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

Article type: Short Communication

Authors: Wischik, Claude M.a; * | Staff, Roger T.b | Wischik, Damon J.c | Bentham, Peterd | Murray, Alison D.e | Storey, John M.D.f | Kook, Karin A.g | Harrington, Charles R.a

Affiliations: [a] School of Medicine and Dentistry, University of Aberdeen, Aberdeen, UK | [b] Aberdeen Royal Infirmary, NHS Grampian, Aberdeen, UK | [c] Computer Science Department, University College London, UK | [d] College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK | [e] Aberdeen Biomedical Imaging Centre, School of Medicine and Dentistry, University of Aberdeen, Aberdeen, UK | [f] Department of Chemistry, University of Aberdeen, Aberdeen, UK | [g] Salamandra LLC, Bethesda, Maryland, USA

Correspondence: [*] Correspondence to: Claude M. Wischik, MD, PhD, TauRx Therapeutics Ltd., Liberty Building, Foresterhill Road, Aberdeen AB25 2ZP, Scotland. Tel.: +44 1224 438550; Fax: +44 1224 555173; E-mail: [email protected].

Keywords: Alzheimer's disease, controlled clinical trial, intervention studies, methylthioninium, safety, tau protein

DOI: 10.3233/JAD-142874

Journal: Journal of Alzheimer's Disease, vol. 44, no. 2, pp. 705-720, 2015

Accepted 17 December 2014
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Published: 22 January 2015
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Supplementary Materials:

Supplementary Material.

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.

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