O3‐04–07: Tau aggregation inhibitor (TAI) therapy with rember™ arrests disease progression in mild and moderate Alzheimer's disease over 50 weeks

Neurofibrillary degeneration is correlated with clinical dementia. Methylthioninium chloride (MTC, rember) dissolves Tau polymers (Paired Helical Filaments) isolated from AD brain, and prevents Tau aggregation in cell models at the nanomolar range (0.15 – 0.58 μM). MTC has efficacy in Tau transgenic animal models, reversing cognitive and other behavioural defects, and reversing Tau pathology in the brain. An exploratory, dose-range finding, parallel design, double-blind, randomised, placebo-controlled trial of rember monotherapy was conducted in 332 subjects meeting DSM-IV and NINCDS-ADRDA for probable AD in UK and Singapore. The primary objective was to investigate the effects of oral MTC at 30, 60 and 100 mg three times per day, compared with placebo, on cognitive function (ADAS-cog) in patients with mild or moderate AD stratified by CDR. The 100mg dose was found to have a formulation defect limiting release of the therapeutic form of MTC. Secondary outcomes included MMSE, CDRsb, CGIC, ADFACS and NPI. Nested studies of SPECT- and PET-scan outcomes at 6 months are reported separately. In the prespecified analysis at 24 weeks, rember produced a significant improvement relative to placebo of -5.4 ADAS-cog units in CDR-moderate subjects at the 60mg dose. There was no placebo decline in CDR-mild AD over the first 24 weeks preventing initial efficacy analysis, although efficacy was demonstrated in mild AD by the SPECT-scan outcomes. rember stabilised the progression of AD over 50 weeks in both mild and moderate AD. The overall effect size was -6.8 ADAS-cog units vs. decline if 7.8 units in the placebo/comparator arm, with significant efficacy demonstrated separately in mild and moderate subgroups. rember efficacy was confirmed on all secondary outcomes. The rember efficacy analysis met new EMEA guidelines for disease-modifying therapy by slope analysis and two-time-point analysis, supported by SPECT and PET evidence of efficacy in brain regions strongly affected by Tau pathology. This represents the first evidence that TAI monotherapy with rember is a viable disease-modifying treatment for mild and moderate AD which may also have preventative application at preclinical Braak stages of AD.