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.

SUBMITTER: Shiells H 

PROVIDER: S-EPMC7306898 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature