impairment or Mild Dementia Due to Alzheimer’s Disease: Results From the Phase 2 LUMINARY Study,” at the American Academy of Neurology’s 74th Annual Meeting.

“Cognitive impairment is often one of the earliest signs of Alzheimer’s disease, can be very difficult for patients and their families, and represents an area of great unmet medical need,” Aaron Koenig, MD, Sage’s vice president of early clinical development, said in an AAN press release.

“These results support further research with larger numbers of people to determine whether this therapy is safe and effective in treating cognitive impairment in Alzheimer’s disease and related disorders and in improving how well people can function independently in their everyday lives,” Koenig added.

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The trial (NCT04602624) enrolled 26 individuals, ages 50–80, with mild cognitive impairment or mild dementia due to Alzheimer’s disease. Patients were treated for two weeks with SAGE-718, given once daily as a 3 mg tablet.

LUMINARY’s primary goal was to determine the treatment’s safety. Overall, no serious side effects were reported during or in the two weeks after treatment. Seven participants reported eight mild-to-moderate adverse events, such as headache or constipation, with six side effects determined to be treatment-related.

Participants also underwent a battery of tests to assess cognitive function at the study’s start (baseline), after the two weeks of treatment (14 days), and again two weeks after treatment ended (28 days, or one month from the study’s start).

After 14 days, improvements were observed in a number of tests of learning, memory, and executive function — a set of skills that include working memory, flexible thinking, and self-control to help manage one’s daily activities — compared with baseline evaluations.

Montreal Cognitive Assessment scores rose by an average of 2.3 points over a month from the study’s start, a statistically significant increase that also suggested an improvement in cognition upon treatment with SAGE-718.

Some participants experienced better functioning in their daily lives. In particular, patients reported an easier time with complex daily activities, such as using a computer, doing household chores, and managing medications.

SAGE-718 is a first-in-class oral therapy designed to modulate activity of the brain’s N-methyl-D-aspartate (NMDA) receptors, which are critical for proper nerve cell communication. Evidence suggests that NMDA signaling is disrupted in Alzheimer’s, leading to cognitive declines.

The therapy is thought to normalize NMDA signaling, thereby helping to restore normal cognition.

LUMINARY joins ongoing Phase 2 trials of the therapy in Parkinson’s and Huntington’s diseases as part of Sage’s CogNEXT platform, designed to test the treatment in multiple neurological disorders characterized by cognitive dysfunction.

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The Phase 2 DIMENSION trial (NCT05107128) is testing whether about three months of daily SAGE-718 treatment is safe and can improve cognition in people with Huntington’s disease — an indication for which the therapy currently has fast track designation from the U.S. Food and Drug Administration to speed its development.

Similarly, the PARADIGM Phase 2 trial (NCT04476017) evaluated the safety and efficacy of two weeks of daily SAGE-718 in people with mild cognitive impairment due to Parkinson’s. Preliminary evidence suggested that the therapy’s use might safely improve cognition in these individuals. A second part of the trial is now testing the effects of four weeks of the treatment.

“We are encouraged by the positive results shared from the LUMINARY Study, which are consistent with signals suggesting improvement in cognitive performance seen across the SAGE-718 program, including in people with Parkinson’s and Huntington’s disease,” Jim Doherty, PhD, chief development officer at Sage, said in a press release .

“We look forward to learning more about the potential of SAGE-718 as we continue to advance our program with multiple ongoing or planned Phase 2 studies,” Doherty added.

Note: The Alzheimer’s News Today team is providing coverage of the American Academy of Neurology (AAN) 2022 Annual Meeting.