Concentration-Dependent Activity of Hydromethylthionine on Clinical Decline and Brain Atrophy in a Randomized Controlled Trial in Behavioral Variant Frontotemporal Dementia

Helen Shiells; Bjoern O. Schelter; Peter Bentham; Thomas C. Baddeley; Christopher M. Rubino; Harish Ganesan; Jeffrey Hammel; Vesna Vuksanovic; Roger T. Staff; Alison D. Murray; Luc Bracoud; Damon J. Wischik; Gernot Riedel; Serge Gauthier; Jianping  Jia; Hans J. Moebius; Jiri Hardlund; Christopher M. Kipps; Karin Kook; John M. D. Storey; Charles R. Harrington; Claude M. Wischik

doi:10.3233/JAD-191173

Concentration-Dependent Activity of Hydromethylthionine on Clinical Decline and Brain Atrophy in a Randomized Controlled Trial in Behavioral Variant Frontotemporal Dementia

Helen Shiells, Bjoern O. Schelter, Peter Bentham, Thomas C. Baddeley, Christopher M. Rubino, Harish Ganesan, Jeffrey Hammel, Vesna Vuksanovic, Roger T. Staff, Alison D. Murray, Luc Bracoud, Damon J. Wischik, Gernot Riedel, Serge Gauthier, Jianping Jia, Hans J. Moebius, Jiri Hardlund, Christopher M. Kipps, Karin Kook, John M. D. StoreyCharles R. Harrington, Claude M. Wischik^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

19 Citations (Scopus)

13 Downloads (Pure)

Abstract

Background: Hydromethylthionine is a potent inhibitor of pathological aggregation of Tau and TDP-43 proteins.

Objective: To compare hydromethylthionine treatment effects at two doses and to determine how drug exposure is related to treatment response in bvFTD.

Methods: We undertook a 52-week Phase 3 study in 220 bvFTD patients randomised to compare hydromethylthionine at 200 mg/day and 8 mg/day (intended as a control). The principal outcomes were change on the Addenbrookes Cognitive Examination – Revised (ACE-R), the Functional Activities Questionnaire (FAQ) and whole brain volume. Secondary outcomes included Modified Clinical Global Impression of Change (Modified-CGIC). A population pharmacokinetic exposure-response analysis was undertaken in 176 of the patients with available blood samples and outcome data using a discriminatory plasma assay for the parent drug.

Results: There were no significant differences between the two doses as randomised. There were steep concentration-response relationships for plasma levels in the range 0.3 – 0.6 ng/ml at the 8 mg/day dose on clinical and MRI outcomes. There were significant exposure dependent differences at 8 mg/day for FAQ, Modified-CGIC and whole brain atrophy comparing patients with plasma levels greater than 0.346 ng/ml with having minimal drug exposure. The exposure-response is biphasic with worse outcomes at the high concentrations produced by 200 mg/day.

Conclusions: Hydromethylthionine has a similar concentration-response profile for effects on clinical decline and brain atrophy at the 8 mg/day dose in bvFTD as recently reported in AD. Treatment responses in bvFTD are predicted to be maximal at doses in the range 20 – 60 mg/day. A confirmatory placebo-controlled trial is now planned.

Original language	English
Pages (from-to)	501-519
Number of pages	19
Journal	Journal of Alzheimer's Disease
Volume	75
Issue number	2
DOIs	https://doi.org/10.3233/JAD-191173
Publication status	Published - 19 May 2020

Bibliographical note

Funding
The study was sponsored by TauRx Therapeutics (Singapore).

Acknowledgments
We gratefully acknowledge study investigators and the generosity of study participants.

Keywords

Hydromethylthionine
Leucomethylthioninium
Behavioural variant frontotemporal dementia
Clinical trials
Tau protein
TDP-43
leucomethylthioninium
hydromethylthionine
Behavioral variant frontotemporal dementia
clinical trials
tau protein
METHYLENE-BLUE
LOBAR DEGENERATION
ALZHEIMERS-DISEASE
SEROTONIN TOXICITY
PICK BODIES
AGGREGATION INHIBITOR THERAPY
DOUBLE-BLIND
TAU-AGGREGATION
DIAGNOSTIC-CRITERIA
PROGRESSION

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

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© 2020 – IOS Press and the authors. All rights reserved This article is published online with Open Access and distributed under the terms of the Creative Commons Attribution License (CC-BY 4.0) https://creativecommons.org/licenses/by/4.0/
Final published version, 463 KBLicence: CC BY

Cite this

Shiells, H., Schelter, B. O., Bentham, P., Baddeley, T. C., Rubino, C. M., Ganesan, H., Hammel, J., Vuksanovic, V., Staff, R. T., Murray, A. D., Bracoud, L., Wischik, D. J., Riedel, G., Gauthier, S., Jia, J., Moebius, H. J., Hardlund, J., Kipps, C. M., Kook, K., ... Wischik, C. M. (2020). Concentration-Dependent Activity of Hydromethylthionine on Clinical Decline and Brain Atrophy in a Randomized Controlled Trial in Behavioral Variant Frontotemporal Dementia. Journal of Alzheimer's Disease, 75(2), 501-519. https://doi.org/10.3233/JAD-191173

Concentration-Dependent Activity of Hydromethylthionine on Clinical Decline and Brain Atrophy in a Randomized Controlled Trial in Behavioral Variant Frontotemporal Dementia. / Shiells, Helen; Schelter, Bjoern O.; Bentham, Peter et al.
In: Journal of Alzheimer's Disease, Vol. 75, No. 2, 19.05.2020, p. 501-519.

Research output: Contribution to journal › Article › peer-review

Shiells, H, Schelter, BO, Bentham, P, Baddeley, TC, Rubino, CM, Ganesan, H, Hammel, J, Vuksanovic, V, Staff, RT , Murray, AD, Bracoud, L, Wischik, DJ, Riedel, G, Gauthier, S, Jia, J, Moebius, HJ, Hardlund, J, Kipps, CM, Kook, K, Storey, JMD , Harrington, CR & Wischik, CM 2020, 'Concentration-Dependent Activity of Hydromethylthionine on Clinical Decline and Brain Atrophy in a Randomized Controlled Trial in Behavioral Variant Frontotemporal Dementia', Journal of Alzheimer's Disease, vol. 75, no. 2, pp. 501-519. https://doi.org/10.3233/JAD-191173

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title = "Concentration-Dependent Activity of Hydromethylthionine on Clinical Decline and Brain Atrophy in a Randomized Controlled Trial in Behavioral Variant Frontotemporal Dementia",

abstract = "Background: Hydromethylthionine is a potent inhibitor of pathological aggregation of Tau and TDP-43 proteins.Objective: To compare hydromethylthionine treatment effects at two doses and to determine how drug exposure is related to treatment response in bvFTD.Methods: We undertook a 52-week Phase 3 study in 220 bvFTD patients randomised to compare hydromethylthionine at 200 mg/day and 8 mg/day (intended as a control). The principal outcomes were change on the Addenbrookes Cognitive Examination – Revised (ACE-R), the Functional Activities Questionnaire (FAQ) and whole brain volume. Secondary outcomes included Modified Clinical Global Impression of Change (Modified-CGIC). A population pharmacokinetic exposure-response analysis was undertaken in 176 of the patients with available blood samples and outcome data using a discriminatory plasma assay for the parent drug.Results: There were no significant differences between the two doses as randomised. There were steep concentration-response relationships for plasma levels in the range 0.3 – 0.6 ng/ml at the 8 mg/day dose on clinical and MRI outcomes. There were significant exposure dependent differences at 8 mg/day for FAQ, Modified-CGIC and whole brain atrophy comparing patients with plasma levels greater than 0.346 ng/ml with having minimal drug exposure. The exposure-response is biphasic with worse outcomes at the high concentrations produced by 200 mg/day.Conclusions: Hydromethylthionine has a similar concentration-response profile for effects on clinical decline and brain atrophy at the 8 mg/day dose in bvFTD as recently reported in AD. Treatment responses in bvFTD are predicted to be maximal at doses in the range 20 – 60 mg/day. A confirmatory placebo-controlled trial is now planned.",

keywords = "Hydromethylthionine, Leucomethylthioninium, Behavioural variant frontotemporal dementia, Clinical trials, Tau protein, TDP-43, leucomethylthioninium, hydromethylthionine, Behavioral variant frontotemporal dementia, clinical trials, tau protein, METHYLENE-BLUE, LOBAR DEGENERATION, ALZHEIMERS-DISEASE, SEROTONIN TOXICITY, PICK BODIES, AGGREGATION INHIBITOR THERAPY, DOUBLE-BLIND, TAU-AGGREGATION, DIAGNOSTIC-CRITERIA, PROGRESSION",

author = "Helen Shiells and Schelter, {Bjoern O.} and Peter Bentham and Baddeley, {Thomas C.} and Rubino, {Christopher M.} and Harish Ganesan and Jeffrey Hammel and Vesna Vuksanovic and Staff, {Roger T.} and Murray, {Alison D.} and Luc Bracoud and Wischik, {Damon J.} and Gernot Riedel and Serge Gauthier and Jianping Jia and Moebius, {Hans J.} and Jiri Hardlund and Kipps, {Christopher M.} and Karin Kook and Storey, {John M. D.} and Harrington, {Charles R.} and Wischik, {Claude M.}",

note = "Funding The study was sponsored by TauRx Therapeutics (Singapore). Acknowledgments We gratefully acknowledge study investigators and the generosity of study participants.",

year = "2020",

month = may,

day = "19",

doi = "10.3233/JAD-191173",

language = "English",

volume = "75",

pages = "501--519",

journal = "Journal of Alzheimer's Disease",

issn = "1387-2877",

publisher = "IOS Press",

number = "2",

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TY - JOUR

T1 - Concentration-Dependent Activity of Hydromethylthionine on Clinical Decline and Brain Atrophy in a Randomized Controlled Trial in Behavioral Variant Frontotemporal Dementia

AU - Shiells, Helen

AU - Schelter, Bjoern O.

AU - Bentham, Peter

AU - Baddeley, Thomas C.

AU - Rubino, Christopher M.

AU - Ganesan, Harish

AU - Hammel, Jeffrey

AU - Vuksanovic, Vesna

AU - Staff, Roger T.

AU - Murray, Alison D.

AU - Bracoud, Luc

AU - Wischik, Damon J.

AU - Riedel, Gernot

AU - Gauthier, Serge

AU - Jia, Jianping

AU - Moebius, Hans J.

AU - Hardlund, Jiri

AU - Kipps, Christopher M.

AU - Kook, Karin

AU - Storey, John M. D.

AU - Harrington, Charles R.

AU - Wischik, Claude M.

N1 - Funding The study was sponsored by TauRx Therapeutics (Singapore). Acknowledgments We gratefully acknowledge study investigators and the generosity of study participants.

PY - 2020/5/19

Y1 - 2020/5/19

N2 - Background: Hydromethylthionine is a potent inhibitor of pathological aggregation of Tau and TDP-43 proteins.Objective: To compare hydromethylthionine treatment effects at two doses and to determine how drug exposure is related to treatment response in bvFTD.Methods: We undertook a 52-week Phase 3 study in 220 bvFTD patients randomised to compare hydromethylthionine at 200 mg/day and 8 mg/day (intended as a control). The principal outcomes were change on the Addenbrookes Cognitive Examination – Revised (ACE-R), the Functional Activities Questionnaire (FAQ) and whole brain volume. Secondary outcomes included Modified Clinical Global Impression of Change (Modified-CGIC). A population pharmacokinetic exposure-response analysis was undertaken in 176 of the patients with available blood samples and outcome data using a discriminatory plasma assay for the parent drug.Results: There were no significant differences between the two doses as randomised. There were steep concentration-response relationships for plasma levels in the range 0.3 – 0.6 ng/ml at the 8 mg/day dose on clinical and MRI outcomes. There were significant exposure dependent differences at 8 mg/day for FAQ, Modified-CGIC and whole brain atrophy comparing patients with plasma levels greater than 0.346 ng/ml with having minimal drug exposure. The exposure-response is biphasic with worse outcomes at the high concentrations produced by 200 mg/day.Conclusions: Hydromethylthionine has a similar concentration-response profile for effects on clinical decline and brain atrophy at the 8 mg/day dose in bvFTD as recently reported in AD. Treatment responses in bvFTD are predicted to be maximal at doses in the range 20 – 60 mg/day. A confirmatory placebo-controlled trial is now planned.

AB - Background: Hydromethylthionine is a potent inhibitor of pathological aggregation of Tau and TDP-43 proteins.Objective: To compare hydromethylthionine treatment effects at two doses and to determine how drug exposure is related to treatment response in bvFTD.Methods: We undertook a 52-week Phase 3 study in 220 bvFTD patients randomised to compare hydromethylthionine at 200 mg/day and 8 mg/day (intended as a control). The principal outcomes were change on the Addenbrookes Cognitive Examination – Revised (ACE-R), the Functional Activities Questionnaire (FAQ) and whole brain volume. Secondary outcomes included Modified Clinical Global Impression of Change (Modified-CGIC). A population pharmacokinetic exposure-response analysis was undertaken in 176 of the patients with available blood samples and outcome data using a discriminatory plasma assay for the parent drug.Results: There were no significant differences between the two doses as randomised. There were steep concentration-response relationships for plasma levels in the range 0.3 – 0.6 ng/ml at the 8 mg/day dose on clinical and MRI outcomes. There were significant exposure dependent differences at 8 mg/day for FAQ, Modified-CGIC and whole brain atrophy comparing patients with plasma levels greater than 0.346 ng/ml with having minimal drug exposure. The exposure-response is biphasic with worse outcomes at the high concentrations produced by 200 mg/day.Conclusions: Hydromethylthionine has a similar concentration-response profile for effects on clinical decline and brain atrophy at the 8 mg/day dose in bvFTD as recently reported in AD. Treatment responses in bvFTD are predicted to be maximal at doses in the range 20 – 60 mg/day. A confirmatory placebo-controlled trial is now planned.

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KW - Leucomethylthioninium

KW - Behavioural variant frontotemporal dementia

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KW - Tau protein

KW - TDP-43

KW - leucomethylthioninium

KW - hydromethylthionine

KW - Behavioral variant frontotemporal dementia

KW - clinical trials

KW - tau protein

KW - METHYLENE-BLUE

KW - LOBAR DEGENERATION

KW - ALZHEIMERS-DISEASE

KW - SEROTONIN TOXICITY

KW - PICK BODIES

KW - AGGREGATION INHIBITOR THERAPY

KW - DOUBLE-BLIND

KW - TAU-AGGREGATION

KW - DIAGNOSTIC-CRITERIA

KW - PROGRESSION

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Concentration-Dependent Activity of Hydromethylthionine on Clinical Decline and Brain Atrophy in a Randomized Controlled Trial in Behavioral Variant Frontotemporal Dementia

Abstract

Bibliographical note

Keywords

UN SDGs

Access to Document

Other files and links

Fingerprint

Charles Harrington

Gernot Riedel

Discovery and development of a new drug for the treatment of dementia

Cite this

Concentration-Dependent Activity of Hydromethylthionine on Clinical Decline and Brain Atrophy in a Randomized Controlled Trial in Behavioral Variant Frontotemporal Dementia

Abstract

Bibliographical note

Keywords

UN SDGs

Access to Document

Other files and links

Fingerprint

Profiles

Charles Harrington

Gernot Riedel

Impacts

Discovery and development of a new drug for the treatment of dementia

Cite this