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Randomized, double-blind study of zervimesine in mild to moderate Alzheimer's disease
Abstract
Background: Zervimesine (CT1812) is a first-in-class, brain-penetrant sigma-2 receptor ligand that prevents binding and displaces Aβ 42 oligomers from receptors on neuronal synapses. Objective: This study evaluated the safety and efficacy of zervimesine in mild to moderate Alzheimer's disease (AD). Methods: This was a Phase 2, randomized, double-blind, placebo-controlled study . Participants were randomized to zervimesine 100 mg or 300 mg or placebo . In addition to ADAS-Cog11, outcomes were evaluated from baseline plasma p-tau217 in prespecified subgroups. Results: Of 153 adults randomized, 150 were included in the mITT population. Adverse events occurred in 70.6% with zervimesine 100 mg, 82.4% with zervimesine 300 mg, and 78.0% with placebo. At Day 182, the ADAS-Cog 11 increased from baseline (indicating a decline in cognitive function) with the LS mean (SE) change of 2.69 (0.81) points in the placebo group versus 1.66 (0.60) points in the pooled zervimesine group [δ = −1.03 (−3.01, 0.96), p = 0.310]. For participants with baseline plasma p-tau217 levels below the median (1.0 pg/mL), the pooled zervimesine group showed greater improvement on the ADAS-Cog 11 at Day 182 relative to placebo (δ = −2.66; p = 0.080). Conclusions: This phase 2 study indicated that zervimesine was safe and well tolerated and showed consistently favorable numerical treatment differences versus placebo. More robust treatment differences were observed in the below median baseline plasma p-tau217 group suggesting potentially greater efficacy of zervimesine in less advanced AD. These results support larger pivotal trials with zervimesine. Registered at clinicaltrials.gov: NCT03507790
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In SHINE mITT, participants treated with zervimesine experienced a 38% slowing in cognitive decline as measured by ADAS-Cog11 compared to placebo.
“In mITT, participants treated with zervimesine experienced a slowing in cognitive decline (38% for ADAS-Cog11) and showed a decrease in CSF NfL levels relative to placebo (p = 0.016) [8, 20, 21].”
SHINE is a completed Phase 2 randomized, double-blind, placebo-controlled clinical trial conducted in participants with mild to moderate AD.
“SHINE (COG0201; NCT03507790) is a completed Phase 2 randomized, double-blind, placebo-controlled clinical trial conducted in participants with mild to moderate AD [7, 8].”
The 95% slowing in the low p-tau217 subgroup represented a 2.7-point improvement on ADAS-Cog11 versus placebo over the 6 months study duration.
“This robust clinical benefit represented a 2.7-point improvement on ADAS-Cog11 versus placebo over the 6 months study duration [8]”
The trends of decreases in plasma Aβ40, Aβ42 and NfL align with those observed in CSF of zervimesine treated participants compared to placebo (NfL p = 0.016, Aβ40 p = 0.305, and Aβ42 p = 0.150 in mITT population).
“Notably, the trends seen of decreases in Aβ40, Aβ42 and NfL align with that observed in CSF of zervimesine treated participants compared to placebo (NfL p = 0.016, Aβ40 p = 0.305, and Aβ42 p = 0.150 in mITT population) [8].”
Findings from the SHINE p-tau217 subgroup analysis identified a patient population most likely to respond to zervimesine treatment, with favorable findings of a biological impact - decrease in GFAP and trends in decreases in NfL and Aβ42 - consistent with improved clinical outcomes.
“Findings from the SHINE p-tau217 subgroup analysis identified a patient population most likely to respond to zervimesine treatment, with favorable findings of a biological impact – decrease in GFAP and trends in decreases in NfL and Aβ42 – consistent with improved clinical outcomes [7, 8].”
In SHINE mITT, participants treated with zervimesine showed a decrease in CSF NfL levels relative to placebo (p = 0.016).
“In mITT, participants treated with zervimesine experienced a slowing in cognitive decline (38% for ADAS-Cog11) and showed a decrease in CSF NfL levels relative to placebo (p = 0.016) [8, 20, 21].”
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Diagnostic Accuracy of a Plasma Phosphorylated Tau 217 Immunoassay for Alzheimer Disease Pathology
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“22,23 This prompted a pre-speci fi ed subgroup analysis to assess outcomes in subjects above and below this study ’ s median baseline plasma p-tau217 levels.”
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Lizama, B. N., Kahle, J., Catalano, S. M., Caggiano, A. O., Grundman, M., & Hamby, M. E. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24076251 · Cited by 54
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Di Caro, V., Cho, E., Thiel, J., Lizama, B. N., Koel-Simmelink, M. J. A., Pandey, K., Duong, D., Seyfried, N. T., Grundman, M., Teunissen, C. E., et al. (2026) · Alzheimer's Research & Therapy · doi:10.1186/s13195-026-02025-4 · Cited by 1
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Metadata
- Authors
- Vijverberg, E. G. B., Scharre, D. W., Woodward, M., Catalano, S., Hamby, M. E., Grundman, M., Morgan, R. E., Iaci, J., Devins, T., & Caggiano, A. O.
- Affiliations
- Brain Research Center, Amsterdam, Netherlands
- Department of Neurology, The Ohio State University Wexner Medical Center
- Head of Dementia Research, Austin Health
- Chief Scientific Officer, Capsida Biotherapeutics
- Clinical, Cognition Therapeutics, Inc
- President and CEO, Global R&D Partners, LLC, San Diego, CA, USA
- MedSurgPI, LLC
- Venue
- Journal of Alzheimer’s Disease
- Publisher
- SAGE Publications
- Published
- 2026-04-03
- Volume
- 111
- Issue
- 2
- Pages
- 897-908
- ISSN
- 1387-2877
- 1875-8908
- Cited by
- 2
- References
- 5
- Language
- en
- Funders
- National Institutes of Aging (1R01AG058660-01)
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