Mieke Nuytten, Marieke Voets, Eveline Debroux, Katrien Princen, Lentel Pringels, Marc Fivaz, Eline Byl, Steven Ramael, Koen De Witte, Mercé Boada, Xavier Morató, Juan Pablo Tartari, Asunción Lafuente, Emilio Franco Macias, Jordi A. Matias-Guiu, Everard Vijverberg, Charlotte E. Teunissen, Peter Anderer, Vincent Staggs, Vincent Hayman, Anne Corbett, Clive Ballard, John E. Harrison, Manfred Windisch, Ann Brinkmalm Westman, Henrik Zetterberg, Sam Dickson, Craig Mallinckrodt, Suzanne Hendrix, Jeffrey Cummings, Gerard Griffioen
{"title":"Randomized phase 2a trial assessing a novel septin molecular glue in Alzheimer's disease","authors":"Mieke Nuytten, Marieke Voets, Eveline Debroux, Katrien Princen, Lentel Pringels, Marc Fivaz, Eline Byl, Steven Ramael, Koen De Witte, Mercé Boada, Xavier Morató, Juan Pablo Tartari, Asunción Lafuente, Emilio Franco Macias, Jordi A. Matias-Guiu, Everard Vijverberg, Charlotte E. Teunissen, Peter Anderer, Vincent Staggs, Vincent Hayman, Anne Corbett, Clive Ballard, John E. Harrison, Manfred Windisch, Ann Brinkmalm Westman, Henrik Zetterberg, Sam Dickson, Craig Mallinckrodt, Suzanne Hendrix, Jeffrey Cummings, Gerard Griffioen","doi":"10.1002/alz.70537","DOIUrl":null,"url":null,"abstract":"<div>\n \n \n <section>\n \n <h3> INTRODUCTION</h3>\n \n <p>Pharmacological restoration of septin filament integrity has the potential to provide symptomatic benefit and disease modification in Alzheimer's disease (AD).</p>\n </section>\n \n <section>\n \n <h3> METHODS</h3>\n \n <p>REM127, a septin modulator, was assessed in mild-to-moderate AD (EudraCT: 2022-000080-43) in a phase 2a trial (<i>n</i> = 14). Primary endpoints: safety and tolerability; exploratory endpoints: pharmacokinetics, cerebrospinal fluid (CSF) biomarkers, electroencephalography (EEG), and functional outcomes.</p>\n </section>\n \n <section>\n \n <h3> RESULTS</h3>\n \n <p>In participants on active therapy, dose-dependent increases in serum aminotransferase were observed, leading to study discontinuation. CSF hyperphosphorylated tau (P-tau181), endpoints reflecting synaptic function and cognitive outcomes, were changed significantly (<i>p</i> < 0.05) to normal compared to placebo.</p>\n </section>\n \n <section>\n \n <h3> DISCUSSION</h3>\n \n <p>REM127 triggers off-target liver adverse effects. Anticipated on-target outcomes suggest septin modulation has symptomatic benefit and modifies processes underlying AD. Results are considered exploratory as statistical power is constrained due to the small sample size caused by early termination. Further investigation of the therapeutic concept using an optimized septin molecular glue with an improved safety profile is warranted.</p>\n </section>\n \n <section>\n \n <h3> Highlights</h3>\n \n <div>\n <ul>\n \n <li>Septin 6/7 molecular glue REM127 was assessed in symptomatic participants with Alzheimer's disease (AD).</li>\n \n <li>REM127 triggers off-target effects suggesting liver adverse effects.</li>\n \n <li>REM127 brain exposure was consistent with saturated target engagement.</li>\n \n <li>Biomarker and cognitive outcomes were changed consistent with therapeutic benefit.</li>\n \n <li>Septin modulation may restore synaptic function and mitigate pathology in AD.</li>\n </ul>\n </div>\n </section>\n </div>","PeriodicalId":7471,"journal":{"name":"Alzheimer's & Dementia","volume":"21 9","pages":""},"PeriodicalIF":11.1000,"publicationDate":"2025-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://alz-journals.onlinelibrary.wiley.com/doi/epdf/10.1002/alz.70537","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Alzheimer's & Dementia","FirstCategoryId":"3","ListUrlMain":"https://alz-journals.onlinelibrary.wiley.com/doi/10.1002/alz.70537","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CLINICAL NEUROLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
INTRODUCTION
Pharmacological restoration of septin filament integrity has the potential to provide symptomatic benefit and disease modification in Alzheimer's disease (AD).
METHODS
REM127, a septin modulator, was assessed in mild-to-moderate AD (EudraCT: 2022-000080-43) in a phase 2a trial (n = 14). Primary endpoints: safety and tolerability; exploratory endpoints: pharmacokinetics, cerebrospinal fluid (CSF) biomarkers, electroencephalography (EEG), and functional outcomes.
RESULTS
In participants on active therapy, dose-dependent increases in serum aminotransferase were observed, leading to study discontinuation. CSF hyperphosphorylated tau (P-tau181), endpoints reflecting synaptic function and cognitive outcomes, were changed significantly (p < 0.05) to normal compared to placebo.
DISCUSSION
REM127 triggers off-target liver adverse effects. Anticipated on-target outcomes suggest septin modulation has symptomatic benefit and modifies processes underlying AD. Results are considered exploratory as statistical power is constrained due to the small sample size caused by early termination. Further investigation of the therapeutic concept using an optimized septin molecular glue with an improved safety profile is warranted.
Highlights
Septin 6/7 molecular glue REM127 was assessed in symptomatic participants with Alzheimer's disease (AD).
期刊介绍：
Alzheimer's & Dementia is a peer-reviewed journal that aims to bridge knowledge gaps in dementia research by covering the entire spectrum, from basic science to clinical trials to social and behavioral investigations. It provides a platform for rapid communication of new findings and ideas, optimal translation of research into practical applications, increasing knowledge across diverse disciplines for early detection, diagnosis, and intervention, and identifying promising new research directions. In July 2008, Alzheimer's & Dementia was accepted for indexing by MEDLINE, recognizing its scientific merit and contribution to Alzheimer's research.
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