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

J Prev Alzheimers Dis. 2026 Jan 21;13(3):100480. doi: 10.1016/j.tjpad.2026.100480. Online ahead of print.

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.

PMID:41570392 | DOI:10.1016/j.tjpad.2026.100480