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

• Published in: The journal of prevention of Alzheimer's disease 2022, Vol.9 (4), p.780-790
• Main Authors: Wischik, Claude M., Bentham, P., Gauthier, S., Miller, S., Kook, K., Schelter, B. O.
• Format: Article
• Language: English
• Subjects: Geriatrics/Gerontology; Medicine; Medicine & Public Health; Neurology; Original Research
• ISSN: 2274-5807; 2426-0266
• DOI: 10.14283/jpad.2022.63

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-cog 11 ) and the 23-item Alzheimer’s Disease Cooperative Study — Activities of Daily Living (ADCS-ADL 23 ). Secondary biomarker measures include whole-brain atrophy and temporal lobe 18 F-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.