ABSTRACT
Introduction
Alzheimer’s disease (AD) is a major cause of morbidity worldwide and its prevalence is expected to rise. Previous studies involving compounds that target the accumulation of amyloid β protein have been unsuccessful, renewing interest in therapies directed against intracellular deposits of tau proteins. Derived from methylene blue, hydromethylthionine is a tau aggregation inhibitor that recently emerged as a promising disease-modifying treatment for AD.
Areas covered
Herein, the authors cover the chemistry, pharmacodynamics and pharmacokinetics of hydromethylthionine and its oxidized form methylthionine chloride (MTC) that was first studied, as well as clinical efficacy and safety of hydromethylthionine in the treatment of mild to moderate AD.
Expert opinion
Randomized clinical trials with hydromethylthionine failed to show any impact of the doses used on the disease course. Data analysis from a non-randomized cohort showed that a smaller dose of the drug previously thought to be ineffective and used as placebo, prescribed as monotherapy rather than as add-on to AD approved symptomatic therapies may slow cognitive decline. This finding was further confirmed by a pharmacokinetic analysis study showing a dose/response relationship with doses around 16 mg daily. Future trials need to study the pharmacological properties of hydromethylthionine and ascertain the optimal safe and effective dose to be used.
Article Highlights
Failure of amyloid-based therapies in Alzheimer’s disease research led to an increased interest in tau-based therapies.
Hydromethylthionine is a second-generation tau-aggregation inhibitor studied in phase II and III trials of Alzheimer’s disease.
Data analysis from phase III trials using this compound found that it failed to meet primary efficacy endpoints in terms of attenuating the rate of progression of the disease at doses in the range of 150-250 mg daily initially expected to be therapeutic, compared to 8 mg daily used as placebo. Further pharmacokinetic study analysis revealed that a dose of around 16 mg daily might be optimal to achieve desired clinical outcomes.
Future trials should better characterize the pharmacological properties of hydromethylthionine to ascertain dosages, maintain adequate blinding and separate the funding source from those who design and conduct the study.
Acknowledgments
TauRxTherapeutics Ltd provided a scientific accuracy review at the request of the journal editor.
Declaration of interest
The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
Reviewer disclosures
Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.