CT1812 · program

Zervimesine for Alzheimer's disease

Phase 2ActiveCognition Therapeutics, Inc. (CGTX)
  • FDA Fast Track (Mild-To-Moderate Alzheimer'S Disease; Granted October 2017)

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 Alzheimer's disease — Cognition Therapeutics' lead indication, funded primarily by NIA grants (~$171M cumulative across the program). Completed Phase 2 evidence: the 153-patient SHINE study (mild-to-moderate AD, 100/300 mg vs placebo for 6 months; NIA-funded ~$30M with amendment) met its safety/tolerability primary endpoints and, in a pre-specified analysis reported at CTAD in October 2024, showed a 95% slowing of ADAS-Cog 11 decline at week 26 in participants with baseline plasma p-tau217 below the 1.0 pg/mL median (pooled doses vs placebo); the 16-patient SEQUEL qEEG study showed improvement in prespecified EEG parameters. Ongoing: the ~540-patient Phase 2 START study (COG0203, NCT05531656) in MCI/early AD, run with the NIA-funded Alzheimer's Clinical Trials Consortium under an ~$81M NIA grant — 18 months of treatment, CDR-SB and ADAS-Cog endpoints; enrollment completed November–December 2025, with topline expected after all participants complete 18 months of treatment (registry-estimated primary completion May 2027). Regulatory: end-of-Phase 2 meeting held 2025-07-09; minutes received 2025-08-12 confirmed FDA alignment that two six-month Phase 3 studies of 100 mg zervimesine vs placebo in mild-to-moderate AD patients enriched for lower plasma p-tau217 may support an NDA filing; the Phase 3 plan (iADRS primary) was presented at CTAD on 2025-12-01. EMA scientific advice (per the FY2025 10-K) indicated a preference for a longer trial than proposed, and no Phase 3 study has been registered or started, so the program remains recorded at Phase 2.

Data current as of

Development timeline

Phase 2Oct 2018 – May 2027
  1. UpcomingTopline results from the ~540-patient Phase 2 START study of zervimesine in MCI/early Alzheimer's disease (18-month treatment; CDR-SB and ADAS-Cog endpoints), expected after all participants complete 18 months of treatment — around mid-2027 per the ClinicalTrials.gov estimated primary completion of May 2027.↗
  2. Conference presentationPhase 3 plan for zervimesine in Alzheimer's disease presented at CTAD 2025↗
  3. Enrollment completed in the ~540-patient Phase 2 START study (COG0203, NCT05531656) in MCI/early AD per the company's 2025-11-13 announcement (the FY2025 10-K states the last participant was enrolled in December 2025 — the PR date is used here and the discrepancy noted). FDA alignment on a Phase 3 AD registrational path was already in hand (end-of-Phase 2 minutes received 2025-08-12), but no Phase 3 study has been registered or started, so the phase does not advance.↗
  4. Enrollment completeEnrollment completed in the Phase 2 START study of zervimesine in early Alzheimer's disease↗
  5. metPre-specified analysis of SHINE presented at CTAD (October 2024): mild-to-moderate AD participants with baseline plasma p-tau217 below the 1.0 pg/mL median treated with zervimesine (pooled 100/300 mg) showed a 95% reduction of cognitive decline at week 26 on ADAS-Cog 11 vs placebo, regardless of MMSE stratum — the analysis that defined the p-tau217 enrichment strategy FDA later endorsed for Phase 3.↗
  6. mixedPhase 2 SHINE topline (153 mild-to-moderate AD patients, zervimesine 100/300 mg vs placebo, 6 months): primary safety/tolerability endpoints met; cognitive signal favoring zervimesine, with the strongest effect emerging in patients with lower baseline plasma p-tau217.↗
  7. Phase 2 SHINE study (COG0201, NCT03507790) started: randomized, double-blind, placebo-controlled, 153 adults with mild-to-moderate AD, zervimesine 100 mg or 300 mg vs placebo once daily for six months. NIA-funded ($16.8M initial + $13.6M 2021 amendment).
Phase 1/2Sept 2016 – Oct 2017
  1. Fast TrackFDA grants Fast Track designation to zervimesine (CT1812) for mild-to-moderate Alzheimer's disease↗
  2. First-in-patient study in mild-to-moderate Alzheimer's disease (COG0102, NCT02907567, n=19) started September 2016 (registry month precision; day is a placeholder).
Phase 1Sept 2015
  1. First-in-human ascending-dose study of CT1812 in healthy volunteers (COG0101, NCT02570997) started September 2015 (registry month precision; day is a placeholder). Conducted in Australia; NIA-funded.

Readouts

  • Mid-2027 (registry estimate May 2027)AnticipatedTopline dataNCT05531656

    Topline results from the ~540-patient Phase 2 START study of zervimesine in MCI/early Alzheimer's disease (18-month treatment; CDR-SB and ADAS-Cog endpoints), expected after all participants complete 18 months of treatment — around mid-2027 per the ClinicalTrials.gov estimated primary completion of May 2027. ↗

  • 2024-10-31ReportedFull resultsmetNCT03507790

    Pre-specified analysis of SHINE presented at CTAD (October 2024): mild-to-moderate AD participants with baseline plasma p-tau217 below the 1.0 pg/mL median treated with zervimesine (pooled 100/300 mg) showed a 95% reduction of cognitive decline at week 26 on ADAS-Cog 11 vs placebo, regardless of MMSE stratum — the analysis that defined the p-tau217 enrichment strategy FDA later endorsed for Phase 3. ↗

  • 2024-07-29ReportedTopline datamixedNCT03507790

    Phase 2 SHINE topline (153 mild-to-moderate AD patients, zervimesine 100/300 mg vs placebo, 6 months): primary safety/tolerability endpoints met; cognitive signal favoring zervimesine, with the strongest effect emerging in patients with lower baseline plasma p-tau217. ↗

Clinical trials in Alzheimer's disease

NCT05531656COG0203Phase 2Activen=540

A Study to Evaluate the Safety and Efficacy of CT1812 in Early Alzheimer's Disease (START)

Started Jun 2023· Primary completion May 2027· 📍 50 sites across 1 country (United States)

NCT04735536COG0202Phase 2Completedn=16

Pilot Clinical Study of CT1812 in Mild to Moderate Alzheimer's Disease Using EEG (SEQUEL)

Started Jul 2020· Primary completion Apr 2023· 📍 1 site across 1 country (Netherlands)

NCT03507790COG0201Phase 2Completedn=153

A Study to Evaluate the Safety and Efficacy of CT1812 in Subjects With Mild to Moderate Alzheimer's Disease (SHINE)

Started Oct 2018· Primary completion May 2024· 📍 32 sites across 5 countries (United States, Czechia, Spain, Australia)

NCT03493282COG0105Phase 1/2Completedn=43

Effect of CT1812 Treatment on Brain Synaptic Density (SPARC)

Started Mar 2018· Primary completion Oct 2020· 📍 1 site across 1 country (United States)

Formulations

FormulationRouteRegimenPharmacokinetics
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).
OralOnce daily—

Mechanism of action (compound-wide)

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.

TargetActionAffinity
σ2 receptor (TMEM97)primaryTMEM97Antagonist—ⓘ
PGRMC1PGRMC1Antagonist—ⓘ

← Full CT1812 compound page (identity, identifiers, all indications)

Sources

  1. Cognition Therapeutics Announces Results of Pre-specified Analysis of SHINE Study Data Presented at CTAD (October 2024) — Cognition Therapeutics, Inc.
  2. Cognition Therapeutics Completes Enrollment in Phase 2 Study of Zervimesine (CT1812) in Early Alzheimer's Disease (2025-11-13) — Cognition Therapeutics, Inc. (via GlobeNewswire)
  3. Cognition Therapeutics Presents Phase 3 Plan for Zervimesine (CT1812) in Alzheimer's Disease at Clinical Trials on Alzheimer's Disease (CTAD) Conference (2025-12-01) — Cognition Therapeutics, Inc.
  4. Cognition Therapeutics, Inc. Form 10-K for fiscal year 2024 — SHINE topline conference call held July 29, 2024; p-tau217 subgroup analysis — U.S. Securities and Exchange Commission (EDGAR)
  5. 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)
  6. 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
  7. NCT02570997 (COG0101) — Ascending Dose Study of CT1812 in Healthy Volunteers; started September 2015; completed — ClinicalTrials.gov (U.S. National Library of Medicine)
  8. NCT02907567 (COG0102) — Clinical Trial of CT1812 in Mild to Moderate Alzheimer's Disease; started September 2016; completed — ClinicalTrials.gov (U.S. National Library of Medicine)
  9. NCT03493282 (COG0105, SPARC) — Effect of CT1812 Treatment on Brain Synaptic Density; completed — ClinicalTrials.gov (U.S. National Library of Medicine)
  10. NCT03507790 (COG0201, SHINE) — A Study to Evaluate the Safety and Efficacy of CT1812 in Subjects With Mild to Moderate Alzheimer's Disease; 153 participants; completed 2024-05-29 — ClinicalTrials.gov (U.S. National Library of Medicine)
  11. NCT04735536 (COG0202, SEQUEL) — Pilot Clinical Study of CT1812 in Mild to Moderate Alzheimer's Disease Using EEG; completed — ClinicalTrials.gov (U.S. National Library of Medicine)
  12. NCT05531656 (COG0203, START) — A Study to Evaluate the Safety and Efficacy of CT1812 in Early Alzheimer's Disease; 540 participants; active, not recruiting; est. primary completion 2027-05-31 — ClinicalTrials.gov (U.S. National Library of Medicine)