Tau Aggregation Inhibitor Therapy: An Exploratory Phase 2 Study in Mild or Moderate Alzheimer's Disease

Abstract

Abstract.Background: As tau aggregation pathology correlates with clinical dementia in Alzheimer's disease (AD), a tau aggregation inhibitor (TAI) could have therapeutic utility. Methylthioninium (MT) acts as a selective TAI in vitro and reduces tau pathology in transgenic mouse models. Objective: To determine the minimum safe and effective dose of MT required to prevent disease progression on clinical and functional molecular imaging outcomes. Methods: An exploratory double-blind, randomized, placebo-controlled, dose-finding trial of MT (69, 138, and 228 mg/day) was conducted in 321 mild/moderate AD subjects. The primary outcome was change on the Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog) at 24 weeks relative to baseline severity. Effect of treatment on regional cerebral blood flow decline was determined in a sub-study in 135 subjects. After 24 weeks, subjects were re-consented to enter sequential 6-and 12-month blinded extension phases. Registered with ClinicalTrials.gov (NCT00515333). Results: At 24 weeks, there were significant treatment benefits in two independent populations at the 138 mg/day dose: in moderate subjects on the ADAS-cog scale (treatment effect: −5.42 units, corrected p = 0.047) and two other clinical scales; in mild subjects on the more sensitive regional cerebral blood flow measure (treatment effect: 1.97%, corrected p < 0.001). With continued treatment for 50 weeks, benefit was seen on the ADAS-cog scale in both mild and moderate subjects. The delivery of the highest dose was impaired due to dose-dependent dissolution and absorption limitations. Conclusion:The minimum safe and effective daily MT dose is 138 mg and suggests that further study of MT is warranted in AD.

Development of a core outcome set for disease modification trials in mild to moderate dementia: a systematic review, patient and public consultation and consensus recommendations

“…The majority of trials (n = 94) used at least one cognitive outcome, 25,27-29, 51,52,55,57,64,66,68,75,78,[86][87][88][89][90][91][92][93]97,104,106,107,110,112,115,118,119,121,123,125,126,130,131,133,134,[137][138][139][140]143,145,146 with a variety of 16 measures used. ADLs were measured in 55 trials, using 12 measures.…”

“…ADLs were measured in 55 trials, using 12 measures. 27,28,33,37,41,45,46,49,51,52,54,55,57,59,61,63,64,66,68,77,78,81,[85][86][87][88][89][90]92,97,104,[106][107][108][110][111][112]114,115,118,119,[121][122][123][124][125]128,134,135,137,138,[142][143][144][145] Biological markers were measured in 51 trials using a variety of nine biological t...…”

Exploratory study of sublimed sulfur, in cognitively normal subjects and in Alzheimer’s dementia (AD) subjects: implications for Sulfur targeting Hydrogen sulfide (H2S)/Homocysteine (Hcy) and beta-galactosidase (GALAC)/Autophagy Signaling in AD

“…Modulation of autophagy has entered to the main stage of AD drug development. Recently, the promising findings of the old compound, methylthioninium chloride (methylene blue) inhibits Tau aggregation through inducing autophagy [54,55]. At nanomolar concentrations, MB can reduce Tau levels in both organotype brain slices from the mouse model of frontal-temporal dementia (FTD).…”

Alzheimer’s Disease: Dawn of a New Era?

“…The purported action of both of these compounds is to act as tau aggregation inhibitors by not only inhibiting the formation of new oligomers, but more importantly to release soluble tau from oligomers and paired helical filaments in a monomeric form which is susceptible to proteases (97). In a large 12-month phase II study in 321 subjects, MTC was found to stabilize the progression of AD over 50 weeks in both mild and moderate AD (98). The more stable, reduced version of methylthioninium, LMTX, was tested in two parallel phase III studies in AD in 250 centers in 22 countries world-wide enrolling 891 patients with mild-to-moderate AD (NCT01689246) completed at the end of 2015 and in 800 patients with mild AD (NCT01689233) completed in June 2016.…”