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

Bjoern O. Schelter, Helen C. 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* (Corresponding Author)

*Corresponding author for this work

Research output: Contribution to journalArticle

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 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.
Original languageEnglish
Pages (from-to)931-946
Number of pages16
JournalJournal of Alzheimer's Disease
Volume72
Issue number3
Early online date21 Oct 2019
DOIs
Publication statusPublished - 26 Nov 2019

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Atrophy
Alzheimer Disease
Brain
Therapeutics
Pharmaceutical Preparations
Pharmacokinetics
Placebos
Pharmacology
Cognitive Dysfunction
Population

Keywords

  • Acetylcholinesterase inhibitor
  • Alzheimer’s disease
  • clinical trials
  • drug interaction
  • leucomethylthioninium
  • population pharmacokinetics
  • hydromethylthionine

Cite this

Concentration-Dependent Activity of Hydromethylthionine on Cognitive Decline and Brain Atrophy in Mild to Moderate Alzheimer’s Disease. / Schelter, Bjoern O.; Shiells, Helen C.; 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. (Corresponding Author).

In: Journal of Alzheimer's Disease, Vol. 72, No. 3, 26.11.2019, p. 931-946.

Research output: Contribution to journalArticle

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title = "Concentration-Dependent Activity of Hydromethylthionine on Cognitive Decline and Brain Atrophy in Mild to Moderate Alzheimer’s Disease",
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 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.",
keywords = "Acetylcholinesterase inhibitor, Alzheimer’s disease, clinical trials, drug interaction, leucomethylthioninium, population pharmacokinetics, hydromethylthionine",
author = "Schelter, {Bjoern O.} and Shiells, {Helen C.} 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 Gernot Riedel and Serge Gauthier and Jianping Jia and Peter Bentham and Karin Kook and Storey, {John M. D.} and Harrington, {Charles R.} and Wischik, {Claude M.}",
note = "ACKNOWLEDGMENTS We gratefully acknowledge study investigators and the generosity of study participants. We gratefully acknowledge Professor Gordon Wilcock for critical review and commentary on drafts of the manuscript. Author’s disclosures available online (https://www.j-alz.com/manuscript-disclosures/19-0772r1). SUPPLEMENTARY MATERIAL The supplementary material is available in the electronic version of this article: http://dx.doi.org/10.3233/JAD-190772. Availability of data and materials The datasets and analyses used during the current study are available from the corresponding author on reasonable request.",
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T1 - Concentration-Dependent Activity of Hydromethylthionine on Cognitive Decline and Brain Atrophy in Mild to Moderate Alzheimer’s Disease

AU - Schelter, Bjoern O.

AU - Shiells, Helen C.

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 - Riedel, Gernot

AU - Gauthier, Serge

AU - Jia, Jianping

AU - Bentham, Peter

AU - Kook, Karin

AU - Storey, John M. D.

AU - Harrington, Charles R.

AU - Wischik, Claude M.

N1 - ACKNOWLEDGMENTS We gratefully acknowledge study investigators and the generosity of study participants. We gratefully acknowledge Professor Gordon Wilcock for critical review and commentary on drafts of the manuscript. Author’s disclosures available online (https://www.j-alz.com/manuscript-disclosures/19-0772r1). SUPPLEMENTARY MATERIAL The supplementary material is available in the electronic version of this article: http://dx.doi.org/10.3233/JAD-190772. Availability of data and materials The datasets and analyses used during the current study are available from the corresponding author on reasonable request.

PY - 2019/11/26

Y1 - 2019/11/26

N2 - 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.

AB - 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.

KW - Acetylcholinesterase inhibitor

KW - Alzheimer’s disease

KW - clinical trials

KW - drug interaction

KW - leucomethylthioninium

KW - population pharmacokinetics

KW - hydromethylthionine

U2 - 10.3233/JAD-190772

DO - 10.3233/JAD-190772

M3 - Article

VL - 72

SP - 931

EP - 946

JO - Journal of Alzheimer's Disease

JF - Journal of Alzheimer's Disease

SN - 1387-2877

IS - 3

ER -