The effect of latent confounding processes on the estimation of the strength of causal influences in chain-type networks

The authors acknowledge GTD TauRx Therapeutics centres for generous funding of this research.Peer reviewedPublisher PD

Long-term hydromethylthionine treatment is associated with delayed clinical onset and slowing of cerebral atrophy in a pre-symptomatic P301S MAPT mutation carrier

ACKNOWLEDGMENTS We thank the patient for permitting publication of the present report. Authors’ disclosures available online (https://www.j-alz.com/manuscript-disclosures/21-0390r1).Peer reviewedPublisher PD

Exploring the Anti-Hypoxaemia Effect of Hydromethylthionine : A Prospective Study of Phase 3 Clinical Trial Participants

Funding Information: This work was funded by TauRx Therapeutics Ltd., Singapore.Peer reviewedPublisher PD

Concentration-Dependent Activity of Hydromethylthionine on Cognitive Decline and Brain Atrophy in Mild to Moderate Alzheimer’s Disease

ACKNOWLEDGMENTS We gratefully acknowledge study investigators and the generosity of study participants. We gratefully acknowledge Professor Gordon Wilcock for critical review and commentary on drafts of the manuscript. Author’s disclosures available online (https://www.j-alz.com/manuscript-disclosures/19-0772r1). SUPPLEMENTARY MATERIAL The supplementary material is available in the electronic version of this article: http://dx.doi.org/10.3233/JAD-190772. Availability of data and materials The datasets and analyses used during the current study are available from the corresponding author on reasonable request.Peer reviewedPublisher PD

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

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