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 3 study in 220 bvFTD patients randomised 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 176 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 randomised. 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.
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