Minimum dose of hydromethylthionine could slow clinical decline and brain 
atrophy in behavioural variant Fronto-Temporal Dementia as well as Alzheimer's 
Disease

In a paper published online in the Journal of Alzheimer's Disease 
(https://doi.org/10.3233/JAD-191173), TauRx reported that the drug it is 
developing for the treatment of Alzheimer's disease (hydromethylthionine) also 
has significant pharmacological activity in behavioural variant Fronto-Temporal 
Dementia (bvFTD). The study reports a pharmacokinetic analysis of the 
relationship between treatment dose, blood levels and pharmacological activity 
of the drug hydromethylthionine on the brain in 176 patients with bvFTD. The 
results showed that, even at the lowest dose of hydromethylthionine tested (8 
mg/day), the drug (taken as a tablet) produced statistically significant 
concentration-dependent effects on clinical decline and brain atrophy with 
results similar to those reported recently in Alzheimer's Disease (AD).

Professor George Perry, Editor-in-Chief of Journal of Alzheimer's Disease, 
commented: "This is the first report of a drug that has pharmacological 
activity on clinical decline and brain atrophy in bvFTD. The data now available 
in two different diseases highlight the potential of hydromethylthionine as an 
important new avenue for treatment of neurodegenerative diseases."

Hydromethylthionine blocks abnormal aggregation in the brain of the proteins 
linked to over 80% of bvFTD (tau protein and TDP-43 protein).1 A global Phase 3 
clinical trial was conducted in 220 patients meeting international consensus 
criteria for a diagnosis of bvFTD1 who also had definite evidence of brain 
atrophy on their brain scan. Hydromethylthionine was tested at doses of 200 
mg/day against a low dose of 8 mg/day which was intended only as a control to 
mask the discolouration of urine that can sometimes occur with the drug. The 
study design was based on the findings from an earlier trial in AD that used a 
different variant of the drug.2 As in the recently reported hydromethylthionine 
trials in AD, there was no difference between the high dose and the low dose on 
any of the clinical outcomes in the trial.3,4

To explore these results further, the researchers conducted a pharmacokinetic 
population analysis using plasma concentration data from patients who 
participated in the trial to measure how blood levels of the drug relate to its 
effects on the brain. Of the 220 patients initially randomised to the trial, 
blood samples and outcome data at baseline and at 12 months were available for 
176. Using a new assay, the researchers found that the effects of 
hydromethylthionine at the 8 mg/day dose were determined by the blood level, 
and that the majority of patients had high enough blood levels of the drug even 
at this low dose to reduce clinical decline and brain atrophy by about half 
over 12 months compared to those with minimal blood levels. The high dose of 
200 mg/day gave no additional benefit. The analyses suggest that a dose of 
about 30 mg/day would be optimal for treating bvFTD and could reduce the rate 
of disease progression even more. TauRx now plans to test this dose in a 
placebo-controlled confirmatory trial.

The analysis also showed that the concentration-response profile in bvFTD is 
similar to that recently reported in AD.5 Disease progression is linked to 
abnormal aggregation of Tau and TDP-43 proteins inside nerve cells in the brain 
in both diseases. The present results support the idea that hydromethylthionine 
works in a similar way in both AD and bvFTD.

Prof. Claude Wischik, of Aberdeen University and executive chairman of TauRx 
Therapeutics Ltd.  commented: "These new results, coming as they do on top of 
the similar results we recently reported in AD, provide independent 
confirmation that hydromethylthionine has important pharmacological activity on 
brain structure and function in neurodegenerative diseases caused by abnormal 
protein aggregation. The results in bvFTD now give us the confidence to 
progress with a further confirmatory trial which we hope to begin recruiting 
early next year. A confirmatory trial in AD is already under way."

Professor Serge Gauthier, Director of the Alzheimer Disease Research Unit, 
McGill Center for Studies in Aging, commented: "Although much rarer than AD, 
bvFTD is a severely debilitating and rapidly progressive disease that is 
extremely distressing for families. The possibility of a new drug on the 
horizon in the form of hydromethylthionine for the first time offers a real 
hope for those affected."

About the Journal of Alzheimer's Disease (JAD)

Now in its 22nd year of publication, the Journal of Alzheimer's Disease is an 
international multidisciplinary journal to facilitate progress in understanding 
the etiology, pathogenesis, epidemiology, genetics, behaviour, treatment and 
psychology of Alzheimer's disease. The journal publishes research reports, 
reviews, short communications, book reviews and letters to the editor. Ground 
breaking research that has appeared in the journal includes novel therapeutic 
targets, mechanisms of disease and clinical trial outcomes. The Journal of 
Alzheimer's Disease has a 2018 Journal Impact Factor of 3.517 according to 
Journal Citation Reports (Web of Science Group, 2019). JAD is published by IOS 
Press. www.j-alz.com

About the Study 

This study reports the results of a global Phase 3 trial in 220 patients with 
bvFTD conducted between 2013 and 2016 at 70 sites in 13 countries (Canada, 
United States, Australia, Asia, Europe). Patients had to be younger than 80 
years of age and have a diagnosis bvFTD according to criteria revised by the 
International bvFTD Criteria Consortium1 with Mini-mental Status Examination 
score greater than or equal to 20 at screening. Patients were randomly assigned 
to receive hydromethylthionine at doses of 200 or 8 mg/day. The validated lower 
limit of quantification of the pharmacokinetic assay was 0.20 ng/mL, 
corresponding to an estimated steady-state peak plasma concentration of 0.346 
ng/mL in bvFTD patients. About 35% of patients taking the 8 mg/day dose had 
plasma concentrations below this level. 

About hydromethylthionine (LMTM) and protein aggregation inhibitors

TauRx's protein aggregation inhibitors have arisen from nearly 30 years of 
research. They work by preventing the abnormal aggregation process responsible 
for protein accumulations inside cells that impair neuronal function. The 
first-generation version of the drug, Rember® was a patented, highly-purified 
version of methylthioninium chloride (methylene blue), a compound previously 
used to treat a variety of conditions. Methylene blue was previously shown to 
reduce aggregation of TDP-43 in cell models,6 and likewise for tau with both 
methylene blue and hydromethylthionine.7 Hydromethylthionine is a stable 
reduced form of methylthioninium, which is better absorbed8 than methylene blue 
and has been tested in clinical trials in mild-to-moderate Alzheimer's disease 
and in bvFTD. A 12-month placebo-controlled clinical trial for AD is currently 
ongoing at 150 sites in the US and EU.

About TauRx Therapeutics Ltd

TauRx Therapeutics Ltd is a member of the TauRx Pharmaceuticals group, which is 
developing technology spun-out from the University of Aberdeen, Scotland. The 
company was established in Singapore in 2002 with the aim of developing new 
treatments and diagnostics for a range of neurodegenerative diseases. The 
company's protein aggregation inhibitor, hydromethylthionine, targets 
aggregates of abnormal fibres of tau and TDP-43 proteins that form inside nerve 
cells in the brain. TauRx's headquarters are in Singapore and its primary 
research facilities are based in Aberdeen. For more information, please visit: 
http://www.taurx.com.

References

1.  Rascovsky K, et al. Sensitivity of revised diagnostic criteria for the 
behavioural variant of frontotemporal dementia. 
Brain 2011;134:2456–2477.

2.  Wischik CM, et al. Tau aggregation inhibitor therapy: an exploratory phase 
2 study in mild or moderate Alzheimer's disease. 
J Alzheimers Dis 2015;44:705–720.

3.  Wilcock GK, et al. Potential of low dose leuco-methylthioninium 
bis(hydromethanesulphonate) (LMTM) monotherapy for treatment of mild Alzheimers 
disease: cohort analysis as modified primary outcome in a phase 3 clinical 
trial. 
J Alzheimers Dis 2018;61:435–457.

4.  Gauthier S, et al. 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. Lancet  
2016;388:2873–2884.

5.  Schelter BO, et al. Concentration-dependent activity of hydromethylthionine 
on cognitive decline and brain atrophy in mild to moderate Alzheimer's disease. 
J Alzheimers Dis 2019;72:931–946.

6.  Yamashita M, et al. Methylene blue and dimebon inhibit aggregation of 
TDP-43 in cellular models. 
FEBS Lett 2009;583:2419–2424.

7.  Harrington C, et al. Cellular models of aggregation-dependent 
template-directed proteolysis to characterize tau aggregation inhibitors for 
treatment of AlzheimerDisease. J Biol Chem 2015;290:10862–10875.

8.  Baddeley TC, et al. Complex disposition of methylthioninium redox forms 
determines efficacy in tau aggregation inhibitor therapy for Alzheimer's 
disease. J Pharmacol Exp Ther 2015;352:110–118.

Media Contacts

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Email: Taurxpress@syneoshealth.com 
Website: http://www.taurx.com


Source: TauRx Therapeutics Ltd