A Pilot Electroencephalography Study of the Effect of CT1812 Treatment on Synaptic Activity in Patients with Mild to Moderate Alzheimer’s Disease

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BackgroundCT1812 is a first-in-class, sigma-2 receptor ligand, that prevents and displaces binding of amyloid beta (Aβ) oligomers. Normalization of quantitative electroencephalography (qEEG) markers suggests that CT1812 protects synapses from Aβ oligomer toxicity.ObjectivesEvaluate CT1812 impact on synaptic function using qEEG measurements.DesignPhase 2, randomized, double-blind, placebo-controlled, 4-week crossover study.SettingVU University Medical Center and Brain Research Center Amsterdam, The Netherlands.ParticipantsAdults with mild or moderate Alzheimer’s disease (AD).InterventionA daily 300 mg dose of CT1812 or placebo for 4 weeks.MeasurementsA resting-state, eyes closed qEEG assessment occurred on Day 1 and on Day 29 of Treatment Periods 1 and 2, and at follow-up. The primary endpoint was global relative theta power (4–8 Hz), along with secondary EEG measures including global alpha corrected Amplitude Envelope Correlation (AEC-c). Cognitive and functional assessments, fluid biomarkers, and safety and tolerability were assessed.Results16 patients were randomized, and 15 completed. A non-significant (p=0.123) but consistent reduction occurred in global relative theta power and in relative theta power in frontal, temporal, parietal, occipital and central (p<0.006) brain regions with CT1812. A nominally significant (p=0.034) improvement was observed in global alpha AEC-c. Adverse events occurred in 11 patients with CT1812 and 6 with placebo -most commonly nausea, diarrhea, and procedural headache. No severe or serious AEs, deaths or discontinuations were reported.ConclusionCT1812 improved established EEG markers of spontaneous brain activity (spectral power, functional connectivity) in patients with mild-to-moderate AD, suggesting improved neuronal/synaptic function within a 4-week timespan.