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CT1812 Consistently Improves EEG Patterns in Phase 2 SEQUEL Study of Mild-to-Moderate Alzheimer Disease
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Investigational drug CT1812 showed potential to improve neurophysiological markers in mild-to-moderate Alzheimer's disease, with notable EEG changes observed in a recent phase 2 study.
Anthony Caggiano, MD, PhD
A phase 2 study published in The Journal of Prevention of Alzheimer’s Disease showed that treatment with investigational CT1812 (Cognition Therapeutics) resulted in improved established electroencephalography (EEG) markers of spontaneous brain activity in patients with mild-to-moderate Alzheimer disease (AD). Although the pilot study was small in scale, the findings suggest improved neuronal/synaptic function within a 4-week timespan.
Otherwise known as SEQUEL, the phase 2, randomized, double-blind, placebo-controlled, crossover study randomly assigned 34 patients to a daily 300 mg dose of CT1812 (n = 16) or placebo (n = 16) for 4 weeks. In the study, a resting-state, eyes closed quantitative EEG assessment was taken on Day 1 and on Day 29 of treatment periods 1 and 2, and at follow-up. Conducted at the VU University Medical Center and Brain Research Center Amsterdam, The Netherlands, the study’s primary end point was global relative theta power (4-8 Hz), along with secondary EEG measures that included global alpha corrected Amplitude Envelope Correlation (AEC-c).
After 29 days of treatment, a non-significant (P = .123) but consistent reduction was observed in global relative theta power and in relative theta power in frontal, temporal, parietal, occipital, and central (P <.006) brain regions among CT1812-treated patients. In addition, a nominally significant (least square [LS] mean difference, 0.016 [SE, 0.007]; P = .034) improvement in global alpha AEC-c was observed with CT1812. Furthermore, a numerically favorable treatment difference (LS mean difference, 0.026 [SE, 0.017]; P = .149) was documented for increases in global relative alpha power with CT1812.
"The gradual slowing of brain wave patterns and impaired connectivity that is a hallmark of Alzheimer’s disease is due to the loss of synapses, which are the connection points between neurons," Anthony Caggiano, MD, PhD, chief medical officer and head of Research & Development at Cognition, said in a statement.1 "Quantitative qEEG is a sensitive method of measuring the electrical activity of neurons in the brain. The changes we observed across EEG parameters in SEQUEL may indicate that CT1812 is normalizing brain wave patterns and facilitating communication between different brain regions. We believe that CT1812 was able to rescue these early deficits by protecting synapses through its unique mechanism as an Aβ oligomer antagonist."
CT1812 is an experimental orally delivered small molecule designed to penetrate the blood-brain barrier and selectively to the sigma-2 receptor complex. Over the 29-day treatment period, the agent showed no change on plasma and cerebrospinal fluid (CSF) concentrations of exploratory pre-specified biomarkers. In addition, relative to placebo, CT1812-treated patients showed no significant difference in any cognitive or functional outcomes.
At day 29, mean ADCS-GCI-I scores were 4.0 (SD, 0.76) for placebo and 4.0 (SD, 0.73) for those treated with CT1812. Notably, all 16 patients with CT1812 had minimal or no change as did 14 of 15 patients with placebo. Investigators also observed no differences between placebo and treated groups on the Amsterdam IADL and the NTI Battery.
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In terms of safety, more treatment-emergent adverse events (TEAEs) occurred in the CT1812 group (n = 11) than placebo (n = 6). Overall, there were no severe or serious AEs reported, as well as no deaths or discontinuations because of TEAEs. Six TEAEs (diarrhea, nausea, and vomiting with placebo; diarrhea, nausea, and hepatic enzyme increased with CT1812) were considered to be treatment-related. Of note, 1 CT1812-treated patient experienced an increase in alanine aminotransferase levels that was twice the upper limit of normal and reported as a TEAE. The TEAE was deemed mild in severity and possibly related to CT1812, but the participant continued treatment.
In the published piece, the study authors concluded that, "results from this study showed that resting state qEEG improved after CT1812. Although qEEG is an exploratory endpoint in patients with AD, substantial evidence suggests that qEEG can detect changes in both whole-brain and regional electrical patterns that are impaired in AD. Results from this study suggest that CT1812 has an effect on neurophysiological endpoints, and contribute to the growing body of preclinical and clinical evidence of the benefits of CT1812."
CT1812 is currently being assessed in larger proof-of-concept studies, including the START study (NCT05531656) of early AD, SHINE trial (NCT03507790) of mild-to-moderate AD, and SHIMMER study (NCT05225415) of dementia with Lewy bodies. At the recently concluded 2024 Alzheimer’s Association International Conference, new data from SHINE showed that CT1812 achieved its primary objective and demonstrated a favorable safety and tolerability profile, consistent with previous clinical experience.
The study, which featured 153 adults with mild-to-moderate AD, showed that CT1812-treated participants declined an average of 1.66 points on Alzheimer’s Disease Assessment Scale-Cognitive subscale 11 over a 6-month period in comparison with declines of 2.70 for those on placebo, resulting in a 39% slowing of decline favoring CT1812. Overall, CT1812 did not achieve statistical significance on the first of the ordered secondary efficacy end points in the pooled 100 mg and 300 mg dose group compared with placebo. It did however demonstrate an effect on several CSF biomarkers, further supporting its development as a potential treatment for AD.3
