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 III study in 220 bvFTD patients randomized 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 175 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 randomized. 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.

• Authors: 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
• Journal: Journal of Alzheimer's disease : JAD (J Alzheimers Dis) Vol. 75 Issue 2 Pg. 501-519 ( 2020) ISSN: 1875-8908 [Electronic] Netherlands
• PMID: 32280089 (Publication Type: Clinical Trial, Phase III, Journal Article, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)

Chemical References

• hydromethylthionine
• Methylene Blue

Topics

• Adult
• Aged
• Atrophy (diagnostic imaging, drug therapy, pathology)
• Brain (diagnostic imaging, drug effects, pathology)
• Disease Progression
• Dose-Response Relationship, Drug
• Double-Blind Method
• Female
• Frontotemporal Dementia (diagnostic imaging, drug therapy, pathology)
• Humans
• Magnetic Resonance Imaging
• Male
• Methylene Blue (analogs & derivatives, pharmacology, therapeutic use)
• Middle Aged
• Treatment Outcome