CT1812 · program
Zervimesine for Lewy body dementia
Indications for CT1812: Alzheimer's disease · Phase 2 Lewy body dementia · Phase 2
Zervimesine (CT1812), an oral once-daily sigma-2 receptor complex allosteric antagonist, for dementia with Lewy bodies — now being steered specifically toward DLB psychosis, which affects up to ~75% of DLB patients and has no FDA-approved treatment. The completed Phase 2 SHIMMER study (COG1201, NCT05225415; 130 patients with mild-to-moderate DLB, zervimesine 100 or 300 mg vs placebo for six months; NIA-funded, ~$29.5M) met its primary safety/tolerability endpoint (topline 2024-12-18) and showed consistent exploratory efficacy signals vs placebo: 82% slowing of neuropsychiatric symptom progression (NPI-12, strongest on anxiety, hallucinations and delusions), 91% on cognitive fluctuations (CAF), 62% on parkinsonian motor decline (UPDRS-III) and 52% on activities of daily living (ADCS-ADL). Full results were presented in an AAIC podium presentation (2025-07-29) and published in Alzheimer's & Dementia (Galvin et al. 2025). An open-label expanded access program (COG1202, NCT06961760; 100 mg daily for ~1 year) enrolled 32 SHIMMER completers and additional mild-to-moderate DLB patients between June and December 2025 and was extended in February 2026. Regulatory path: after a January 2026 FDA Type C meeting, Cognition announced (2026-03-02) it would develop zervimesine for DLB psychosis; a 2026-05-20 meeting with the FDA Division of Psychiatry and the minutes received by 2026-06-24 aligned on key aspects of a pivotal design — a randomized Phase 3 of 100 mg once-daily zervimesine vs placebo over nine months in DLB patients experiencing hallucinations and delusions (patients on stable off-label antipsychotics eligible), with the Neuropsychiatric Inventory (NPI) as a novel primary endpoint — and the FDA agreed DLB psychosis could be an approvable indication. The registrational program is expected to begin in mid-2027; the program stays at Phase 2 until that pivotal is registered or started.
Development timeline
- Program active and pointed at a registrational path in DLB PSYCHOSIS: following a January 2026 Type C meeting, the 2026-03-02 decision to develop zervimesine for DLB psychosis, and a 2026-05-20 meeting with the FDA Division of Psychiatry, Cognition announced on 2026-06-24 (on receipt of meeting minutes) alignment with FDA on key aspects of a pivotal study — nine-month randomized Phase 3, 100 mg once daily vs placebo, in DLB patients with hallucinations and delusions (stable off-label antipsychotics allowed), NPI as a novel primary endpoint — and FDA agreement that DLB psychosis could be an approvable indication. Registrational program expected to begin mid-2027. Phase not advanced: no pivotal trial is registered or started. (No event logged: the closed vocabulary has no code for a regulatory meeting/alignment.)↗
- metFull SHIMMER results presented in an AAIC 2025 podium presentation (with additional analyses spanning DLB and AD) and published in Alzheimer's & Dementia (Galvin et al. 2025): consistent benefit of zervimesine over placebo across neuropsychiatric, cognitive, motor and functional domains in mild-to-moderate DLB.↗
- metPhase 2 SHIMMER topline (130 mild-to-moderate DLB patients, zervimesine 100/300 mg vs placebo, 6 months): primary safety/tolerability endpoint met, with exploratory efficacy signals across behavioral (NPI-12 -82% vs placebo decline), cognitive-fluctuation (CAF -91%), motor (UPDRS-III -62%) and functional (ADCS-ADL -52%) measures.↗
- SHIMMER completed per ClinicalTrials.gov (primary completion and study completion 2024-11-25); the company announced all participants had completed final visits on 2024-11-26, with topline following on 2024-12-18.
- Phase 2 SHIMMER study (COG1201, NCT05225415) started per ClinicalTrials.gov: randomized, double-blind, placebo-controlled study of zervimesine 100 mg or 300 mg vs placebo once daily for six months in 130 adults with mild-to-moderate dementia with Lewy bodies. Funded primarily by an NIA grant (~$29.5M, awarded 2021).
Readouts
- 2025-07-29ReportedFull resultsmetNCT05225415
Full SHIMMER results presented in an AAIC 2025 podium presentation (with additional analyses spanning DLB and AD) and published in Alzheimer's & Dementia (Galvin et al. 2025): consistent benefit of zervimesine over placebo across neuropsychiatric, cognitive, motor and functional domains in mild-to-moderate DLB. ↗
- 2024-12-18ReportedTopline datametNCT05225415
Phase 2 SHIMMER topline (130 mild-to-moderate DLB patients, zervimesine 100/300 mg vs placebo, 6 months): primary safety/tolerability endpoint met, with exploratory efficacy signals across behavioral (NPI-12 -82% vs placebo decline), cognitive-fluctuation (CAF -91%), motor (UPDRS-III -62%) and functional (ADCS-ADL -52%) measures. ↗
Clinical trials in Lewy body dementia
NCT05225415COG1201Phase 2Completedn=130
Study to Evaluate the Safety, Tolerability and Efficacy of CT1812 in Subjects With Mild to Moderate Dementia With Lewy Bodies (SHIMMER)
Formulations
| Formulation | Route | Regimen | Pharmacokinetics |
|---|---|---|---|
| Zervimesine oral capsule (100 mg / 300 mg once daily) 100 mg or 300 mg once daily in the Phase 2 SHIMMER (DLB) and SHINE (mild-to-moderate AD) studies; 100 mg once daily in the DLB expanded access program (COG1202) and in the FDA-aligned pivotal design for DLB psychosis (nine months) and the Phase 3 AD design (six months). | Oral | Once daily | — |
Mechanism of action
Orally bioavailable, brain-penetrant allosteric antagonist of the sigma-2 receptor complex — the transmembrane protein TMEM97 operating in a complex with progesterone receptor membrane component 1 (PGRMC1), which GtoPdb describes as zervimesine's binding subunit. The sigma-2 receptor complex regulates the synaptic receptors to which amyloid-beta oligomers bind; zervimesine binding increases the oligomer off-rate, displacing amyloid-beta oligomers from synapses into the CSF. This was demonstrated in humans in the Phase 1 SNAP study, where treated mild-to-moderate AD patients showed increased amyloid-beta oligomer concentrations in serially sampled CSF, confirming the preclinical displacement mechanism. Supporting synaptic evidence: improvement in prespecified qEEG parameters (SEQUEL) and reduced loss of brain volume in hippocampus, prefrontal and pericentral cortex on volumetric MRI (SPARC program imaging). In DLB the same synaptoprotective mechanism is hypothesized against alpha-synuclein oligomer toxicity. Selectivity is reported in reviews as roughly 100-fold over non-sigma receptors; no absolute Ki for CT1812 at the sigma-2 site is citable from an open source.
| Target | Action | Affinity |
|---|---|---|
| σ2 receptor (TMEM97)primaryTMEM97 | Antagonist | —ⓘ |
| PGRMC1PGRMC1 | Antagonist | —ⓘ |
← Full CT1812 compound page (identity, identifiers, all indications)
Sources
- Cognition Therapeutics Aligns on Key Aspects of Pivotal Study for Zervimesine (CT1812) in DLB Psychosis Following Receipt of FDA Meeting Minutes (2026-06-24; registrational program expected to begin mid-2027) — Cognition Therapeutics, Inc. (via GlobeNewswire)
- Cognition Therapeutics Announces Positive Results in Phase 2 Study of CT1812 in Dementia with Lewy Bodies (2024-12-18, SHIMMER topline) — Cognition Therapeutics, Inc. (via GlobeNewswire)
- Cognition Therapeutics Presents Data at AAIC Highlighting Broad Neurological Impact of Zervimesine (CT1812) in Dementia with Lewy Bodies and Alzheimer's Disease (2025-07-29) — Cognition Therapeutics, Inc. (via GlobeNewswire)
- Cognition Therapeutics, Inc. Form 10-K for fiscal year 2025 (filed 2026-03-26) — SHIMMER NIA grant ($29.5M); SHIMMER effect sizes; COG1202 EAP (32 enrolled, June–December 2025, 100 mg daily ~1 year); January 2026 Type C meeting and DLB-psychosis strategy; corporate facts — U.S. Securities and Exchange Commission (EDGAR)
- CT1812 (zervimesine), GtoPdb ligand 13335 — orally bioactive, brain-penetrant sigma-2 receptor complex allosteric antagonist binding at the PGRMC1 subunit; displaces amyloid-beta for disposal via CSF — IUPHAR/BPS Guide to PHARMACOLOGY
- NCT05225415 (COG1201, SHIMMER) — Study to Evaluate the Safety, Tolerability and Efficacy of CT1812 in Subjects With Mild to Moderate Dementia With Lewy Bodies; 130 participants; completed 2024-11-25 — ClinicalTrials.gov (U.S. National Library of Medicine)