SAGE-718 Falls Short in Phase 2 PRECEDENT Study of Mild Cognitively Impaired Parkinson Disease

Barry Greene

Sage Therapeutics recently announced topline data from its pivotal phase 2 PRECEDENT study, with results showing that SAGE-718, an investigational agent, did not demonstrate statistically significant differences vs placebo on the primary end point in patients with Parkinson disease (PD) who had mild cognitive impairment (MCI). The company still plans to report topline data from studies assessing the NMDA receptor positive allosteric modulator in patients with Alzheimer disease (AD) and Huntington disease (HD) later this year.¹

After 6 weeks of treatment, those on SAGE-718 failed to distinguish themselves from placebo on the primary end point of Wechsler Adult Intelligence Scale Fourth Edition (WAIS-IV) Coding Test score. The trial, which randomly assigned 86 patients to either study drug or placebo, showed no between-group differences on other exploratory end points such as SCOPA-Cog. SAGE-718, also known as dalzanemdor, was well tolerated, with no new safety signals and treatment-emergent adverse events that were all mild to moderate in severity.

"We are disappointed by the results of the Phase 2 PRECEDENT study given the significant burden of mild cognitive impairment on people and families affected by Parkinson Disease," Barry Greene, chief executive officer, Sage Therapeutics, said in a statement.¹ "We are thankful for the patients and healthcare professionals who participated in this research. Although cognitive impairment is common in neurodegenerative disorders, the underlying pathophysiology and symptomatology in Parkinson’s disease is distinctive, and these results do not necessarily predict results with dalzanemdor in other neurodegenerative conditions. We look forward to the topline data readouts from the Phase 2 studies in Huntington disease and Alzheimer disease expected later this year."

While the results did not pan out as Sage would like, the company expects additional data from its phase 2 LIGHTWAVE study (NCT04602624) in people with MCI and mild dementia in AD and its phase 2 DIMENSION trial in HD cognitive impairment later this year. It also plans to report topline data from SURVEYOR, another phase 3 study (NCT05655520) of patients with HD cognitive impairment, midway through this year.

READ MORE: Cerevel’s Tavapadon Meets Primary End Point in Phase 3 TEMPO-3 Study of Parkinson Disease

At the 2022 American Academy of Neurology (AAN) Annual Meeting, data from the open-label phase 2 LUMINARY study (NCT04602624) demonstrated SAGE-718’s impact on cognitive and functional improvement in patients with AD. The analysis, which included 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

In the trial, 3 mg of daily SAGE-718 was administered 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]). After 28 days, the therapy was considered well tolerated, with 8 treatment-related adverse events (TEAEs) reported in 7 patients (26.8%). All of which were deemed mild or moderate, and 6 were considered treatment-related. No serious AEs or deaths were reported in LUMINARY.

DIMENSION, one of the ongoing trials assessing SAGE-718, recruited 178 patients with HD with MCI to test a regimen of 1.2 mg daily for 1 month, followed by 2 months at 0.9 mg. The primary outcome of the study is change in composite score of the Huntington’s Disease Cognitive Assessment Battery (HD-CAB), while the key secondary end point is Unified Huntington Disease Rating Scale Independence Scale. Eligible patients must be ambulatory, have scores of less than 26 on MoCA, and be willing to invite a study partner, if available, who is reliable, competent, and at least 18 years of age to participate in the study.³

REFERENCES
1. 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. News release. April 17, 2024. Accessed April 22, 2024. https://www.businesswire.com/news/home/20240416114636/en/Sage-Therapeutics-Announces-Topline-Results-from-Phase-2-PRECEDENT-Study-of-Dalzanemdor-SAGE-718-in-the-Treatment-of-Mild-Cognitive-Impairment-in-Parkinson%E2%80%99s-Disease
2. 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.
3. SAGE-718 DIMENSION Study Design. Accessed April 22, 2024. https://investor.sagerx.com/static-files/b4842269-3e93-4ed3-8ad6-ad374411d53f