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.

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

“…Hydromethylthionine therefore has pharmacological activity on brain structure and function in the majority of AD patients at this dose. We also found that there is a predicted plateau in response at theoretical doses above 16 mg/day, consistent with the lack of dose-response at much higher doses in AD [49].…”

“…As in two similarly designed trials in AD [44,45], there were no significant differences between these two doses on any efficacy outcome. In AD, we have reported recently that there are steep concentration-response relationships on cognitive and MRI outcomes for steady state plasma levels in the range 0.3-0.8 ng/ml at the 8 mg/day dose, and that plasma concentrations in the range 4-21 ng/ml produced by doses in the range 150-250 mg/day are not associated with any additional benefit [49]. We now report a similar exposure-response profile in bvFTD.…”

“…We now report that, as in AD, there was no overall difference on any endpoint between these two doses in bvFTD. We also report the results of the embedded population PK analysis of clinical and MRI biomarker outcomes similar to that recently reported in AD [49], to determine how drug exposure is related to treatment response in bvFTD.…”

“…5). Using data from the combined AD and bvFTD populations, we have reported previously that a dose of 16 mg/day would be sufficient to ensure that all patients have plasma levels above the threshold required for pharmacological activity [49]. However, the Hill equation analyses suggests that pharmaco-logical activity is predicted to peak in the vicinity of a 30 mg/day dose ( Fig.…”

“…We have developed a sensitive assay which can measure parent drug levels in plasma and which has been found to be reliable and accurate in preclinical and Phase I studies. Using this assay in a population pharmacokinetic (PK) study in 1,162 patients participating in the AD trials, we recently reported [49] that there is a steep concentration-response relationship on all clinical and brain magnetic resonance imaging (MRI) outcomes in patients receiving the 8 mg/day dose. Hydromethylthionine therefore has pharmacological activity on brain structure and function in the majority of AD patients at this dose.…”