Background
CT1812 is a small-molecule antagonist of the sigma2 receptor. The rationale behind this therapeutic approach is that ligands for the sigma2 receptor complex are negative allosteric regulators that reduce the affinity of oligomeric Aβ for neuronal receptors, and thus interfere with Aβ-induced synaptic toxicity.
CT1812 grew out of screening programs at Cognition Therapeutics. Company scientists have reported that compounds in this series not only block binding of a range of different Aβ species to neuronal receptors but also displace it when applied after Aβ has bound (Dec 2014 conference news). Subsequently, company scientists reported the compounds also inhibit the ability of α-synuclein oligomers to induce lysosomal trafficking defects in rat neurons and glia (Limegrover et al., 2021).
CT1812 was chemically optimized from a series of small molecules selected for their ability to reverse the synaptotoxicity of soluble Aβ oligomers on cultured neurons (Rishton et al., 2021). Similar compounds in the series have been reported to enter the brain, occupy up to 80 percent of sigma2 receptors, and restore behavioral deficits in APP transgenic mice (Izzo et al., 2014; Izzo et al., 2014). In preclinical work, CT1812 facilitated brain clearance of Aβ oligomers and improved cognitive behaviors in transgenic mouse models of Alzheimer’s disease. The compound also displaced Aβ oligomers from human postmortem AD brain tissue (Izzo et al., 2021).
The identification of the gene encoding the sigma2 protein has allowed more detailed mechanistic studies on the receptor and the actions of CT1812 (Alon et al., 2017). It was reported that a complex of the sigma 2 protein, progesterone receptor membrane component 1, and the low-density lipoprotein receptor controls the internalization of Aβ monomers and oligomers in synapses (Riad et al., 2020). Further studies found evidence for increased synaptic levels of sigma2, also known as TMEM97, in Alzheimer’s disease (Hesse et al., 2019). FRET imaging suggests a close synaptic interaction between Aβ oligomers and TMEM97 in Alzheimer’s brain tissue. In mouse and human models, CT1812 inhibited this interaction, and also caused changes in the expression of genes related to synaptic function (Colom-Cadena et al., 2024).
Findings
From September 2015 to May 2016, Cognition Therapeutics ran a Phase 1 trial in 80 healthy volunteers aged 18 to 75 in Melbourne, Australia; target enrollment was originally listed as 114. Single-ascending-dose administration was followed by multiple ascending doses given once daily for two weeks. The dose range in this trial spanned 10 to 650 mg; if this would not generate data to set a maximum tolerated dose, doses up to 1,350 mg were to be tried. Outcome measures included safety, tolerability, plasma pharmacokinetics, and CSF CT1812 concentration. At the 2016 and 2017 AAIC conferences, company scientists reported that single doses up to 1,120 mg were given, as were multiple doses of up to 840 mg in young and up to 560 mg in elderly volunteers. The drug was reported to be well-tolerated, with suitable pharmacokinetics, sufficient brain penetrance and target exposure, and minimal drug-drug interactions affecting cytochrome P450 activity (Catalano et al., 2016). Results have been published (Grundman et al., 2019). Another Phase 1 trial in 2016 assessed drug-drug interactions in 16 healthy volunteers.
From September 2016 to August 2017, Cognition Therapeutics ran a Phase 1/2 trial at four sites in Australia, enrolling 19 participants with mild to moderate Alzheimer's disease supported by a recent MRI. It compared a four-week course of 90, 280, or 560 mg of CT1812 to placebo, taken once daily, on safety and tolerability parameters. At the subsequent CTAD conference, Elayta was reported to have been generally safe and well-tolerated, though there were four cases of lymphocytopenia. Exploratory measures such as ADAS-Cog14, verbal or category fluency tests recorded no difference between groups, but exploratory biomarker analyses yielded possible signals of synapse protection (Dec 2017 conference news). Later, investigators reported that CT1812 increased Aβ oligomers in CSF, suggesting CT1812 promoted oligomer clearance from the brain (2019 AAIC meeting abstract). According to published data, the Aβ oligomer concentration in CSF rose after treatment, while the concentration of synaptic proteins neurogranin and synaptotagmin fell, compared to placebo. CSF Aβ40 or 42 monomers, neurofilament light chain, SNAP-25, total Tau, and p-Tau181 were unchanged (Izzo et al., 2021).
In April 2018, a Phase 1/2 study started enrolling 23 people whose mild to moderate AD was confirmed by amyloid PET or CSF testing. Conducted at Yale University School of Medicine and dubbed COG0105 or SPARC, this trial compared a six-month course of 100 or 300 mg of Elayta to placebo. A six-month, double-blind extension was later added. The primary outcome was originally listed as cognition as assessed by the Alzheimer's Disease Clinical Study Activities of Daily Living (ADCS-ADL), but was changed in September 2018 to safety. The trial used the investigational PET tracer UCB-J, which binds to the synaptic vesicle glycoprotein 2A, in an attempt to monitor synapse density before and after treatment (see company press release; Jul 2016 news). Midway through the study, synaptic density was added as co-primary. The trial finished in October 2020 after enrolling 43 patients, and results are posted on clinicaltrials.gov. At the 2022 AAIC, the company disclosed that treatment had not altered synaptic density, measured by SV2a PET, compared to baseline. CSF proteomics analysis revealed a reduction in the inflammatory marker YKL-40. Other CSF proteins related to synaptic biology and amyloid were reportedly normalized after treatment (company presentation). According to published results, treatment caused no change in FDG-PET, clinical cognitive scales, or CSF biomarkers (Van Dyck et al., 2024). Volumetric MRI revealed a trend toward tissue preservation with treatment.
In May 2018, a Phase 1b target engagement study at the University of Pennsylvania began enrolling 18 people whose mild to moderate AD was to be confirmed by amyloid PET. Called COG0104 or SNAP, the study was to compare single injections of 90, 280, or 560 mg of Elayta to placebo for their ability to displace Aβ oligomers and clear them into the CSF. This was assessed by an Aβ oligomer assay on CSF samples collected hourly for 24 hours after treatment. This study ended in February 2019, with only three participants enrolled. According to published results, the investigators had difficulty recruiting because of the study's requirement for a 28-hour spinal catherization and the lack of an optional open-label extension (LaBarbera et al., 2023). Of the three participants, two received 560 mg CT1812, one placebo. CSF Aβ oligomers increased by 2.5- and fivefold over baseline in the treated patients, and did not change in the one who received placebo. Concentrations of monomeric Aβ stayed the same in all three. One patient who had higher blood levels of CT1812 also had higher CSF Aβ oligomer concentrations.
A similar pilot trial in Sweden was to measure CSF Aβ oligomers after a single 100 mg dose in 16 people with mild to moderate AD, followed by six months of open-label daily dosing. The trial was to assess drug effects on CSF biomarkers of Aβ, tau, and synaptic function after six months. In November 2020, this trial was stopped early.
In October 2018, a Phase 2 multicenter safety study called SHINE or COG0201 began enrolling 24 people with mild to moderate AD as confirmed by amyloid PET for a six-month course of 100 or 300 mg of CT1812, or placebo. The primary outcome is the number of adverse events. The company later increased the study size to 144, and added cognitive endpoints. The trial, at 36 sites in the U.S., Europe, and Australia, finished enrollment at 153 participants in November 2023 (press release). At the 2020 AAIC, the company reported positive trends for cognitive endpoints in the first 24 people who completed six months of treatment (Aug 2020 conference news). A proteomics analysis of CSF from 18 participants revealed treatment-related changes in proteins linked to synapses, lipoprotein and Aβ biology, and neuroinflammation (Lizama et al., 2024). The trial was completed in May 2024, and results presented on July 29 at AAIC (press release). The drug met its safety endpoint, with no discontinuations due to side effects in the 100 mg dose. Elevations in liver enzymes were detected in nine of the 42 patients on the 300 mg dose, and reversed when drug was stopped. On cognitive endpoints, CT1812 treatment slowed decline by about one point on the ADAS-Cog11 compared to placebo; the difference was not statistically significant. At the 300 mg dose, CSF NfL and Aβ42 did decline. Other markers of amyloid and tau pathology, inflammation, and synaptic function were unchanged.
In July 2020, a pilot study started in Amsterdam to assess synaptic effects of CT1812 using quantitative electroencephalography. Sixteen participants with mild to moderate Alzheimer’s disease receive 300 mg Elayta and placebo for 29 days each, in a crossover design. Outcomes include EEG, cognitive and functional measures, CSF biomarkers, and safety. The study was completed in April 2023 and results were presented at the October 2023 CTAD conference. All prespecified EEG parameters trended toward improvement; significant increases in theta power and functional connectivity suggested the drug may be able to enhance synaptic activity (Vijverberg et al., 2024).
In January 2022, the company conducted an eight-patient study of the absorption, metabolism, and secretion of a single oral dose of [14C]-CT1812; results are posted at clinicaltrials.gov. In February to June, they conducted a pharmacokinetic study in 35 older healthy volunteers, evaluating 150 mg once or twice a day, and 300 mg once a day.
In June 2022, a Phase 2 trial called SHIMMER began assessing CT1812 in 120 people with mild to moderate dementia with Lewy bodies. At 37 centers in the U.S., this six-month study is comparing 100 or 300 mg of CT1812 to placebo on primary outcomes of safety and tolerability. Secondary outcomes include measures of cognition, sleepiness, clinical change, daily function, movement, and neuropsychiatric symptoms. The study completed enrollment with 130 patients, and is planned to finish in November 2024.
In September 2022, the company registered a Phase 2 trial called START. It will compare 18 months of 100 or 300 mg CT1812 to placebo in 540 people with mild cognitive impairment or mild dementia due to Alzheimer’s. The primary outcome is change in CDR-SB, with planned secondaries of the ADAS-Cog13, ADCS-Activities of Daily Living, CSF biomarkers of Aβ, tau, neurofilament light chain, neurogranin, and synaptotagmin, as well as volumetric MRI. The Alzheimer’s Clinical Trial Consortium is running the trial, with funding from the National Institute on Aging (press release). After awaiting FDA clearance, the trial began in June 2023, and will run until spring 2027. According to a presentation at the October 2023 CTAD conference, inclusion criteria were modified to permit enrollment of people who are taking the since-approved anti-amyloid antibody lecanemab; however, the trial is not designed to be a concurrent or combination trial.
In June 2023, the company began a Phase 2 study testing CT1812 for age-related macular degeneration (press release).
For all trials of this compound, see clinicaltrials.gov and EU Clinical Trials Register.
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