SAGE-718 Demonstrates Safety, Signs of Improvement in Phase 2 Alzheimer Disease Study

Sage Therapeutics’ investigational NMDA receptor positive allosteric modulator was well-tolerated, with signs of cognitive and functional improvements reported for patients with AD in the phase 2 LUMINARY study.

According to data presented at the 2022 American Academy of Neurology (AAN) Annual Meeting, April 2-7, in Seattle, Washington, the investigational SAGE-718, a first-in-class positive allosteric modulator of the N-methyl-D-aspartate (NMDA) receptor developed by Sage Therapeutics, showed an association with cognitive and functional improvement in patients with Alzheimer disease (AD).1

Data from the open-label phase 2 LUMINARY study (NCT04602624), which included a total of 26 patients (mean age, 67 years; 69.2% women), demonstrated a statistically significant 2.3-point improvement in Montreal Cognitive Assessment (MoCA) scores at day 28 compared with baseline. Additionally, functional evaluations—measured with the Clinical Global Impressions Scales and Amsterdam Instrumental Activities of Daily Living Questionnaire—were suggestive of noteworthy improvements in some patients, with particular promise displayed on items assessing complex activities.2,3

“Cognitive impairment is often one of the earliest signs of Alzheimer disease, can be very difficult for patients and their families, and represents an area of great unmet medical need,” study author Aaron Koenig, MD, vice president, early clinical development, Sage Therapeutics, said in a statement.2 “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 disease and related disorders and in improving how well people can function independently in their everyday lives.”

Overall, the study assessed 3 mg daily SAGE-718 for a 14-day treatment period in patients with AD, including individuals with MoCA scores ranging between 15 and 24 (mean, 20.7 [SD, 2.61]). The majority of those enrolled (n = 23; 88.4%) had a Clinical Dementia Rating score of 0.5.

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The incidence of treatment-emergent adverse events (TEAEs) through Day 28 was the primary end point of the trial, with other safety outcomes—the percentages of participants with significant changes in vital sign measurements, laboratory assessments, electrocardiogram measurements, and baseline responses on the Columbia Suicide Severity Rating Scale— as secondary end points. SAGE-718 was generally considered well-tolerated in the study. All told, 8 TEAEs were reported in 7 patients (26.9%), though all were deemed mild or moderate, and 6 were considered treatment-related. No serious adverse events (AEs) or deaths were reported in LUMINARY.

Additional functional measurements at day 14, included improvements on Digit Symbol Substitution, Multitasking, One Touch Stockings, Spatial Working Memory, and 2-Back tests. Learning and memory improvements were observed in Pattern Recognition Memory and Verbal Recognition Memory tests, as well. There were no reported changes in attention or psychomotor speed.

Jim Doherty, PhD, chief development officer, Sage, noted in a statement that the global estimated population of patients with AD numbers in the hundreds of millions, representing a great area of unmet need with minimal options for 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 and Huntington disease. 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 said.3

As Doherty alluded to, SAGE-718 is also being assessed in other neurodegenerative diseases, with the NMDA receptor modulator winning fast track designation for Huntington disease,4 and Sage recently announcing promising data from its phase 2 development for patients with mild cognitive impairment due to Parkinson disease (PD).5 Announced in mid-March 2022, data from the PARADIGM study (NCT04476017) were presented virtually at the AD/PD 2022 Advances in Science & Therapy International Conference on Alzheimer’s and Parkinson’s Diseases and Related Neurological Disorders.5

Data from PARADIGM suggested that the therapy was associated with similar improvements to what was reported in LUMINARY, with patients experiencing gains in tests of executive function and promising signals on tests of learning and memory at day 14. These effects were sustained—along with trends of improvement—as far out as Day 28 for assessments completed at the follow-up visit. The therapy was also deemed well-tolerated, with no serious AEs or TEAEs related to SAGE-718.

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REFERENCES
1. Koenig A, Malhotra S, Wald J, et al. SAGE-718 in Patients With Mild Cognitive Impairment or Mild Dementia Due to Alzheimer's Disease: Results From the Phase 2 LUMINARY Study. Presented at: AAN Annual Meeting; April 2-7, 2022; Seattle, WA, and virtual.
2. Preliminary study: Drug may be safe in those with mild cognitive impairment, mild dementia. News release. AAN. March 31, 2022. Accessed April 2, 2022. https://www.aan.com/PressRoom/home/PressRelease/4975
3. Sage Therapeutics Announces Presentation of Promising Results from the Phase 2 LUMINARY Study of SAGE-718 in Patients with Mild Cognitive Impairment and Mild Dementia due to Alzheimer’s Disease. News release. Sage Therapeutics. April 1, 2022. Accessed April 2, 2022. https://investor.sagerx.com/news-releases/news-release-details/sage-therapeutics-announces-presentation-promising-results-phase
4. Sage Therapeutics Receives Fast Track Designation for SAGE-718 for the Treatment of Huntington’s Disease. News release. Sage Therapeutics. September 15, 2021. Accessed April 2, 2022. https://investor.sagerx.com/news-releases/news-release-details/sage-therapeutics-receives-fast-track-designation-sage-718
5. Sage Therapeutics Announces Presentation of Encouraging Results from the Phase 2 PARADIGM Study (Part A) of SAGE-718 in Patients with Mild Cognitive Impairment due to Parkinson’s Disease. News release. Sage Therapeutics. March 15, 2022. Accessed April 2, 2022. https://investor.sagerx.com/news-releases/news-release-details/sage-therapeutics-announces-presentation-encouraging-results