Randomized phase 2a trial assessing a novel septin molecular glue in Alzheimer's disease.

Everard Vijverberg, Gerard Griffioen, Jeffrey Cummings, Suzanne Hendrix, Craig Mallinckrodt, Sam Dickson, Henrik Zetterberg, Ann Brinkmalm Westman, Manfred Windisch, John E Harrison, Clive Ballard, Anne Corbett, Vincent Hayman, Vincent Staggs, Peter Anderer, Charlotte E Teunissen, Mieke Nuytten, Jordi A Matias-Guiu, Emilio Franco Macias, Asunción Lafuente, Juan Pablo Tartari, Xavier Morató, Mercé Boada, Koen De Witte, Steven Ramael, Eline Byl, Marc Fivaz, Lentel Pringels, Katrien Princen, Eveline Debroux, Marieke Voets

Journal: Alzheimer's & dementia : the journal of the Alzheimer's Association 2025;21(9):e70537

PMID: 40937833

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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). REM127 triggers off-target effects suggesting liver adverse effects. REM127 brain exposure was consistent with saturated target engagement. Biomarker and cognitive outcomes were changed consistent with therapeutic benefit. Septin modulation may restore synaptic function and mitigate pathology in AD.

Address: remynd NV, Leuven, Belgium.; Ace Alzheimer Center Barcelona-Universitat Internacional de Catalunya, Les Corts, Barcelona, Spain.; Pentara Corp., Salt Lake City, Utah, USA.; Ace Alzheimer Center Barcelona-Universitat Internacional de Catalunya, Les Corts, Barcelona, Spain.; Networking Research Center on Neurodegenerative Diseases (CIBERNED), Instituto de Salud Carlos III, Madrid, Spain.; Ace Alzheimer Center Barcelona-Universitat Internacional de Catalunya, Les Corts, Barcelona, Spain.; Department of Neurology, Memory Unit, Hospital Virgen del Rocío, Sevilla, Spain.; Department of Neurology, Instituto de Investigación Sanitaria San Carlos (IdISSC), Hospital Clínico San Carlos, San Carlos, Madrid, Spain.; Neurochemistry Laboratory, Department of Clinical Chemistry, Amsterdam Neuroscience, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.; The Siesta Group Schlafanalyse GmbH, Vienna, Austria.; IDDI, Inc., Raleigh, North Carolina, USA.; Department of Health & Community Sciences, University of Exeter, Exeter, UK.; Neurochemistry Laboratory, Department of Clinical Chemistry, Amsterdam Neuroscience, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.; Metis Cognition Ltd., Wiltshire, UK.; Centre for Affective Disorders, IoPPN, KCL, London, UK.; NeuroScios GmbH, St. Radegund, Austria.; Department of Psychiatry and Neurochemistry, Sahlgrenska Academy, University of Gothenburg, Sahlgrenska University Hospital/Mölndal, Mölndal, Sweden.; Department of Psychiatry and Neurochemistry, Sahlgrenska Academy, University of Gothenburg, Sahlgrenska University Hospital/Mölndal, Mölndal, Sweden.; Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital/Mölndal, Mölndal, Sweden.; Department of Neurodegenerative Disease, UCL Institute of Neurology, London, UK.; UK Dementia Research Institute at UCL, London, UK.; Hong Kong Center for Neurodegenerative Diseases, Hong Kong, China.; Wisconsin Alzheimer's Disease Research Center, University of Wisconsin School of Medicine and Public Health, University of Wisconsin-Madison, Madison, Wisconsin, USA.; Pentara Corp., Salt Lake City, Utah, USA.; Department of Brain Health, Chambers-Grundy Center for Transformative Neuroscience, Kirk Kerkorian School of Medicine, University of Nevada, Las Vegas, Maryland, USA.

DOI: 10.1002/alz.70537

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MeSH Terms: Humans, Alzheimer Disease, Male, Female, Aged, Septins, Biomarkers, tau Proteins, Electroencephalography, Double-Blind Method, Middle Aged, Aged, 80 and over