The Allosteric Antagonist of the Sigma-2 Receptors—Elayta (CT1812) as a Therapeutic Candidate for Mild to Moderate Alzheimer’s Disease: A Scoping Systematic Review

Abstract

Nearly 35 million people worldwide live with Alzheimer’s disease (AD). The prevalence of the disease is expected to rise two-fold by 2050. With only symptomatic treatment options available, it is essential to understand the developments and existing evidence that aims to target brain pathology and dementia outcomes. This scoping systematic review aimed to collate existing evidence of CT1812 for use in patients with AD and summarize the methodologies of ongoing trials. Adhering to PRISMA Statement 2020 guidelines, PubMed/MEDLINE, Embase, Cochrane, and ClinicalTrials.gov were systematically searched through up to 15 November 2022 by applying the following keywords: CT1812, Alzheimer’s disease, dementia, and/or sigma-2 receptor. Three completed clinical trials were included along with three ongoing records of clinical trials. The three completed trials were in Phases I and II of testing. The sample size across all three trials was 135. CT1812 reached endpoints across the trials and obtained a maximum concentration in the cerebrospinal fluid with 97–98% receptor occupancy. The findings of this systematic review must be used with caution as the results, while mostly favorable so far, must be replicated in higher-powered, placebo-controlled Phase II–III trials.

Treatment for dry age-related macular degeneration: where we stand in 2024

“…CT1812 is a sigma-2 receptor antagonist also known as Elayta. It has been studied to target neurodegenerative conditions such as Alzheimer's disease and Parkinson disease by destabilizing amyloid beta oligomers [28]. The sigma-2 receptor is therefore thought to be implicated in the oxidative stress brought on my aging and potentially contributing to the development of dry AMD [29].…”

Development of a Highly Specific 18F-Labeled Radioligand for Imaging of the Sigma-2 Receptor in Brain Tumors

“…5,8−15 CT1812, an antagonist of the σ 2 receptor, has proven to be effective for the treatment of AD in clinical trials. 8,9,15 In the past decades, the σ 2 receptor/TMEM97 has been proposed as a biomarker for the proliferative status of solid tumors in light of its approximately 10-fold higher expression in proliferating than quiescent tumors. 6,7,16−20 The σ 2 receptor/TMEM97, progesterone receptor membrane component 1 (PGRMC1), and low-density lipoprotein receptor (LDLR) were reported to form a trimeric complex to accelerate the internalization of LDL in proliferating versus quiescent tumor cells.…”

“…Different from the sigma-1 (σ 1 ) receptor, the bovine σ 2 receptor/TMEM97 is a four-helix transmembrane bundle based on the high-resolution crystal structures of the σ 2 receptor in complex with roluperidone (MIN-101) and PB28 . The σ 2 receptor/TMEM97 has attracted increasing interests due to its involvements in the pathophysiology of various cancers − and brain disorders including Alzheimer’s disease (AD), Parkinson’s disease (PD), schizophrenia, neuropathic pain, drug addiction, and depression. ,− CT1812, an antagonist of the σ 2 receptor, has proven to be effective for the treatment of AD in clinical trials. ,, In the past decades, the σ 2 receptor/TMEM97 has been proposed as a biomarker for the proliferative status of solid tumors in light of its approximately 10-fold higher expression in proliferating than quiescent tumors. ,,− The σ 2 receptor/TMEM97, progesterone receptor membrane component 1 (PGRMC1), and low-density lipoprotein receptor (LDLR) were reported to form a trimeric complex to accelerate the internalization of LDL in proliferating versus quiescent tumor cells . In addition, the σ 2 receptor/TMEM97 has also been regarded as a potential therapeutic target in human glioma, squamous cell carcinoma of the lung (SQCLC), gastric cancer, colorectal cancer (CRC), nasopharyngeal carcinoma, hepatocellular carcinoma (HCC), breast cancer, and pancreatic cancer .…”

Discovery of WLB-89462, a New Drug-like and Highly Selective σ2 Receptor Ligand with Neuroprotective Properties

“…Most of them have been used as tools to illustrate the therapeutic potential of the target but present poor drug-like attributes. Only Elayta (CT-1812, 10 ), which in fact is a dual σ 1 R and σ 2 R ligand, has progressed to the clinic and is currently undergoing phase II clinical trials for the treatment of AD . Roluperidone (MIN-101, 11 ) is also a σ 2 R ligand in clinical development for schizophrenia, but its main action is the 5-HT 2A receptor antagonism, as well as blockade of the α-adrenergic subtypes α 1A , and to a lesser extent α 1B .…”