CT1812

CT1812 (zervimesine; CAS 1802632-22-9) is a first-in-class, orally bioavailable small-molecule antagonist of the sigma-2 receptor complex (also designated TMEM97, transmembrane protein 97) developed by Cognition Therapeutics for the treatment of Alzheimer's disease (AD), dementia with Lewy bodies (DLB), and geographic atrophy secondary to dry age-related macular degeneration. The compound was identified through a phenotypic neuronal screening assay designed to detect reversal of amyloid-beta oligomer (ABO) induced synaptotoxicity and was chemically optimized from a series of isoindoline scaffolds selected for central nervous system penetration, metabolic stability, and selectivity against cardiac ion channel (hERG) liability. CT1812 binds the sigma-2 receptor with a Ki of 8.5 nM and demonstrates greater than 100-fold selectivity over a broad receptor panel, with approximately 10-fold selectivity over the sigma-1 receptor. The mechanism of action is allosteric antagonism of the sigma-2 receptor complex, which includes TMEM97, progesterone receptor membrane component 1 (PGRMC1), and low-density lipoprotein receptor (LDLR) at the neuronal surface. Engagement of this complex by CT1812 induces a conformational change that displaces prebound amyloid-beta oligomers from synaptic receptors without affecting oligomer assembly or dissociation, thereby restoring synaptic trafficking, reducing synaptotoxicity, and facilitating clearance of oligomers into the cerebrospinal fluid.

In preclinical studies, CT1812 demonstrated robust brain penetration (brain-to-plasma ratio of 5.7 at 24 hours; unbound brain-to-plasma partition coefficient Kp,uu of 6.75), achieved greater than 84 percent sigma-2 receptor occupancy at therapeutically relevant doses, and improved cognitive performance in transgenic Alzheimer's mouse models across Y-maze, Morris water maze, and fear conditioning paradigms. The compound is not a P-glycoprotein substrate, exhibits favorable oral absorption with time to peak plasma concentration of 1 to 2 hours and a plasma elimination half-life of approximately 12 hours in humans, and is metabolized primarily by CYP3A4 with secondary contributions from CYP2D6 and CYP2C19.

A Phase 1 trial in 80 healthy volunteers established safety and tolerability at single doses up to 1120 mg and multiple doses up to 840 mg for 14 days, with dose-proportional pharmacokinetics and cerebrospinal fluid penetration achieving estimated receptor occupancy of 97 to 98 percent. A Phase 1b/2 trial (COG0102) in 19 patients with mild to moderate AD demonstrated reductions in cerebrospinal fluid synaptic damage markers (neurogranin and synaptotagmin-1) and decreases of 30 percent or more in six tau phosphorylation sites after 28 days of treatment. The Phase 2 SHINE trial (COG0201) enrolled 153 patients with mild to moderate AD randomized to 100 mg, 300 mg, or placebo for 182 days; the 100 mg dose produced a 39 percent reduction in ADAS-Cog 11 decline relative to placebo, with a 95 percent slowing of cognitive decline in the subpopulation with baseline plasma p-tau217 below the median. The Phase 2 SHIMMER trial (COG1201) enrolled 130 patients with mild to moderate DLB and met its primary safety endpoint; secondary analyses showed 82 percent of treated patients demonstrated slowing on the total Neuropsychiatric Inventory, with a 91 percent reduction in decline of attentional fluctuation measures. CT1812 has also been evaluated in the Phase 2 MAGNIFY trial for geographic atrophy, where treated patients showed 28.6 percent slower lesion growth over 18 months compared to placebo. The compound is generally well tolerated; the principal adverse events are headache, gastrointestinal symptoms (nausea, diarrhea, constipation), and, at the 300 mg dose in SHINE, transient elevations in liver function tests that resolved upon drug discontinuation. CT1812 is positioned for Phase 3 development in Alzheimer's disease. This monograph reviews the compound identification, discovery and development history, molecular pharmacology, pharmacokinetics, preclinical and clinical evidence, sourcing, reconstitution, stack interactions, safety profile, and a comparative assessment of five alternative approaches to amyloid-beta oligomer or sigma-2 receptor pharmacology.