Concentration-Dependent Activity of Hydromethylthionine on Cognitive Decline and Brain Atrophy in Mild to Moderate Alzheimer’s Disease

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

doi:10.3233/jad-190772

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Concentration-Dependent Activity of Hydromethylthionine on Cognitive Decline and Brain Atrophy in Mild to Moderate Alzheimer’s Disease

Bjoern O. Schelter, Helen Shiells, Thomas C. Baddeley, Christopher M. Rubino, Harish Ganesan, Jeffrey Hammel, Vesna Vuksanovic

, Roger T. Staff, Alison D. Murray, Luc Bracoud, Gernot Riedel, Serge Gauthier, Jianping Jia, Peter Bentham, Karin Kook, John M.D. Storey, Charles R. Harrington, Claude M. Wischik

Journal of Alzheimer's Disease, Volume: 72, Issue: 3, Pages: 931 - 946

Swansea University Author: Vesna Vuksanovic

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DOI (Published version): 10.3233/jad-190772

Abstract

Background:Although hydromethylthionine is a potent tau aggregation inhibitor, no difference was found in either of two Phase III trials in mild to moderate Alzheimer’s disease (AD) comparing doses in the range 150–250 mg/day with 8 mg/day intended as a control.Objective:To determine how drug exposu...

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Published in:	Journal of Alzheimer's Disease
ISSN:	1387-2877 1875-8908
Published:	IOS Press 2019
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URI:	https://cronfa.swan.ac.uk/Record/cronfa60500
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Using a threshold based on the lower limit of quantitation of the assay on Day 1, there are highly significant differences in cognitive decline and brain atrophy in patients with above threshold plasma levels, both for monotherapy and add-on therapy, but with effect sizes reduced by half as add-on. Plasma concentrations in the range 4–21 ng/ml produced by the high doses are not associated with any additional benefit.Conclusions:Hydromethylthionine has pharmacological activity on brain structure and function at the 8 mg/day dose as monotherapy or as add-on to symptomatic treatments. This combined with a plateau at higher doses is consistent with the lack of dose-response seen in the Phase III trials. Treatment benefit is predicted to be maximal at 16 mg/day as monotherapy. 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spelling	2022-07-21T14:19:28.4616275 v2 60500 2022-07-14 Concentration-Dependent Activity of Hydromethylthionine on Cognitive Decline and Brain Atrophy in Mild to Moderate Alzheimer’s Disease a1a6e2bd0b6ee99f648abb6201dea474 0000-0003-4655-698X Vesna Vuksanovic Vesna Vuksanovic true false 2022-07-14 HDAT Background:Although hydromethylthionine is a potent tau aggregation inhibitor, no difference was found in either of two Phase III trials in mild to moderate Alzheimer’s disease (AD) comparing doses in the range 150–250 mg/day with 8 mg/day intended as a control.Objective:To determine how drug exposure is related to treatment response.Methods:A sensitive plasma assay for the drug was used in a population pharmacokinetic analysis of samples from 1,162 of the 1,686 patients who participated in either of the Phase III trials with available samples and efficacy outcome data.Results:There are steep concentration-response relationships for steady state plasma levels in the range 0.3–0.8 ng/ml at the 8 mg/day dose. Using a threshold based on the lower limit of quantitation of the assay on Day 1, there are highly significant differences in cognitive decline and brain atrophy in patients with above threshold plasma levels, both for monotherapy and add-on therapy, but with effect sizes reduced by half as add-on. Plasma concentrations in the range 4–21 ng/ml produced by the high doses are not associated with any additional benefit.Conclusions:Hydromethylthionine has pharmacological activity on brain structure and function at the 8 mg/day dose as monotherapy or as add-on to symptomatic treatments. This combined with a plateau at higher doses is consistent with the lack of dose-response seen in the Phase III trials. Treatment benefit is predicted to be maximal at 16 mg/day as monotherapy. A placebo-controlled trial in mild/moderate AD is now ongoing to confirm efficacy at this dose. Journal Article Journal of Alzheimer's Disease 72 3 931 946 IOS Press 1387-2877 1875-8908 Acetylcholinesterase inhibitor, Alzheimer’s disease, clinical trials, drug interaction, leucomethylthioninium, population pharmacokinetics, hydromethylthionine 26 11 2019 2019-11-26 10.3233/jad-190772 COLLEGE NANME Health Data Science COLLEGE CODE HDAT Swansea University 2022-07-21T14:19:28.4616275 2022-07-14T10:29:53.5246961 Faculty of Medicine, Health and Life Sciences Swansea University Medical School - Medicine Bjoern O. Schelter 1 Helen Shiells 2 Thomas C. Baddeley 3 Christopher M. Rubino 4 Harish Ganesan 5 Jeffrey Hammel 6 Vesna Vuksanovic 0000-0003-4655-698X 7 Roger T. Staff 8 Alison D. Murray 9 Luc Bracoud 10 Gernot Riedel 11 Serge Gauthier 12 Jianping Jia 13 Peter Bentham 14 Karin Kook 15 John M.D. Storey 16 Charles R. Harrington 17 Claude M. Wischik 18 60500__24688__6402ee34bd9e4be1981a4aa2425d0b8d.pdf 60500_VoR.pdf 2022-07-21T14:18:20.6693375 Output 762527 application/pdf Version of Record true This article is published online with Open Access and distributed under the terms of the Creative Commons Attribution License (CC-BY 4.0). true eng https://creativecommons.org/licenses/by/4.0/
title	Concentration-Dependent Activity of Hydromethylthionine on Cognitive Decline and Brain Atrophy in Mild to Moderate Alzheimer’s Disease
spellingShingle	Concentration-Dependent Activity of Hydromethylthionine on Cognitive Decline and Brain Atrophy in Mild to Moderate Alzheimer’s Disease Vesna Vuksanovic
title_short	Concentration-Dependent Activity of Hydromethylthionine on Cognitive Decline and Brain Atrophy in Mild to Moderate Alzheimer’s Disease
title_full	Concentration-Dependent Activity of Hydromethylthionine on Cognitive Decline and Brain Atrophy in Mild to Moderate Alzheimer’s Disease
title_fullStr	Concentration-Dependent Activity of Hydromethylthionine on Cognitive Decline and Brain Atrophy in Mild to Moderate Alzheimer’s Disease
title_full_unstemmed	Concentration-Dependent Activity of Hydromethylthionine on Cognitive Decline and Brain Atrophy in Mild to Moderate Alzheimer’s Disease
title_sort	Concentration-Dependent Activity of Hydromethylthionine on Cognitive Decline and Brain Atrophy in Mild to Moderate Alzheimer’s Disease
author_id_str_mv	a1a6e2bd0b6ee99f648abb6201dea474
author_id_fullname_str_mv	a1a6e2bd0b6ee99f648abb6201dea474_***_Vesna Vuksanovic
author	Vesna Vuksanovic
author2	Bjoern O. Schelter Helen Shiells Thomas C. Baddeley Christopher M. Rubino Harish Ganesan Jeffrey Hammel Vesna Vuksanovic Roger T. Staff Alison D. Murray Luc Bracoud Gernot Riedel Serge Gauthier Jianping Jia Peter Bentham Karin Kook John M.D. Storey Charles R. Harrington Claude M. Wischik
format	Journal article
container_title	Journal of Alzheimer's Disease
container_volume	72
container_issue	3
container_start_page	931
publishDate	2019
institution	Swansea University
issn	1387-2877 1875-8908
doi_str_mv	10.3233/jad-190772
publisher	IOS Press
college_str	Faculty of Medicine, Health and Life Sciences
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hierarchy_top_id	facultyofmedicinehealthandlifesciences
hierarchy_top_title	Faculty of Medicine, Health and Life Sciences
hierarchy_parent_id	facultyofmedicinehealthandlifesciences
hierarchy_parent_title	Faculty of Medicine, Health and Life Sciences
department_str	Swansea University Medical School - Medicine{{{_:::_}}}Faculty of Medicine, Health and Life Sciences{{{_:::_}}}Swansea University Medical School - Medicine
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description	Background:Although hydromethylthionine is a potent tau aggregation inhibitor, no difference was found in either of two Phase III trials in mild to moderate Alzheimer’s disease (AD) comparing doses in the range 150–250 mg/day with 8 mg/day intended as a control.Objective:To determine how drug exposure is related to treatment response.Methods:A sensitive plasma assay for the drug was used in a population pharmacokinetic analysis of samples from 1,162 of the 1,686 patients who participated in either of the Phase III trials with available samples and efficacy outcome data.Results:There are steep concentration-response relationships for steady state plasma levels in the range 0.3–0.8 ng/ml at the 8 mg/day dose. Using a threshold based on the lower limit of quantitation of the assay on Day 1, there are highly significant differences in cognitive decline and brain atrophy in patients with above threshold plasma levels, both for monotherapy and add-on therapy, but with effect sizes reduced by half as add-on. Plasma concentrations in the range 4–21 ng/ml produced by the high doses are not associated with any additional benefit.Conclusions:Hydromethylthionine has pharmacological activity on brain structure and function at the 8 mg/day dose as monotherapy or as add-on to symptomatic treatments. This combined with a plateau at higher doses is consistent with the lack of dose-response seen in the Phase III trials. Treatment benefit is predicted to be maximal at 16 mg/day as monotherapy. A placebo-controlled trial in mild/moderate AD is now ongoing to confirm efficacy at this dose.
published_date	2019-11-26T04:18:39Z
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Concentration-Dependent Activity of Hydromethylthionine on Cognitive Decline and Brain Atrophy in Mild to Moderate Alzheimer’s Disease

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