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

TitleConcentration-Dependent Activity of Hydromethylthionine on Clinical Decline and Brain Atrophy in a Randomized Controlled Trial in Behavioral Variant Frontotemporal Dementia.
Publication TypeJournal Article
Year of Publication2020
AuthorsShiells 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
JournalJ Alzheimers Dis
Volume75
Issue2
Pagination501-519
Date Published2020
ISSN1875-8908
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.

DOI10.3233/JAD-191173
Alternate JournalJ Alzheimers Dis
PubMed ID32280089
PubMed Central IDPMC7306898