Efficacy and safety of tau-aggregation inhibitor therapy in patients with mild or moderate Alzheimer's disease: a randomised, controlled, double-blind, parallel-arm, phase 3 trial
Open accessAbstract
Background Leuco-methylthioninium bis(hydromethanesulfonate; LMTM), a stable reduced form of the methylthioninium moiety, acts as a selective inhibitor of tau protein aggregation both in vitro and in transgenic mouse models. Methylthioninium chloride has previously shown potential efficacy as monotherapy in patients with Alzheimer's disease. We aimed to determine whether LMTM was safe and effective in modifying disease progression in patients with mild to moderate Alzheimer's disease.Methods We did a 15-month, randomised, controlled double-blind, parallel-group trial at 115 academic centres and private research clinics in 16 countries in Europe, North America, Asia, and Russia with patients younger than 90 years with mild to moderate Alzheimer's disease. Patients concomitantly using other medicines for Alzheimer's disease were permitted to be included because we considered it infeasible not to allow their inclusion; however, patients using medicines carrying warnings of methaemoglobinaemia were excluded because the oxidised form of methylthioninium in high doses has been shown to induce this condition. We randomly assigned participants (3:3:4) to 75 mg LMTM twice a day, 125 mg LMTM twice a day, or control (4 mg LMTM twice a day to maintain blinding with respect to urine or faecal discolouration) administered as oral tablets. We did the randomisation with an interactive web response system using 600 blocks of length ten, and stratified patients by severity of disease, global region, whether they were concomitantly using Alzheimer's disease-labelled medications, and site PET capability. Participants, their study partners (generally carers), and all assessors were masked to treatment assignment throughout the study. The coprimary outcomes were progression on the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) and the Alzheimer's Disease Co-operative Study-Activities of Daily Living Inventory (ADCS-ADL) scales from baseline assessed at week 65 in the modified intention-to-treat population. This trial is registered with Clinicaltrials.gov (NCT01689246) and the European Union Clinical Trials Registry (2012-002866-11).Findings Between Jan 29, 2013, and June 26, 2014, we recruited and randomly assigned 891 participants to treatment (357 to control, 268 to 75 mg LMTM twice a day, and 266 to 125 mg LMTM twice a day). The prespecified primary analyses did not show any treatment benefit at either of the doses tested for the coprimary outcomes (change in ADAS-Cog score compared with control [n=354, 6·32, 95% CI 5·31-7·34]: 75 mg LMTM twice a day [n=257] -0·02, -1·60 to 1·56, p=0·9834, 125 mg LMTM twice a day [n=250] -0·43, -2·06 to 1·20, p=0·9323; change in ADCS-ADL score compared with control [-8·22, 95% CI -9·63 to -6·82]: 75 mg LMTM twice a day -0·93, -3·12 to 1·26, p=0·8659; 125 mg LMTM twice a day -0·34, -2·61 to 1·93, p=0·9479). Gastrointestinal and urinary effects were the most common adverse events with both high doses of LMTM, and the most common causes for discontinuation. Non-clinically significant dose-dependent reductions in haemoglobin concentrations were the most common laboratory abnormality. Amyloid-related imaging abnormalities were noted in less than 1% (8/885) of participants.Interpretation The primary analysis for this study was negative, and the results do not suggest benefit of LMTM as an add-on treatment for patients with mild to moderate Alzheimer's disease. Findings from a recently completed 18-month trial of patients with mild Alzheimer's disease will be reported soon.Funding TauRx Therapeutics.
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Two earlier studies indicated TRx0237 demonstrated good safety and potential benefits as a monotherapy in participants with mild AD and mild to moderate AD.
“Two earlier studies (NCT01689233 and NCT01689246) conducted on participants with mild AD and mild to moderate AD, respectively, indicated that the drug demonstrated good safety and potential benefits as a monotherapy.466,467”
From Recent advances in Alzheimer's disease: Mechanisms, clinical trials and new drug development strategies. (2024) · cites this paper as [467]
Two phase 3 trials of LMTM in all-cause dementia and mild-to-moderate Alzheimer disease showed no reduction in rate of decline of cognition or activities of daily living compared to placebo.
“Unfortunately, in two different phase 3 trials testing LMTM in all-cause dementia and mild-to-moderate AD, there was no reduction in rate of decline of cognition or ADL compared to placebo (Gauthier et al., 2016).”
From Alzheimer Disease: An Update on Pathobiology and Treatment Strategies (2019) · cites this paper as Gauthier et al., 2016
The LMTM trials did not test whether the doses administered prevented accumulation of aggregated tau or decreased existing deposits.
“Whether LMTM at the doses administered prevented accumulation of aggregated tau or decreased existing deposits was not tested.”
From Alzheimer Disease: An Update on Pathobiology and Treatment Strategies (2019) · cites this paper as Gauthier et al., 2016
Clinical trials of methylene blue-derived tau inhibitors in AD have generally yielded disappointing results.
“Clinical trials of methylene blue-derived tau inhibitors in AD have generally yielded disappointing results [47–49].”
From Systems-based proteomics to resolve the biology of Alzheimer’s disease beyond amyloid and tau (2021) · cites this paper as [47]
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“Moreover, two Phase III studies [(NCT01689246)/the European Union Clinical Trials Registry (2012-002866-11), (NCT01689233) and the European Union Clinical Trials Registry (21012-002847- 28)] confirmed that TRx0237 improved the cognition in patients with mild to moderate AD, such as changes in ADAS-Cog and Alzheimer’s…”
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“LMTM (or Methylene Blue or TRx0237), an aggregator inhibitor, did not prove beneficial in large human trials in AD [102], even if subsequent analyses suggested a possible positive effect on rates of brain atrophy [103], and currently a phase 1b/2a is ongoing in mild cognitive impairment (MCI) and mild AD (Table 1).”
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“The results of phase III trial completed in 2016 failed to suggest benefit of LMTM as an addon treatment for patients with mild-to-moderate AD [77].”
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“However, there are no effective therapies for AD involving pharmacological agents that target either Aβ or tau aggregation inhibitors (Doody et al., 2014; Salloway et al., 2014; Lovestone et al., 2015; Gauthier et al., 2016).”
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“TRx 0237 (LMTXTM) Tau aggregation inhibitor Phase 3 Failed to improve cognition Gauthier et al.[118]”
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“Of these small molecules, only methylene blue advanced to phase III clinical trials, albeit with unsuccessful results [39].”
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“However, these efforts have also failed in recent clinical trials.(18) Nevertheless,”
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“Likewise, tau aggregation inhibitors failed to improve the memory and cognitive function during AD progression (Gauthier et al., 2016).”
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“LMTM was found to produce better outcomes when given as a monotherapy than as an add-on to symptomatic AD treatments (269, 270).”
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“Despite the pressing need for more targeted treatments, to date, all Phase III clinical trials testing therapeutics directed at the neuropathological substrates of AD have failed (Mullane and Williams, 2013; Gauthier et al., 2016).”
BackgroundRecent Progress in the Pharmacotherapy of Alzheimer’s Disease
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“For example, the overall safety of leuco-methylthioninium (LMT) as a monotherapy has several drawbacks, with adverse events affecting the gastrointestinal and urinary tracts being the most common and the most common reason for the cessation of high doses of LMTM [96].”
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The Potentials of Methylene Blue as an Anti-Aging Drug
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Highly specific and selective anti‐pS396‐tau antibody C10.2 targets seeding‐competent tau
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“In light of failed clinical trials using small molecules to inhibit tau phosphorylation (glycogen synthase kinase 3 inhibitor [41]) or aggregation (leuco-methylthioninium bis [42]), immunotherapy targeting the propagation of tau pathology offers an attractive new endeavor to treat AD.”
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Small-molecule drugs development for Alzheimer's disease
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“LMTX (TRx0237), a stable reduced form of the methylthioninium (MT) moiety, has been extensively studied as a tau aggregation inhibitor (Gauthier et al., 2016).”
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Self-citation
- Authors
- Gauthier, S., Feldman, H. H., Schneider, L. S., Wilcock, G. K., Frisoni, G. B., Hardlund, J. H., Moebius, H. J., Bentham, P., Kook, K. A., Wischik, D. J., Schelter, B. O., Davis, C. S., Staff, R. T., Bracoud, L., Shamsi, K., Storey, J. M. D., Harrington, C. R., & Wischik, C. M.
- Affiliations
- Douglas Mental Health University Institute (CA)
- University of California San Diego (US)
- University of Southern California (US)
- University of Oxford (GB)
- University of Geneva (CH)
- TauRx (United Kingdom) (GB)
- University of Aberdeen (GB)
- Corresponding author
- Wischik, Claude M
- ORCID
- Venue
- The Lancet
- Publisher
- Elsevier BV
- Published
- 2016-12
- Volume
- 388
- Issue
- 10062
- Pages
- 2873-2884
- ISSN
- 0099-5355 (ISSN-L)
- 0140-6736
- PMC
- PMC5164296
- OpenAlex
- W2553774099
- Cited by
- 427
- References
- 31
- Citations by year
- 2026: 25 · 2025: 46 · 2024: 47 · 2023: 41 · 2022: 47 · 2021: 46 · 2020: 48 · 2019: 47 · 2018: 48 · 2017: 27 · 2016: 4
- FWCI
- 33.77
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- The Lancet (publishedVersion)
- PubMed (publishedVersion)
- Archive ouverte UNIGE (University of Geneva) (publishedVersion)
- PubMed Central (acceptedVersion)
- Aberdeen University Research Archive (Aberdeen University) (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Archive ouverte UNIGE (University of Geneva) (submittedVersion, cc-by)
- Funders
- TauRx Pharmaceuticals
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Health Sciences › Medicine › Pharmacology › Cholinesterase and Neurodegenerative Diseases
- Keywords
- Alzheimer's disease, tau aggregation, methylene blue, disease progression, ADAS-Cog, cognitive decline, activities of daily living, methemoglobinemia, drug safety, mild to moderate Alzheimer's disease, amyloid PET, FDG-PET
- MeSH terms
- Activities of Daily Living, Aged, Aged, 80 and over, Alzheimer Disease, Animals, Brain, Dose-Response Relationship, Drug, Double-Blind Method, Female, Humans, Male, Middle Aged, Psychiatric Status Rating Scales, tau Proteins, Treatment Failure, Mice
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