CT1812 Shows Positive Impact on Underlying Brain Function in Alzheimer Study

Anthony Caggiano, MD, PhD

Recently announced topline findings from the phase 2 SEQUEL study (NCT04735536) showed that CT1812 (Cognition Therapeutics), an investigational agent, met its primary end points for safety and tolerability, with positive, non-statistically significant impacts observed in underlying brain function. Full analyses of the results from SEQUEL, along with analyses of Alzheimer disease (AD) canonical biomarkers and proteomics from participants in the study, will be presented at an upcoming medical meeting.¹

Supported by a grant from the National Institute on Aging, SEQUEL was designed to assess differences in synaptic function in CT1812-treated patients vs placebo using quantitative electroencephalogram (qEEG). The single-site, randomized, double-blind, placebo-controlled, 29-day, 2-period crossover study featured 16 individuals with mild to moderate AD. Patients who received active treatment in period 1 received placebo in period 2, and vice versa.

Over 4 weeks of treatment, patients on CT1812 experienced a numerical reduction in relative theta power to the period when they were on placebo. Although not statistically significant, these data indicated a positive impact on underlying brain function, which was further supported by nominally significant and directionally positive changes in AECc and alpha power. Furthermore, findings also showed that treatment with CT1812 was associated with decreases in relative theta in frontal, central, temporal, and posterior regions, with statistically significant changes observed in the central region.

"My colleagues and I are excited to see this favorable result, which suggests that treatment with CT1812 may be directly impacting overall brain health, as illustrated in a change in relative theta power globally and across brain regions," principal investigator Everand Vijverberg, MD, PhD, neurologist and senior research at the Amsterdam University Medical Centers, said in a statement.¹ "We look forward to continuing our work with Cognition as a clinical trial collaborator in the SHINE study, which is studying CT1812 over a six-month treatment period in 144 adults with mild-to-moderate Alzheimer’s disease."

In SEQUEL, patients were between 50 and 85 years old, with at least a 6-month history of decline in cognitive function documented in their medical record. Patients were positive for amyloid-ß in the cerebrospinal fluid (CSF), had Mini Mental State Examination scores between 18 and 26, and had neuroimaging consistent with the clinical diagnosis of AD and without findings of significant exclusionary abnormalities.

"Though an exploratory endpoint, there is substantial evidence to believe that qEEG can detect changes in both whole-brain and regional electrical patterns that are impaired in Alzheimer’s disease,” Anthony Caggiano, MD, PhD, chief medical officer and head of Research & Development at Cognition, said in a statement.¹ "These results show CT1812’s impact on neurophysiological endpoints, which add to the growing body of evidence that we have compiled in our preclinical and clinical programs: CT1812’s target engagement observed in the SNAP study, its impact on anatomical endpoints observed in the SPARC study, and preliminary cognitive impact seen in the first cohort of patients in the SHINE study."

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CT1812 is an experimental orally delivered small molecule designed to penetrate the blood-brain barrier and bind selectively to the sigma-2 receptor complex. The agent is currently in development for mild to moderate AD in the phase 2 SHINE study (NCT03507790) and dementia with Lewy bodies in the SHIMMER study (NCT05225415).

At AD/PD 2023: the International Conference on Alzheimer’s and Parkinson’s Disease, Caggiano presented results from a meta-analysis of portion of SHINE and the complete dataset of the phase 1b SPARC trial (NCT03493282). The meta-analysis presented leveraged commonalities across trials including same treatment duration (6 months), same patient population (mild to moderate AD), and same methods to access CSF proteomes. When combining the trials and including patients with available data, the sample size increased from 17-18 to 35, resulting in enough statistical power.

After preprocessing was conducted to remove batch effects, investigators began to observe pharmacodynamic biomarkers of CT1812, with brain network mapping that supported the of the agent in synapses. All told, 302 proteins were significantly altered (P <.05) in CT1812-treated patients vs placebo CSF from patients with AD. Furthermore, 11 AD priority biomarkers were altered by CT1812 vs placebo, and 9 biomarkers showed replication across trials with similar directionality and degree of change. Nineteen biomarkers found to be significant in the meta-analysis just missed significance (P <.10) in both cohorts when analyzed along. Pathway analysis performed on the most robust (9 + 19) biomarkers showed a significant STRING network interaction, and revealed that the most robust biomarkers impacted are linked to synaptic and amyloid-ß biology.²

REFERENCES
1. Cognition Therapeutics announces positive topline results for CT1812 phase 2 SEQUEL study for mild-to-moderate Alzheimer’s disease. News release. June 28, 2023. Accessed June 28, 2023. https://www.globenewswire.com/news-release/2023/06/28/2696052/0/en/Cognition-Therapeutics-Announces-Positive-Topline-Results-for-CT1812-Phase-2-SEQUEL-Study-for-Mild-to-Moderate-Alzheimer-s-Disease.html
2. Pandey K, Duong D, Waybright L, et al. Pharmacodynamic effects of the S2R modulator CT1812 in Alzheimer’s disease (AD) patients observed in a meta-analysis of CSF proteomes from SPARC and SHINE part A. Presented at: AD/PD 2023.