PR84083

ABERDEEN, Scotland and SINGAPORE, May 19, 2020 /PRNewswire=KYODO JBN/ --

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

Alana Keating

+44(0)7795-432-022

Andrew Thomas

+44(0)7803-585-254

Email: Taurxpress@syneoshealth.com

Website: http://www.taurx.com

Source: TauRx Therapeutics Ltd