Jennifer Rose V. Molano, MD reviewing Gauthier S et al. Lancet 2016 Nov 15. Rafii MS. Lancet 2016 Nov 15.
A tau-aggregation inhibitor, leuco-methylthioninium bis(hydromethanesulfonate), did not provide treatment benefit in disease randomized trial.
Neurofibrillary tangles are associated with tau pathology in Alzheimer disease (AD). To investigate the safety and efficacy of leuco-methylthioninium bis(hydromethanesulfonate) (LMTM), an investigational selective tau-aggregation inhibitor, as a disease-modifying treatment for mild-to-moderate AD, researchers conducted an international, randomized, placebo-controlled, manufacturer-funded, phase III clinical trial . Primary outcomes included scores on the Alzheimer's Disease Assessment Scale–Cognitive Subscale (ADAS-Cog) and the Alzheimer's Disease Co-operative Study–Activities of Daily Living Inventory (ADCS-ADL) scales. Secondary outcomes included lateral ventricular volume, global impression of change, and Mini-Mental State Examination (MMSE) scores.
Participants were randomized to 75 mg LMTM (n=268), 125 mg LMTM (n=266), or the control dose of 4 mg LMTM (n=357) twice a day for up to 65 weeks. More than 80% of the participants were taking acetylcholinesterase inhibitors, memantine, or both at stable doses for at least 18 weeks. At baseline, study group mean values were age 70.6 years, ADAS-Cog score 26.9, ADCS-ADL score 57.0, lateral ventricular volume 52 cm3, and MMSE score 18.6. ADAS-Cog worsened by six points and ADCS-ADL scores worsened by eight points from baseline to week 65 in the control group. In both the 75-mg and 125-mg groups, changes in ADAS-Cog and ADCS-ADL scores were not significantly different from those in controls. There were also no significant differences in secondary outcomes between the treatment groups and controls. The rate of disease progression was reduced in those taking LMTM as monotherapy but not as add-on therapy. The most common adverse effects were gastrointestinal and urinary symptoms.
CITATION(S):
Gauthier S et al. 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 2016 Nov 15; 388:2873.
Rafii MS.Targeting tau protein in Alzheimer's disease. Lancet 2016 Nov 15; 388:2842.
