A phase 1 clinical trial of the sigma‐2 receptor complex allosteric antagonist CT1812, a novel therapeutic candidate for Alzheimer's disease

Abstract

BackgroundElayta (CT1812) is a novel allosteric antagonist of the sigma-2 receptor complex that prevents and displaces binding of Aβ oligomers to neurons. By stopping a key initiating event in Alzheimer's disease, this first-in–class drug candidate mitigates downstream synaptotoxicity and restores cognitive function in aged transgenic mouse models of Alzheimer's disease.MethodsA phase 1, two-part single and multiple ascending dose study was conducted in 7 and 4 cohorts of healthy human subjects, respectively. In part A, healthy, young subjects (<65 years old) received CT1812 doses ranging from 10 to 1120 mg (6:2 active to placebo [A:P] per cohort). In part B, subjects were administered 280, 560, and 840 mg once daily for 14 days (8:2 A:P per cohort). An elderly cohort, aged 65-75 years, was dosed at 560 mg once daily for 14 days (7:2 A:P). Serum concentrations of CT1812 in part B were measured on day 3 and 14 and cerebrospinal fluid concentrations on day 7 or 9. Cognitive testing was performed in the healthy elderly cohort at baseline and at day 14 of treatment.ResultsTreatment with CT1812 was well tolerated in all cohorts. Adverse events were mild to moderate in severity and included headache and GI tract symptoms. Plasma concentrations of drug were dose proportional across two orders of magnitude with minimal accumulation over 14 days. Cognitive scores in the healthy elderly cohort were similar before and after treatment.ConclusionsCT1812 was well tolerated with single dose administration up to 1120 mg and with multiple dose administration up to 840 mg and 560 mg in healthy young and healthy elderly subjects, respectively. CT1812 is currently being studied in early phase 2 trials in patients with Alzheimer's disease.

The clinical promise of biomarkers of synapse damage or loss in Alzheimer’s disease

“…While Aβ monomers may interact with many receptors, in model systems, AβO have been demonstrated to bind to synaptic receptors including cellular prion protein, NgR1, EphB2, and PirB/LilrB2; additional receptor proteins have yet to be rigorously defined [55][56][57][58][59][60][61]. One important regulator of the oligomer receptor complex is the sigma-2 protein receptor complex [62,63], the target of the AD disease-modifying drug candidate CT1812 [64]. Downstream of interacting with synaptic receptors, robust evidence suggests AβO cause calcium influx and downstream synaptic dysfunction [15,65,66].…”

Functional study of the AMD-associated geneTMEM97in retinal pigmented epithelium using CRISPR interference

“…antagonist CT1812 has demonstrated a safety profile in the clinic [10] and is currently being tested as a treatment for Alzheimer's disease in Phase II trial (ClinicalTrials.gov: NCT03507790). Future studies that evaluate the efficacy of Sigma 2 receptor antagonists in RPE could pave the way to development of novel treatments to improve vision in patients with AMD.…”

“…Activation of Sigma-2 receptor signaling has been shown to induce apoptosis and cytotoxicity [9]. Significant progress has been made to treat neurodegenerative diseases using Sigma-2 receptor inhibitors, including clinical trials in Alzheimer's disease [10] and schizophrenia [11]. However, the expression pattern of TMEM97 in different cell types within the human retina is not well studied.…”

Translational Scoring of Candidate Treatments for Alzheimer’s Disease: A Systematic Approach

“…Cognition Therapeutics Inc. (Pittsburgh, PA, USA) performed a phase 1 trial on CT1812, an agent that protects synapses from Aβ protein toxicity in assays and models [40]. In the SAD study, 6 doses spanned 10–1,120 mg.…”