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

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.

Keywords: Alzheimer’s disease; LMTM; Leuco-methylthioninium bis(hydromethanesulphonate); hydromethylthionine mesylate; tau aggregation inhibitor.

Figure 1

Relationship between steady-state plasma levels of hydromethylthionine and decline on the ADAS-Cog₁₁ scale over 65 weeks in 566 participants receiving hydromethylthionine mesylate at 8 mg/day (100 as monotherapy, 466 as add-on to standard AD symptomatic drugs) in completed Phase 3 trials TRx-237-015 and TRx-237-005) Patient groups with subthreshold and above-threshold exposure to hydromethylthionine mesylate 8 mg/day were defined based on the lower calibration limit of the assay (0.373 ng/mL, dotted line). The predicted mean Cmax, ss and change in ADAS-cog₁₁ for participants receiving hydromethylthionine mesylate 16 mg/day is shown, based on pharmacokinetic modelling described previously (18). AD = Alzheimer’s Disease; ADAS-Cog₁₁ = Alzheimer’s Disease Assessment Scale-Cognitive subscale (11-item); Cmax, ss = steady state maximum plasma concentration.

Figure 2

Change in (A) ADAS-Cog₁₁ and (B) ADCS-ADL₂₃ over 52 weeks in participants receiving hydromethylthionine mesylate at 8 mg/day as monotherapy or as add-on to standard AD symptomatic drugs in completed Phase 3 trials TRx-237-015 and TRx-237-005, grouped according to subthreshold or above-threshold exposure at the 8 mg/day dose Of participants receiving 8 mg/day, 193 had subthreshold exposure and 373 had above-threshold exposure, of whom 67 were receiving HMTM as monotherapy and 306 were receiving HMTM as add-on to standard AD symptomatic drugs in completed Phase 3 trials TRx-237-015 and TRx-237-005; The statistical analysis was as described previously (18). Error bars represent standard error of the mean. AD = Alzheimer’s Disease; ADAS-Cog₁₁ = Alzheimer’s Disease Assessment Scale-Cognitive subscale (11-item); ADCS-ADL₂₃ = Alzheimer’s Disease Cooperative Study — Activities of Daily Living (23-item).

Figure 3

Change in ADAS-Cog₁₁ and ADCS-ADL₂₃ over 52 weeks in participants receiving hydromethylthionine mesylate at 8 mg/day as monotherapy or as add-on to standard AD symptomatic drugs in completed Phase 3 trials TRx-237-015 and TRx-237-005 according to subthreshold or above-threshold exposure at the 8 mg/day dose compared with the weighted mean placebo decline over 52 weeks, reported in a meta-analysis of studies in mild/moderate AD Of participants receiving 8 mg/day, 193 had subthreshold exposure and 373 had above-thresheold exposure, of whom 67 were receiving HMTM as monotherapy and 306 were receiving HMTM as add-on to standard AD symptomatic drugs. The statistical analysis model was as described previously (18). Error bars represent standard error of the mean. AD = Alzheimer’s Disease; ADAS-Cog_n = Alzheimer’s Disease Assessment Scale-Cognitive subscale (11-item); ADCS-ADL₂₃ = Alzheimer’s Disease Cooperative Study — Activities of Daily Living (23-item).

Figure 4

LUCIDITY trial design