CT1812’s Impact on Alzheimer-Related Biomarkers Suggests Altering Disease Effect

Anthony Caggiano, MD, PhD

Recently announced results from a meta-analysis of a portion of the phase 2 SHINE study (NCT03507790) and the complete dataset from the phase 1b SPARC trial (NCT03493282) showed that CT1812, an oral sigma-2 (S2R) receptor modulator, had statistically significant impacts on Alzheimer disease (AD)-related biomarkers. Above all, the findings highlight a prominent role of CT1812 in regulating synaptic and amyloid-ß biology, the study investigators concluded.^1,2

These data were presented at AD/PD 2023: the International Conference on Alzheimer’s and Parkinson’s Diseases by Mary Hamby, PhD, vice president of research at Cognition Therapeutics. She said in a statement that, “Combining the proteomic data from two trials that enrolled participants with mild-to-moderate disease and who were similarly treated with CT1812 allowed for a statistically robust analysis of cerebrospinal fluid samples."¹

Developed by Cognition Therapeutics, CT1812 is a highly brain-penetrant small molecule modulator of sigma-2 receptor that displaces amyloid-ß oliogomers bound to neuronal synapses 1. 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 assess cerebrospinal (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.²

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.

Hamby added, "We and our collaborators at Emory University were particularly interested in the change in levels of PRPN (prion protein). This is consistent with other clinical and preclinical data, showing that modulation of the sigma-2 receptor results in displacement of oligomers from their target receptor on neurons."¹

Gene Ontology analysis further highlighted the role of CT1812 in regulating synapse biology. Some of the top biological processes impacted were: gephyrin clustering involved in postsynaptic density assembly, neurotrophil aggregation, ventral trunk neural crest cell migration, and many others. A metacore pathway analysis also indicated the role of CT1812 in regulating amyloid biology and inflammation, specifically showing impacts in pathways of gamma-secretase proteolytic targets, and immune response in lectin induced complement pathway, classical complement pathway, alternative complement pathway, and others.² 

"It was encouraging to find that the pathways identified by this new well-powered analysis continue to point towards an important effect of CT1812 on synapses and amyloid biology," Anthony Caggiano, MD, PhD, chief medical officer, and head of R&D, Cognition Therapeutics, said in a statement.¹ "We believe that these findings add to mounting evidence that CT1812 has an impact on the binding of Aβ oligomers to synapses and on the pathways involved. We look forward to seeing how the effect of CT1812 on these underlying biological processes may translate into clinical benefit as our ongoing trials begin to read out in the coming months."

The meta-analysis follows recently published research by Hamby and others looking at sigma-2 receptors and their impact on age-related degenerative diseases. In the paper, the investigators noted S2R modulates key pathways involved in these diseases, including autophagy, trafficking, oxidative stress, and amyloid-ß and α-synuclein toxicity. Additionally, in cell-based and animal models of the disease, S2R modulation has demonstrated ameliorative impacts on functional deficits.³

CT1812 is also currently being assessed in the phase 2 SHIMMER trial (NCT0522514), which had patient dosing commence in July 2022.⁴ The double-blind, placebo-controlled, randomized trial is expected to enroll 120 adults aged 50 to 80 years old with DLB to be assigned to either placebo or 1 of 2 daily doses of CT1812 for 6 months. Supported by a $30 million grant from the National Institutes of Health’s National Institute on Aging, the study will assess outcomes such as safety, along with changes in cognitive performance, physical activity, and pharmacokinetic and pharmacodynamic biomarkers.

REFERENCES
1. Cognition Therapeutics presents proteomic biomarker data demonstrating prominent effects of CT1812 in altering underlying Alzheimer’s disease processes. News release. March 28, 2023. March 29, 2023. https://ir.cogrx.com/news-releases/news-release-details/cognition-therapeutics-presents-proteomic-biomarker-data
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.
3. Lizama BN, Kahle J, Catalano SM, et al. Sigma-2 receptors­–from basic biology to therapeutic target: a focus on age-related degenerative diseases. Int. J. Mol. Sci. 2023;24(7):6251. doi:10.3390/ijms24076251
4. Cognition Therapeutics doses first patient with dementia with Lewy bodies in phase 2 clinical study of CT1812. News release. Cognition Therapeutics. June 23, 2022. Accessed March 29, 2023. https://ir.cogrx.com/news-releases/news-release-details/cognition-therapeutics-doses-first-patient-dementia-lewy-bodies