The Phase 3 clinical trial program involving TauRx’s second-generation tau aggregation inhibitor, LMTX®, comprised two clinical trials (TRX-005 and TRX-015) in Alzheimer’s disease and a further trial (TRX-007) in behavioural variant frontotemporal dementia (bvFTD; neurodegenerative orphan indication). These three studies were completed in 2016. All three studies tested LMTX® at doses in the range 150 – 250 mg/day against a low dose of 8 mg/day as an intended control. This dosing was selected in light of the Phase 2 results with rember® and before the superior absorption and efficacy properties of LMTX® were fully understood.
Study TRx-015 was the first study to report and showed promising results on clinical and brain imaging endpoints at doses of 150 and 250 mg/day. Surprisingly, the low dose of 8 mg/day appeared to show the same benefit as the higher doses. At all doses, the best results were seen in patients taking LMTX® as their only treatment (monotherapy) rather than in combination with the standard symptomatic treatments for Alzheimer’s disease (cholinesterase inhibitors and/or memantine). In light of these outcomes, the analysis plan for the still on-going Study TRx-005 was modified in order to focus on the monotherapy benefits of LMTX®. Study TRx-005 successfully met its modified primary prespecified outcomes and confirmed the results seen in Study TRx-015.
Recent work based on analysis of the blood levels of the drug in all the Phase 3 trial patients has uncovered highly significant concentration-response relationships on cognitive and brain imaging endpoints in patients taking the 8 mg/day dose as monotherapy or as add-on to standard symptomatic treatments for Alzheimer’s disease. The same concentration-response relationship has also been found for monotherapy in bvFTD. These results (which will be published in due course) have confirmed that 8 mg/day (taken as 4 mg twice daily) is the minimum effective dose for both diseases and that the best overall effects are seen for LMTX® as monotherapy. Ongoing studies in animals have identified likely mechanisms responsible for the negative interaction between LMTX® and symptomatic treatments in Alzheimer’s disease.
TauRx’s new clinical trial, named LUCIDITY, is currently underway. The trial uses FDG-PET imaging and a composite cognitive/functional clinical psychometric scale to confirm the efficacy of LMTX®. In this study LMTX® is given as a monotherapy at doses of 8 mg/day (taken as 4 mg twice daily), and a slightly higher dose of 16 mg/day (taken as 8 mg twice daily) is also being tested. Both doses are compared with placebo.
Gauthier S, Feldman H, Schneider L, et al. (2016) Efficacy and safety of tau-aggregation inhibitor therapy in patients with mild or moderate Alzheimer's disease: a randomised, controlled, double-blind, parallel-arm, Phase 3 trial. Lancet 388:2873-2884.
Wilcock G, Gauthier S, Frisoni G, et al. (2018) Potential of low dose leuco-methylthioninium bis(hydromethanesulphonate) (LMTM) monotherapy for treatment of mild Alzheimer’s disease: cohort analysis as modified primary analysis in a phase 3 clinical trial. J Alzheimers Dis. 61:435-57.