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

Journal article

BackgroundHydromethylthionine 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.ObjectiveTo evaluate the efficacy of HMTM in participants with mild cognitive impairment (MCI) and mild to moderate dementia due to Alzheimer's disease (AD).MethodsBecause 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.ParticipantsPropensity 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).InterventionHMTM 16mg/day MEASUREMENTS: Primary outcomes in TRx-237-080 were change from baseline to 78 weeks in ADAS-Cog13 and whole brain volume (WBV). CDR-Sum of Boxes (CDR-SB) and CDR-Global were analysed at 104 weeks. ADAS-cog11 and WBV were analysed in ADNI comparisons, and ADAS-cog11, ADCS-ADL23, CDR-SB and WBV were analysed in meta-analytic comparisons.ResultsCompared with matched CPAD placebo, HMTM 16 mg/day produced statistically significant differences in change on ADAS-Cog13 (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.ConclusionComparisons 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.

Authors: Schelter, BO; Shiells, H; Lo, S; Nazlee, N; Evans, E

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: Elsevier
• Journal: The Journal of Prevention of Alzheimer’s Disease
• Volume: 13
• Issue: 6
• Pages: 100560
• Article number: 100560
• Publication date: 2026-04-17
• DOI: 10.1016/j.tjpad.2026.100560
• EISSN: 2426-0266
• ISSN: 2274-5807
• Pmid: 42000569
• Language: English
• Keywords: Tau Aggregation Inhibitor; Alzheimer’s disease; Hydromethylthionine Mesylate; Critical Path For Alzheimer’s Disease (Cpad)