Oral Tau Aggregation Inhibitor for Alzheimer’s Disease: Design, Progress and Basis for Selection of the 16 mg/day Dose in a Phase 3, Randomized, Placebo-Controlled Trial of Hydromethylthionine Mesylate

Claude M. Wischik* (Corresponding Author), P. Bentham, S. Gauthier, S. Miller, K. Kook, B. O. Schelter

*Corresponding author for this work

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Abstract

Background: Hydromethylthionine mesylate is a tau aggregation inhibitor shown to have exposure-dependent pharmacological activity on cognitive decline and brain atrophy in two completed Phase 3 trials in mild/moderate Alzheimer’s disease (AD). Objectives: The present report summarises the basis for selection of 16 mg/day as monotherapy as the optimal treatment regime and the design rationale of a confirmatory Phase 3 trial (LUCIDITY). Design: The trial comprises a 12-month double-blind, placebo-controlled phase followed by a 12-month modified delayed-start open-label treatment phase. Setting: 76 clinical research sites in North America and Europe. Participants: 545 patients with probable AD or MCI-AD in the final version of the protocol. Intervention: Participants were assigned randomly to receive hydromethylthione mesylate at doses of 16 mg/day, 8 mg/day or placebo at a 4:1:4 ratio during the double-blind phase. All participants in the open-label phase receive the 16 mg/day dose. Measurements: Co-primary clinical outcomes are the 11-item Alzheimer’s Disease Assessment Scale (ADAS-cog11) and the 23-item Alzheimer’s Disease Cooperative Study — Activities of Daily Living (ADCS-ADL23). Secondary biomarker measures include whole-brain atrophy and temporal lobe 18F-fluorodeoxyglucose positron emission tomography. Results: 446 participants are expected to complete the 12-month placebo-controlled phase in March 2022. Conclusions: If the primary end points are met, the data will provide confirmatory evidence of the clinical and biomarker benefits of hydromethylthionine mesylate in minimal to moderate AD. As low-dose oral hydromethylthionine mesylate is simple to use clinically, does not cause amyloid-related imaging abnormalities and has a benign safety profile, it would likely improve AD management.

Original languageEnglish
Pages (from-to)780-790
Number of pages11
JournalJournal of Prevention of Alzheimer's Disease
Volume9
Early online date26 Jun 2022
DOIs
Publication statusPublished - Oct 2022

Bibliographical note

Acknowledgements:
We gratefully acknowledge the contribution of the scientific advisory board, study investigators, and the generosity of study participants. The authors thank EVERSANA™ for providing medical writing support, which was funded by TauRx Therapeutics in accordance with Good Publication Practice (GPP3) guidelines ( http://www.ismpp.org/gpp3 ).
Funding: The study was funded and sponsored by TauRx Therapeutics (Singapore). The funder of the study took the lead in designing and conducting the study, as well as writing of the report.

Keywords

  • Alzheimer’s disease
  • hydromethylthionine mesylate
  • Leuco-methylthioninium bis(hydromethanesulphonate)
  • LMTM
  • tau aggregation inhibitor

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