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Clinical Trial
. 2025 Sep;21(9):e70537.
doi: 10.1002/alz.70537.

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

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
Clinical Trial

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

Mieke Nuytten et al. Alzheimers Dement. 2025 Sep.

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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Conflict of interest statement

P.A. is a paid consultant of The Siesta Group Schlafanalyse GmbH. J.E.H. is an employee and shareholder of Metis Cogniton Ltd and has previously received consultancy fees from remynd. K.D.W. has received consultancy fees from remynd and owns remynd warrants and shares. S.R. is paid consultant for remynd. G.G. is paid consultant for remynd and Babylon Biosciences and owns remynd warrants and shares. M.F., E.D. and K.P. own remynd warrants. H.Z. has served at scientific advisory boards and/or as a consultant for Abbvie, Acumen, Alector, Alzinova, ALZpath, Amylyx, Annexon, Apellis, Artery Therapeutics, AZ Therapies, Cognito Therapeutics, CogRx, Denali, Eisai, Enigma, LabCorp, Merry Life, Nervgen, Novo Nordisk, Optoceutics, Passage Bio, Pinteon Therapeutics, Prothena, Quanterix, Red Abbey Labs, remynd, Roche, Samumed, Siemens Healthineers, Triplet Therapeutics, and Wave, has given lectures sponsored by Alzecure, BioArctic, Biogen, Cellectricon, Fujirebio, Lilly, Novo Nordisk, Roche, and WebMD, and is a co‐founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program (outside submitted work). J.C. received consultancy fees from Acadia, Acumen, ALZpath, Annovis, Aprinoia, Artery, Axsome, Biogen, Biohaven, BioXcel, Bristol‐Myers Squib, Cervomed, Eisai, Fosun, GAP Foundation, Green Valley, Hummingbird Diagnostics. IGC, Janssen, Kinoxis, Lighthouse, Lilly, Lundbeck, LSP/eqt, Mangrove Therapeutics, Merck, MoCA Cognition, New Amsterdam, Novo Nordisk, NSC Therapeutics, Optoceutics, Otsuka, Oxford Brain Diagnostics, Praxis, Prothena, Remynd, Roche, Scottish Brain Sciences, Signant Health, Simcere, sinaptica, T‐Neuro, TrueBinding, and Vaxxinity pharmaceutical, assessment, and investment companies. E.V. received consultancy fees for New Amsterdam Pharma, Treeway, remynd, Vivoryon, Biogen, Vigil Neuroscience, ImmunoBrain Checkpoint, Muna Therapeutics, Esai, Eli Lilly, CogRX, Therini, UCB and Roche. C.E.T. has research contracts with Acumen, ADx Neurosciences, AC‐Immune, Alamar, Aribio, Axon Neurosciences, Beckman‐Coulter, BioConnect, Bioorchestra, Brainstorm Therapeutics, Celgene, Cognition Therapeutics, EIP Pharma, Eisai, Eli Lilly, Fujirebio, Instant Nano Biosensors, Novo Nordisk, Olink, PeopleBio, Quanterix, Roche, Toyama, Vivoryon. C.E.T. received consultancy fees from Aribio, Biogen, Beckman‐Coulter, Cognition Therapeutics, Eisai, Eli Lilly, Merck, Novo Nordisk, Novartis, Olink, Roche, Sanofi and Veravas. XM received research grants from Novo Nordisk and Kern Pharma. M.B. received consulting fees from Grifols, Araclon Biotech, Roche, Biogen, Lilly, Merck, Zambon, Novo‐Nordisk and received payments for lectures sponsored by Roche, Biogen, Grifols, Nutricia, Araclon Biotech, Servier, Novo‐Nordisk. C.B. received grants, contracts or consultancy fees from Novartis, Johnson and Johnson, Novo Noridsk, Roch, remynd, Acadia, AARP, Eli Lily, BMS, Janssen, Orion, Exciva, Sunovion, Suven, Roche, Biogen, TauRx. A.C. received contracts, grants or consultancy fees from remynd, Novo Nordisk, Therini Bio, Suven, Johnson and Johnson. K.P. and G.G. are inventors on patent WO2013/004642 held by remynd; K.P., M.V., M.F., and G.G. are inventors on patent WO 2024/0033479 held by remynd; K.P., M.V., and G.G. are inventors on patent WO 2025/104092 held by remynd. M,N,, M.V., E.D., K.P., L.P., M.F. are employees of remynd. E.B. is a former employee of remynd., J.P.T., A.L., E.F.M., J.A.M.G., V.S., V.H., M.W., A.B.W., S.D., C.M., S.H. have nothing to disclose. Author disclosures are available in the supporting information.

Figures

FIGURE 1
FIGURE 1
Participant flow diagram of REMAD‐02. *Eight participants did not meet the EEG criteria. EEG, electroencephalography.
FIGURE 2
FIGURE 2
REM127 exposure in plasma and CSF at indicated tested doses. (A) Pharmacokinetic profiles. (B) Concentrations in CSF at end of treatment (EoT). Values above the bars indicate fold margin relative to the affinity constant of septin 6. For the 88, 350 and 1400 mg doses the number of patients analyzed per dose group was n = 5, n = 3, n = 2, respectively. CSF, cerebrospinal fluid.
FIGURE 3
FIGURE 3
Pathophysiological biomarker outcomes. Change from baseline after 28 days of treatment of indicated analytes in CSF of the placebo and verum group (*p < 0.05). CSF, cerebrospinal fluid.
FIGURE 4
FIGURE 4
The iEEG power analysis (ECR). (A) Change from baseline after 28 days of treatment of iEEG power at indicated frequency bands of the placebo or verum group. Each of the dots indicates geometric mean change from baseline of iEEG power of the placebo and verum group for each of the 19 electrodes (* p < 0.05). (B) Geometric mean change from baseline of individual (i) total power and i‐alpha1 power for all 19 electrodes in function of the indicated days of treatment. Green dotted line and percentage value indicate the projected improvement required to fully restore late‐onset AD to healthy controls as reported in literature. ECR, resting EEG with eyes closed; EEG, electroencephalography; iEEG, individual electroencephalography.
FIGURE 5
FIGURE 5
Cognitive outcomes. Change from baseline after 28 days of treatment period of indicated cognitive tests of placebo and verum group (*p < 0.05).
FIGURE 6
FIGURE 6
Association matrix of treatment outcomes. Association matrix of the individual longitudinal effect sizes of all participants (placebo and verum group combined) between indicated endpoints across participants.
See this image and copyright information in PMC

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