. 2026 Jan 21;13(3):100480.

doi: 10.1016/j.tjpad.2026.100480. Online ahead of print.

Clinical, imaging and blood biomarker outcomes in a Phase 3 clinical trial of tau aggregation inhibitor hydromethylthionine mesylate in mild cognitive impairment and mild to moderate dementia due to Alzheimer's disease

Claude M Wischik¹, Richard Stefanacci², Peter Bentham³, Serge Gauthier⁴, Henrik Zetterberg⁵, Gordon K Wilcock⁶, Lutz Froelich⁷, Alistair Burns⁸, Emer MacSweeney⁹, Clive Ballard¹⁰, Jin-Tai Yu¹¹, Tay Siew Choon¹², Vahe Asvatourian¹³, Natalia Muehlemann¹³, Jan Priel¹³, Karin Kook¹⁴, Tenecia Sullivan¹⁴, Diane Downie¹², Sonya Miller¹², Carol Pringle¹², John M D Storey¹⁵, Tom Baddeley¹⁵, Charles R Harrington¹⁶, Lewis K Penny¹⁷, Mohammad Arastoo¹⁸, Roger Staff¹⁹, Anca-Larisa Sandu²⁰, Helen Shiells¹², Serena Lo²¹, Nafeesa Nazlee¹², Emily Evans¹², Claire Hull¹², Bjoern O Schelter²¹

Affiliations

¹ Institute of Medical Sciences, University of Aberdeen, Aberdeen AB25 2ZD, UK; TauRx Therapeutics Ltd., Aberdeen, AB24 5RP, UK. Electronic address: cmw@taurx.com.
² TauRx Therapeutics Ltd., Aberdeen, AB24 5RP, UK; Thomas Jefferson University, Philadelphia, PA, USA.
³ TauRx Therapeutics Ltd., Aberdeen, AB24 5RP, UK; Birmingham and Solihull Mental Health NHS Foundation Trust, Birmingham, UK.
⁴ Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec, Canada.
⁵ Department of Psychiatry and Neurochemistry, Institute of Neuroscience & Physiology, Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden; Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden; Department of Neurodegenerative Disease, UCL Institute of Neurology, London, United Kingdom; UK Dementia Research Institute at UCL, London, United Kingdom; Hong Kong Centre for Neurodegenerative Diseases, Clear Water Bay, Hong Kong, China; Wisconsin Alzheimer's Disease Research Centre, University of Wisconsin School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI 53792, USA.
⁶ Emeritus Professor of Geratology, University of Oxford, Oxford, UK.
⁷ Department of Geriatric Psychiatry, Medical Faculty Mannheim, Central Institute of Mental Health, Heidelberg University, (SCU-B), Mannheim, Germany.
⁸ University of Manchester, Manchester, UK.
⁹ Re:Cognition Health London UK.
¹⁰ Clinical and Biomedical Sciences, Faculty of Health and Life Sciences, University of Exeter, Exeter, UK.
¹¹ Department of Neurology, Huashan Hospital, Fudan University, Shanghai, China.
¹² TauRx Therapeutics Ltd., Aberdeen, AB24 5RP, UK.
¹³ Cytel Inc. 675 Massachusetts Ave, Cambridge, MA 02139, UK.
¹⁴ Salamandra LLC, Bethesda, MD, USA.
¹⁵ TauRx Therapeutics Ltd., Aberdeen, AB24 5RP, UK; Department of Chemistry, University of Aberdeen, Aberdeen AB24 3UE, UK.
¹⁶ Institute of Medical Sciences, University of Aberdeen, Aberdeen AB25 2ZD, UK; TauRx Therapeutics Ltd., Aberdeen, AB24 5RP, UK.
¹⁷ Institute of Medical Sciences, University of Aberdeen, Aberdeen AB25 2ZD, UK; TauRx Therapeutics Ltd., Aberdeen, AB24 5RP, UK; Scottish Biologics Facility, University of Aberdeen, Aberdeen, UK.
¹⁸ Institute of Medical Sciences, University of Aberdeen, Aberdeen AB25 2ZD, UK; Scottish Biologics Facility, University of Aberdeen, Aberdeen, UK.
¹⁹ Aberdeen Royal Infirmary NHS Grampian, Aberdeen Royal Infirmary, Foresterhill, Aberdeen AB25 2ZN, UK.
²⁰ Aberdeen Biomedical Imaging Centre, School of Medicine, Medical Sciences and Nutrition, University of Aberdeen, Lilian Sutton Building, Foresterhill, Aberdeen, AB25 2ZD, UK.
²¹ TauRx Therapeutics Ltd., Aberdeen, AB24 5RP, UK; Institute for Complex Systems and Mathematical Biology, University of Aberdeen, Aberdeen, UK.

PMID: 41570392
PMCID: PMC12861207
DOI: 10.1016/j.tjpad.2026.100480

Clinical, imaging and blood biomarker outcomes in a Phase 3 clinical trial of tau aggregation inhibitor hydromethylthionine mesylate in mild cognitive impairment and mild to moderate dementia due to Alzheimer's disease

Claude M Wischik et al. J Prev Alzheimers Dis. 2026.

. 2026 Jan 21;13(3):100480.

doi: 10.1016/j.tjpad.2026.100480. Online ahead of print.

Authors

Affiliations

¹ Institute of Medical Sciences, University of Aberdeen, Aberdeen AB25 2ZD, UK; TauRx Therapeutics Ltd., Aberdeen, AB24 5RP, UK. Electronic address: cmw@taurx.com.
² TauRx Therapeutics Ltd., Aberdeen, AB24 5RP, UK; Thomas Jefferson University, Philadelphia, PA, USA.
³ TauRx Therapeutics Ltd., Aberdeen, AB24 5RP, UK; Birmingham and Solihull Mental Health NHS Foundation Trust, Birmingham, UK.
⁴ Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec, Canada.
⁵ Department of Psychiatry and Neurochemistry, Institute of Neuroscience & Physiology, Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden; Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden; Department of Neurodegenerative Disease, UCL Institute of Neurology, London, United Kingdom; UK Dementia Research Institute at UCL, London, United Kingdom; Hong Kong Centre for Neurodegenerative Diseases, Clear Water Bay, Hong Kong, China; Wisconsin Alzheimer's Disease Research Centre, University of Wisconsin School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI 53792, USA.
⁶ Emeritus Professor of Geratology, University of Oxford, Oxford, UK.
⁷ Department of Geriatric Psychiatry, Medical Faculty Mannheim, Central Institute of Mental Health, Heidelberg University, (SCU-B), Mannheim, Germany.
⁸ University of Manchester, Manchester, UK.
⁹ Re:Cognition Health London UK.
¹⁰ Clinical and Biomedical Sciences, Faculty of Health and Life Sciences, University of Exeter, Exeter, UK.
¹¹ Department of Neurology, Huashan Hospital, Fudan University, Shanghai, China.
¹² TauRx Therapeutics Ltd., Aberdeen, AB24 5RP, UK.
¹³ Cytel Inc. 675 Massachusetts Ave, Cambridge, MA 02139, UK.
¹⁴ Salamandra LLC, Bethesda, MD, USA.
¹⁵ TauRx Therapeutics Ltd., Aberdeen, AB24 5RP, UK; Department of Chemistry, University of Aberdeen, Aberdeen AB24 3UE, UK.
¹⁶ Institute of Medical Sciences, University of Aberdeen, Aberdeen AB25 2ZD, UK; TauRx Therapeutics Ltd., Aberdeen, AB24 5RP, UK.
¹⁷ Institute of Medical Sciences, University of Aberdeen, Aberdeen AB25 2ZD, UK; TauRx Therapeutics Ltd., Aberdeen, AB24 5RP, UK; Scottish Biologics Facility, University of Aberdeen, Aberdeen, UK.
¹⁸ Institute of Medical Sciences, University of Aberdeen, Aberdeen AB25 2ZD, UK; Scottish Biologics Facility, University of Aberdeen, Aberdeen, UK.
¹⁹ Aberdeen Royal Infirmary NHS Grampian, Aberdeen Royal Infirmary, Foresterhill, Aberdeen AB25 2ZN, UK.
²⁰ Aberdeen Biomedical Imaging Centre, School of Medicine, Medical Sciences and Nutrition, University of Aberdeen, Lilian Sutton Building, Foresterhill, Aberdeen, AB25 2ZD, UK.
²¹ TauRx Therapeutics Ltd., Aberdeen, AB24 5RP, UK; Institute for Complex Systems and Mathematical Biology, University of Aberdeen, Aberdeen, UK.

PMID: 41570392
PMCID: PMC12861207
DOI: 10.1016/j.tjpad.2026.100480

Abstract

Background: Hydromethylthionine mesylate (HMTM) targets tau pathology and has tau-independent symptomatic activity.

Objectives: To evaluate the safety and efficacy of HMTM in participants with mild cognitive impairment (MCI) and mild to moderate dementia due to Alzheimer's disease (AD).

Setting: 82 centres in Canada, European Union, United Kingdom and United States of America.

Participants: A total of 598 amyloid β-PET positive participants were included; 44% (263) met clinical criteria for MCI due to Alzheimer's disease and 56% (335) were diagnosed with mild to moderate dementia due to AD.

Intervention: HMTM 16 mg/day and 8 mg/day were compared with methylthioninium chloride (MTC) 4 mg twice weekly, intended as an inactive urinary colourant to preserve blinding with respect to possible urinary discolouration caused by HMTM.

Measurements: HMTM and MTC were compared on cognitive and functional endpoints for the first 52 weeks followed by all receiving HMTM 16 mg/day to 104 weeks in a modified delayed-start trial design. Biomarker outcomes included change in plasma levels of neurofilament light chain (NfL), pTau217 and MRI measures of grey matter atrophy.

Results: It was not possible to demonstrate significant differences on the co-primary clinical endpoints (ADAS-cog₁₁ and ADCS-ADL₂₃) at 52 weeks due to symptomatic activity in the control arm. In participants with MCI, statistically significant differences in cognitive decline (ADAS-cog₁₃) emerged at 78 weeks (p = 0·0291) and 104 weeks (p = 0·0308) between early- and delayed-start HMTM 16 mg/day in analyses specified prior to the 24-month database lock. Statistically significant cognitive improvement over baseline score was sustained for 78 weeks in the early start MCI group, with no significant cognitive or functional decline to 104 weeks. There was a significant reduction in progression of neurodegeneration measured by NfL change (p = 0·0291) at 52 weeks in the whole population, consistent with significant reductions in progression of grey matter atrophy at 52 and 104 weeks, and a reduction in progression of tau pathology (pTau217, p = 0·0165) in MCI. Headache (1·5%) and diarrhoea (1·2%) were the most frequent adverse effects.

Conclusions: Although HMTM 16 mg/day arrested progression of neurodegeneration and reduced grey matter atrophy at 52 weeks, symptomatic activity in the control arm precluded separation of treatment arms at 52 weeks on primary clinical endpoints. In participants with MCI, significant clinical separation was seen only at 78 and 104 weeks. This effect has been confirmed in a further study. HMTM was well tolerated and has the potential to offer an accessible oral treatment option with a benign safety profile which could be delivered with minimal patient/physician burden.

Keywords: Alzheimer’s disease; Hydromethylthionine mesylate; Neurofilament light chain; Phosphorylated-tau 217; Tau aggregation inhibitor.

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Conflict of interest statement

Declaration of competing interest Bjoern Schelter reports a relationship with GT Diagnostics that includes: employment. Serge Gauthier reports a relationship with MBI-C that includes: equity or stocks. Serge Gauthier, Henrik Zetterberg reports a relationship with AbbVie Inc that includes: consulting or advisory. Serge Gauthier reports a relationship with ADvantage that includes: consulting or advisory. Serge Gauthier reports a relationship with AmyriAD that includes: consulting or advisory. Serge Gauthier, Lutz Froelich, Alistair Burns reports a relationship with Eisai Inc that includes: consulting or advisory. Serge Gauthier reports a relationship with ENIGMA that includes: consulting or advisory. Serge Gauthier, Lutz Froelich, Clive Ballard, Alistair Burns reports a relationship with Eli Lilly that includes: consulting or advisory. Serge Gauthier reports a relationship with Otsuka Pharmaceutical Co Ltd that includes: consulting or advisory. Serge Gauthier, Lutz Froelich, Clive Ballard, Henrik Zetterberg reports a relationship with Novo Nordisk Inc that includes: consulting or advisory. Lutz Froelich, Clive Ballard reports a relationship with Biogen Inc that includes:. Lutz Froelich reports a relationship with Hoffmann-LaRoche that includes: funding grants. Lutz Froelich reports a relationship with Hector II Foundation that includes: funding grants. Lutz Froelich reports a relationship with Dietmar Hopp Foundation that includes: funding grants. Lutz Froelich reports a relationship with BioVie that includes: consulting or advisory. Lutz Froelich reports a relationship with GE Healthcare that includes: consulting or advisory. Lutz Froelich reports a relationship with Grifols Inc that includes: consulting or advisory. Lutz Froelich reports a relationship with Janssen Pharmaceuticals Inc that includes: consulting or advisory. Lutz Froelich reports a relationship with Neurimmune AG that includes: consulting or advisory. Lutz Froelich reports a relationship with Noselab that includes: consulting or advisory. Lutz Froelich, Clive Ballard, Henrik Zetterberg reports a relationship with Roche that includes: consulting or advisory. Lutz Froelich reports a relationship with Schwabe that includes: consulting or advisory. Clive Ballard reports a relationship with Novartis that includes: funding grants. Clive Ballard reports a relationship with Johnson and Johnson that includes: consulting or advisory and funding grants. Clive Ballard reports a relationship with ReMynd that includes: funding grants. Clive Ballard reports a relationship with Acadia Pharmaceuticals Inc that includes: funding grants. Clive Ballard reports a relationship with Acadia Pharmaceuticals Inc that includes: consulting or advisory. Clive Ballard reports a relationship with AARP that includes: consulting or advisory. Clive Ballard reports a relationship with BMS Pharmaceutical Ltd that includes: consulting or advisory. Clive Ballard reports a relationship with Janssen Pharmaceuticals that includes: consulting or advisory. Clive Ballard reports a relationship with Orion Corp that includes: consulting or advisory. Clive Ballard reports a relationship with Exciva that includes: consulting or advisory. Clive Ballard reports a relationship with Sumitomo Pharma America Inc that includes: consulting or advisory. Clive Ballard reports a relationship with Suven Pharmaceuticals Limited that includes: consulting or advisory. Henrik Zetterberg reports a relationship with Swedish Research Council that includes: funding grants. Henrik Zetterberg reports a relationship with Horizon Europe that includes: funding grants. Henrik Zetterberg reports a relationship with Swedish State Support for Clinical Research that includes: funding grants. Henrik Zetterberg reports a relationship with Alzheimer’s Drug Discovery Foundation that includes: funding grants. Henrik Zetterberg reports a relationship with AD Strategic Fund that includes: funding grants. Henrik Zetterberg reports a relationship with Alzheimer’s Association that includes: funding grants. Henrik Zetterberg reports a relationship with Bluefield Project that includes: funding grants. Henrik Zetterberg reports a relationship with Cure Alzheimer’s Fund that includes: funding grants. Henrik Zetterberg reports a relationship with Olav Thon Foundation that includes: funding grants. Henrik Zetterberg reports a relationship with Erling Persson Family Foundation that includes: funding grants. Henrik Zetterberg reports a relationship with Stiftelsen för Gamla Tjänarinnor that includes: funding grants. Henrik Zetterberg reports a relationship with Hjärnfonden that includes: funding grants. Henrik Zetterberg reports a relationship with European Union Joint Programme that includes: funding grants. Henrik Zetterberg reports a relationship with National Institute for Health and Care Research University College London Hospitals Biomedical Research Centre that includes: funding grants. Henrik Zetterberg reports a relationship with UK Dementia Research Institute that includes: funding grants. Henrik Zetterberg reports a relationship with Acumen Pharmaceuticals Inc that includes: consulting or advisory. Henrik Zetterberg reports a relationship with Alector Inc that includes: consulting or advisory. Henrik Zetterberg reports a relationship with Alzinova AB that includes: consulting or advisory. Henrik Zetterberg reports a relationship with ALZpath Inc that includes: consulting or advisory. Henrik Zetterberg reports a relationship with Amylyx Pharmaceuticals Inc that includes: consulting or advisory. Henrik Zetterberg reports a relationship with Annexon Biosciences that includes: consulting or advisory. Henrik Zetterberg reports a relationship with Apellis Pharmaceuticals, Inc that includes: consulting or advisory. Henrik Zetterberg reports a relationship with Artery Therapeutics Inc that includes: consulting or advisory. Henrik Zetterberg reports a relationship with AZTherapies that includes: consulting or advisory. Henrik Zetterberg reports a relationship with Cognito Therapeutics Inc that includes: consulting or advisory. Henrik Zetterberg reports a relationship with CogRx that includes: consulting or advisory. Henrik Zetterberg reports a relationship with Denali Therapeutics Inc that includes: consulting or advisory. Henrik Zetterberg reports a relationship with LABCORP that includes: consulting or advisory. Henrik Zetterberg reports a relationship with Merry Life that includes: consulting or advisory. Henrik Zetterberg reports a relationship with NervGen Pharma Corp that includes: consulting or advisory. Henrik Zetterberg reports a relationship with Optoceutics that includes: consulting or advisory. Henrik Zetterberg reports a relationship with Passage Bio Inc that includes: consulting or advisory. Henrik Zetterberg reports a relationship with Pinteon Therapeutics Inc that includes: consulting or advisory. Henrik Zetterberg reports a relationship with Prothena that includes: consulting or advisory. Henrik Zetterberg reports a relationship with Quanterix Corp that includes: consulting or advisory. Henrik Zetterberg reports a relationship with Red Abbey Labs that includes: consulting or advisory. Henrik Zetterberg reports a relationship with reMYND that includes: consulting or advisory. Henrik Zetterberg reports a relationship with Samumed that includes: consulting or advisory. Henrik Zetterberg reports a relationship with Siemens Healthineers that includes: consulting or advisory. Henrik Zetterberg reports a relationship with Triplet Therapeutics Inc that includes: consulting or advisory. Henrik Zetterberg reports a relationship with Wave that includes: consulting or advisory. Henrik Zetterberg reports a relationship with Brain Biomarker Solutions that includes: equity or stocks. Claude M Wischik has patent issued to WisTa Laboratories Ltd. John M.D Storey, Charles R Harrington has patent issued to WisTa Laboratories Ltd. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Figures

Fig 1: dummy alt text — **Fig. 1**
Trial profile. Abbreviations: DB=double-blind; D/C=did not complete; ITT=intention to treat; OL=open label; tx=treatment.

Fig 2: dummy alt text — **Fig. 2**
Cognitive, functional, and imaging endpoints. Prespecified efficacy results for the co-primary clinical, functional and secondary endpoints for all participants at 52-weeks: (A) ADAS-cog₁₁ (B) ADCS-ADL₂₃ and (C) whole brain volume (WBV). Corresponding outcomes in the MCI subgroup are shown at 104 weeks for: (D) ADAS-cog₁₃, (E) ADCS-ADL₂₃ and (F) WBV. p-values indicate statistical significance of differences between arms as randomised. Asterisks indicate statistically significant improvement over baseline; *P < 0.05. Error bars denote SEM.

Fig 3: dummy alt text — **Fig. 3**
Plasma biomarker outcomes. Change in plasma neurofilament light chain (NfL) concentration over 52-weeks in (A) whole population and (B) MCI subgroup. Change in pTau217 concentration over 104-weeks in (C) whole population (D) MCI subgroup. Error bars denote SEM.

Fig 4: dummy alt text — **Fig. 4**
Statistical parametric mapping analysis comparing differences in change in GM volume over 52 and 104 weeks in subjects receiving HMTM (8mg/day or 16 mg/day) vs those receiving MTC 4 mg twice weekly. The locations of differences indicating statistically significant reduction in grey matter atrophy are shown in colour superimposed onto a normal control registered to a standardised template supplied with the SPM software platform (www.fil.ion.ucl.ac.uk/spm/).

Fig 5: dummy alt text — **Fig. 5**
Change from baseline in cognitive, functional, and imaging outcomes in MCI comparing MTC 4 mg twice weekly versus meta-analytic controls. (A) ADAS-Cog₁₃, (B) ADCS-ADL₂₃, and (C) whole-brain volume over 52 weeks in participants with MCI treated with MTC 4 mg twice weekly compared with meta-analytic control data. Error bars represent the standard error of the mean (SEM).

See this image and copyright information in PMC

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Clinical, imaging and blood biomarker outcomes in a Phase 3 clinical trial of tau aggregation inhibitor hydromethylthionine mesylate in mild cognitive impairment and mild to moderate dementia due to Alzheimer's disease

Affiliations

Clinical, imaging and blood biomarker outcomes in a Phase 3 clinical trial of tau aggregation inhibitor hydromethylthionine mesylate in mild cognitive impairment and mild to moderate dementia due to Alzheimer's disease

Authors

Affiliations

Abstract

Conflict of interest statement

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References

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