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

  • Alzheimers Dement. 2025 Sep;21(9):e70537. doi: 10.1002/alz.70537.
Mieke Nuytten  1 ,  Marieke Voets  1 ,  Eveline Debroux  1 ,  Katrien Princen  1 ,  Lentel Pringels  1 ,  Marc Fivaz  1 ,  Eline Byl  1 ,  Steven Ramael  1 ,  Koen De Witte  1 ,  Mercé Boada  2  3 ,  Xavier Morató  2  4 ,  Juan Pablo Tartari  2 ,  Asunción Lafuente  2 ,  Emilio Franco Macias  5 ,  Jordi A Matias-Guiu  6 ,  Everard Vijverberg  7 ,  Charlotte E Teunissen  7 ,  Peter Anderer  8 ,  Vincent Staggs  9 ,  Vincent Hayman  10 ,  Anne Corbett  10 ,  Clive Ballard  10 ,  John E Harrison  7  11  12 ,  Manfred Windisch  13 ,  Ann Brinkmalm Westman  14 ,  Henrik Zetterberg  14  15  16  17  18  19 ,  Sam Dickson  3 ,  Craig Mallinckrodt  3 ,  Suzanne Hendrix  3 ,  Jeffrey Cummings  20 ,  Gerard Griffioen  1
Affiliations
  • 1. remynd NV, Leuven, Belgium.
  • 2. Ace Alzheimer Center Barcelona-Universitat Internacional de Catalunya, Les Corts, Barcelona, Spain.
  • 3. Pentara Corp., Salt Lake City, Utah, USA.
  • 4. Networking Research Center on Neurodegenerative Diseases (CIBERNED), Instituto de Salud Carlos III, Madrid, Spain.
  • 5. Department of Neurology, Memory Unit, Hospital Virgen del Rocío, Sevilla, Spain.
  • 6. Department of Neurology, Instituto de Investigación Sanitaria San Carlos (IdISSC), Hospital Clínico San Carlos, San Carlos, Madrid, Spain.
  • 7. Neurochemistry Laboratory, Department of Clinical Chemistry, Amsterdam Neuroscience, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.
  • 8. The Siesta Group Schlafanalyse GmbH, Vienna, Austria.
  • 9. IDDI, Inc., Raleigh, North Carolina, USA.
  • 10. Department of Health & Community Sciences, University of Exeter, Exeter, UK.
  • 11. Metis Cognition Ltd., Wiltshire, UK.
  • 12. Centre for Affective Disorders, IoPPN, KCL, London, UK.
  • 13. NeuroScios GmbH, St. Radegund, Austria.
  • 14. Department of Psychiatry and Neurochemistry, Sahlgrenska Academy, University of Gothenburg, Sahlgrenska University Hospital/Mölndal, Mölndal, Sweden.
  • 15. Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital/Mölndal, Mölndal, Sweden.
  • 16. Department of Neurodegenerative Disease, UCL Institute of Neurology, London, UK.
  • 17. UK Dementia Research Institute at UCL, London, UK.
  • 18. Hong Kong Center for Neurodegenerative Diseases, Hong Kong, China.
  • 19. Wisconsin Alzheimer's Disease Research Center, University of Wisconsin School of Medicine and Public Health, University of Wisconsin-Madison, Madison, Wisconsin, USA.
  • 20. Department of Brain Health, Chambers-Grundy Center for Transformative Neuroscience, Kirk Kerkorian School of Medicine, University of Nevada, Las Vegas, Maryland, USA.
PMID: 40937833 DOI: 10.1002/alz.70537
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.

Keywords
AD; AD pathology; Alzheimer's disease; amyloid‐beta; calcium dyshomeostasis; disease‐modification; molecular glue; neurodegeneration; phase 2a clinical trial; septin; symptomatic benefit; tau.
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