Therapy Type: Small Molecule (timeline)
Target Type: Amyloid-Related (timeline)
Condition(s): Alzheimer's Disease
U.S. FDA Status: Alzheimer's Disease (Phase 2)
Company: Cognition Therapeutics Inc.
CT1812 is a small-molecule antagonist of the sigma2 receptor. It binds to the progesterone receptor membrane component 1 subunit of the receptor complex. The rationale behind this therapeutic approach is that ligands for the sigma2/PGRMC1 receptor are negative allosteric regulators that reduce the affinity of oligomeric Aβ for its receptor, 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).
The structure of CT1812 has not been disclosed, but similar compounds in the series have been reported to enter the brain, occupy up to 80 percent of sigma2/PGRMC1 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).
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 compares 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 uses 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). This study is expected to finish in March 2021.
In May 2018, a Phase 1b target-engagement study at the University of Pennsylvania began enrolling 18 people whose mild to moderate AD was confirmed by amyloid PET. Called COG0104 or SNAP, it compares 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, as measured by a CSF Aβ oligomer assay. 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 assesses 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 Elayta, or placebo. The primary outcome is the number of adverse events. The company later increased the study size to 120, and added cognitive endpoints. The trial was expected to finish in June 2020. At the 2020 Alzheimer’s Association International Conference, the company reported positive trends for cognitive endpoints in the first 24 people who completed six months of treatment (Aug 2020 conference news).
A pilot study started in July 2020 in Amsterdam to assess the synaptic effects of Elayta using quantitative electroencephalography. Sixteen participants with mild to moderate Alzheimer’s disease receive Elayta or placebo for 29 days. Outcomes include EEG, cognitive and functional measures, CSF biomarkers, and safety.
In June 2020, Cognition Therapeutics received funding from the National Institute on Aging for a Phase 2 trial in 540 people with early AD, to be run with the Alzheimer’s Clinical Trial Consortium (ACTC, press release). The study will compare an 18-month course of Elayta to placebo. According to the company, endpoints are to include cognitive measures and biomarkers of target engagement, neurodegeneration, and disease progression.
Clinical Trial Timeline
- Phase 1/2
- Phase 2
- Study completed / Planned end date
- Planned end date unavailable
- Study aborted
Last Updated: 02 Sep 2020
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- Catalano S, Grundman M, Schneider LS, DeKosky S, Morgan R, Higgin M, Pribyl J, Mozzoni K, Izzo NJ, Safferstein H, Lickliter J. A Two-Part, Double-Blind, Placebo-Controlled, Phase 1 Study of the Safety and Pharmacokinetics of Single and Multiple Ascending Doses of Ct1812 in Healthy Volunteers. Alzheimer's & Dementia, July 2016, Volume 12, Issue 7, Supplement
- Grundman M, Morgan R, Lickliter JD, Schneider LS, DeKosky S, Izzo NJ, Guttendorf R, Higgin M, Pribyl J, Mozzoni K, Safferstein H, Catalano SM. A phase 1 clinical trial of the sigma-2 receptor complex allosteric antagonist CT1812, a novel therapeutic candidate for Alzheimer's disease. Alzheimers Dement (N Y). 2019;5:20-26. Epub 2019 Jan 23 PubMed.
- Izzo NJ, Yuede CM, LaBarbera KM, Limegrover CS, Rehak C, Yurko R, Waybright L, Look G, Rishton G, Safferstein H, Hamby ME, Williams C, Sadlek K, Edwards HM, Davis CS, Grundman M, Schneider LS, DeKosky ST, Chelsky D, Pike I, Henstridge C, Blennow K, Zetterberg H, LeVine H 3rd, Spires-Jones TL, Cirrito JR, Catalano SM. Preclinical and clinical biomarker studies of CT1812: A novel approach to Alzheimer's disease modification. Alzheimers Dement. 2021 Feb 8; PubMed.
- Izzo NJ, Staniszewski A, To L, Fa M, Teich AF, Saeed F, Wostein H, Walko T 3rd, Vaswani A, Wardius M, Syed Z, Ravenscroft J, Mozzoni K, Silky C, Rehak C, Yurko R, Finn P, Look G, Rishton G, Safferstein H, Miller M, Johanson C, Stopa E, Windisch M, Hutter-Paier B, Shamloo M, Arancio O, LeVine H 3rd, Catalano SM. Alzheimer's therapeutics targeting amyloid beta 1-42 oligomers I: Abeta 42 oligomer binding to specific neuronal receptors is displaced by drug candidates that improve cognitive deficits. PLoS One. 2014;9(11):e111898. Epub 2014 Nov 12 PubMed.
- Izzo NJ, Xu J, Zeng C, Kirk MJ, Mozzoni K, Silky C, Rehak C, Yurko R, Look G, Rishton G, Safferstein H, Cruchaga C, Goate A, Cahill MA, Arancio O, Mach RH, Craven R, Head E, LeVine H 3rd, Spires-Jones TL, Catalano SM. Alzheimer's therapeutics targeting amyloid beta 1-42 oligomers II: Sigma-2/PGRMC1 receptors mediate Abeta 42 oligomer binding and synaptotoxicity. PLoS One. 2014;9(11):e111899. Epub 2014 Nov 12 PubMed.
- Limegrover CS, LeVine H 3rd, Izzo NJ, Yurko R, Mozzoni K, Rehak C, Sadlek K, Safferstein H, Catalano SM. Alzheimer's protection effect of A673T mutation may be driven by lower Aβ oligomer binding affinity. J Neurochem. 2020 Oct 6; PubMed.
- Limegrover CS, Yurko R, Izzo NJ, LaBarbera KM, Rehak C, Look G, Rishton G, Safferstein H, Catalano SM. Sigma-2 receptor antagonists rescue neuronal dysfunction induced by Parkinson's patient brain-derived α-synuclein. J Neurosci Res. 2021 Apr;99(4):1161-1176. Epub 2021 Jan 22 PubMed.