Assessment of clinical and neuroimaging efficacy of treatment targeting tau pathology in mild cognitive impairment and mild to moderate Alzheimer’s disease with hydromethylthionine mesylate using external control data - 18/04/26

Doi : 10.1016/j.tjpad.2026.100560

Bjoern O Schelter ^a,^b, Helen Shiells ^a, Serena Lo ^a,^b, Nafeesa Nazlee ^a, Emily Evans ^a, Peter Bentham ^a,^c, Serge Gauthier ^d, Henrik Zetterberg ^e,^f,^g,^h,^i,^j, Gordon K Wilcock ^k, Lutz Froelich ^l, Alistair Burns ^m, Emer MacSweeney ⁿ, Clive Ballard ^o, Jin-Tai Yu ^p, Tay Siew Choon ^a, Vahe Asvatourian ^q, Natalia Muehlemann ^q, Jan Priel ^q, Karin Kook ^r, Tenecia Sullivan ^r, Diane Downie ^a, Sonya Miller ^a, Carol Pringle ^a, John M․D Storey ^a,^s, Tom Baddeley ^a,^s, Charles R Harrington ^a,^t, Roger Staff ^u, Anca-Larisa Sandu ^v, Claire Hull ^a, Richard Stefanacci ^a,^w, Claude M Wischik ^a,^t,^⁎

Alzheimer's Disease Neuroimaging Initiative

^a TauRx Therapeutics Ltd., Aberdeen AB24 5RP, UK

^b Institute for Complex Systems and Mathematical Biology, University of Aberdeen, Aberdeen, UK

^c Birmingham and Solihull Mental Health NHS Foundation Trust, Birmingham, UK

^d Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec, Canada

^e Department of Psychiatry and Neurochemistry, Institute of Neuroscience & Physiology, Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden

^f Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden

^g Department of Neurodegenerative Disease, UCL Institute of Neurology, London, United Kingdom

^h UK Dementia Research Institute at UCL, London, United Kingdom

ⁱ Hong Kong Centre for Neurodegenerative Diseases, Clear Water Bay, Hong Kong, China

^j Wisconsin Alzheimer’s Disease Research Centre, University of Wisconsin School of Medicine and Public Health, University of Wisconsin-Madison, Madison WI 53792, USA

^k Geratology, University of Oxford, Oxford, UK

^l Department of Geriatric Psychiatry, Medical Faculty Mannheim, Central Institute of Mental Health, Heidelberg University, Mannheim (SCU-B), Germany

^m University of Manchester, Manchester, UK

ⁿ Re:Cognition Health London UK

^o Clinical and Biomedical Sciences, Faculty of Health and Life Sciences, University of Exeter, Exeter, UK

^p Department of Neurology, Huashan Hospital, Fudan University, Shanghai, China

^q Cytel Inc. 675 Massachusetts Ave, Cambridge, MA 02139, USA

^r Salamandra LLC, Bethesda, MD, USA

^s Department of Chemistry, University of Aberdeen, Aberdeen AB24 3UE, UK

^t Institute of Medical Sciences, University of Aberdeen, Aberdeen AB25 2ZD, UK

^u Aberdeen Royal Infirmary NHS Grampian, Aberdeen Royal Infirmary, Foresterhill, Aberdeen AB25 2ZN, UK

^v Aberdeen Biomedical Imaging Centre, School of Medicine, Medical Sciences and Nutrition, University of Aberdeen, Lilian Sutton Building, Foresterhill, Aberdeen AB25 2ZD, UK

^w Thomas Jefferson University, Philadelphia, PA, USA

^⁎ Corresponding author.

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Abstract

Background

Hydromethylthionine mesylate (HMTM) targets tau pathology and also has tau-independent symptomatic activity. A traditional randomised placebo-controlled trial (RCT) was precluded by loss of blinding due to urinary colouration and therapeutic activity at the minimum dose required to maintain blinding.

Objective

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

Methods

Because a traditional RCT was not feasible without loss of blinding, we compared HMTM 16 mg/day in TRx-237–039 with propensity score matched true placebo controls from the FDA-sponsored Critical Path for AD (CPAD) database with the same inclusion/exclusion criteria (protocol TRx-237–080). We also compared HMTM 16 mg/day with matched natural history controls from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) and with a meta-analysis of placebo arms from trials in comparable populations in analyses specified prior to the 104-week database lock of TRx-237–039.

Participants

Propensity score matching yielded 127 pairs (HMTM n = 127; CPAD placebo n = 127) in the CPAD comparison, and 189 pairs in the ADNI comparison. A total of 218 receiving HMTM 16 mg/day were compared with meta-analytic controls ( n = 1805–8567).

Intervention

HMTM 16mg/day

Measurements

Primary outcomes in TRx-237–080 were change from baseline to 78 weeks in ADAS-Cog ₁₃ and whole brain volume (WBV). CDR-Sum of Boxes (CDR-SB) and CDR-Global were analysed at 104 weeks. ADAS-cog ₁₁ and WBV were analysed in ADNI comparisons, and ADAS-cog ₁₁ , ADCS-ADL ₂₃ , CDR-SB and WBV were analysed in meta-analytic comparisons.

Results

Compared with matched CPAD placebo, HMTM 16 mg/day produced statistically significant differences in change on ADAS-Cog ₁₃ ( p < 0.0001) and WBV at 78 (primary; p < 0.0001) and 104 weeks ( p < 0.0001), and CDR-SB differed significantly overall (104-weeks; p < 0.001) and in MCI ( p = 0.007). The odds of progressing to a more advanced CDR-Global stage were lower with HMTM (overall OR 0.31) and particularly in MCI (OR 0.15) versus CPAD placebo. Clinical and brain atrophy outcomes were similarly statistically significant in comparisons with ADNI case-matched natural history data and in meta-analytic comparisons.

Conclusion

Comparisons of HMTM treatment with CPAD, ADNI, and meta-analytic controls provide evidence consistent with clinical benefit HMTM. It has the potential to offer an accessible oral treatment option which could be delivered with minimal patient/physician burden.

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Keywords : Hydromethylthionine mesylate, Tau aggregation inhibitor, Alzheimer’s disease, Critical Path for Alzheimer’s Disease (CPAD)

Plan

Introduction

Methods

Study design and participants

Statistical methodology for clinical and WBV outcomes

Meta-analytic comparisons

Comparative summary of external control arm results

Discussion

Funding

Availability of data and materials

Declaration of generative AI and AI-assisted technologies in the writing process

CRediT authorship contribution statement

✰

Data used in preparation of this article were obtained from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database (adni.loni.usc.edu). As such, the investigators within the ADNI contributed to the design and implementation of ADNI and/or provided data but did not participate in the analysis or writing of this report. A complete listing of ADNI investigators can be found at: ADNI_Acknowledgement_List.pdf

✰✰

Data used in the preparation of this article were obtained from the Critical Path for Alzheimer’s Disease (CPAD) Database. In 2008, Critical Path Institute, in collaboration with the Engelberg Center for Health Care Reform at the Brookings Institution, formed the Coalition Against Major Diseases (rebranded to Critical Path for Alzheimer’s Disease (CPAD) consortium in 2018). The consortium brings together patient groups, biopharmaceutical companies, and scientists from academia, the U.S. Food and Drug Administration (FDA), the European Medicines Agency (EMA), the National Institute of Neurological Disorders and Stroke (NINDS), and the National Institute on Aging (NIA). The CPAD consortium includes over 200 scientists from member and non-member organizations. The data available in the CPAD database have been volunteered by CPAD member companies and non-member organizations.

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Vol 13 - N° 6

Article 100560- juin 2026 Retour au numéro

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Assessment of clinical and neuroimaging efficacy of treatment targeting tau pathology in mild cognitive impairment and mild to moderate Alzheimer’s disease with hydromethylthionine mesylate using external control data - 18/04/26

Abstract

Background

Objective

Methods

Participants

Intervention

Measurements

Results

Conclusion

Plan

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