Phase 2

TauRx evaluated its first-generation tau aggregation inhibitor (TAI), rember®, in a large, double-blind, long-duration, Phase 2 clinical trial in 321 patients with mild or moderate Alzheimer’s disease. The purpose of the study was to identify the minimum effective dose for treatment of Alzheimer’s disease. The study met its primary prespecified efficacy endpoint at a dose of 138 mg/day and provided the first clinical indication that treatment with TAIs holds promise in modifying the progression of the disease.

In this study, rember® showed statistically significant benefit relative to placebo at 26 weeks on the primary psychometric scale (ADAS-cog), and showed an 80% reduction in the rate of clinical decline over 50 weeks relative to controls, with benefit sustained over 2 years in patients continuing with treatment at the 138 mg/day dose.

Functional neuroimaging results from the trial supported the psychometric data: in patients taking rember®, the loss of function in the areas of the brain known to be particularly affected by the tau tangle pathology of disease was eliminated over 6 months in patients taking the 138 mg/day dose. Functional brain scan benefits seen at 6 months were predictive of clinical benefit at 12 months.

Phase 2 Results Lead to Second-Generation TAI Development

The Phase 2 study, and subsequent Phase 1 studies, also showed that there are limitations in the absorption of the active component of rember® (methylthioninium, MT) given in combination with food. The charged form of methylthioninium (MT+) present in rember® (as methylthioninium chloride, MTC) must be converted to the uncharged leuco-MT form (LMT) in the stomach to permit efficient absorption and distribution to the brain. This conversion is limited at doses higher than 138 mg/day when MTC is taken with food, which is needed to improve tolerability.

This finding led to the development of TauRx’s second-generation TAI, which is a stable, reduced form that permits direct absorption of LMT without need for the conversion step. It has also been found recently that LMT is the active form of the drug at the tau aggregation site, and so a lower dose is needed for efficacy. In Phase 1 studies, our second-generation TAI was found to be well tolerated at much higher doses than rember®.


Wischik CM, Staff RT, Wischik DJ, et al. (2015) Tau aggregation inhibitor therapy: an exploratory phase 2 study in mild or moderate Alzheimer's disease. J Alzheimers Dis 44(2):705-20.

Baddeley TC, McCaffrey J, Storey JMD, et al. (2015) Complex disposition of methylthioninium redox forms determines efficacy in tau aggregation inhibitor therapy for Alzheimer’s disease. J Pharmacol Exp Ther 352:1-9.

Al-Hilaly YK, Pollack SJ, Rickard JE et al., (2018) Cysteine-independent inhibition of Alzheimer’s disease-like paired helical filament assembly by leuco-methylthioninium (LMT) J. Molec. Biol.

Phase 2 Imaging Studies - Imaging Reveals Brain Regions Protected by TAIs

Molecular imaging (SPECT/PET) provided a key result in the Phase 2 rember® clinical trial by identifying regions within the brain that were protected by the drug. These regions coincided with areas known to be affected by Alzheimer’s neuropathology and provide significant support for the use of TAIs to treat the disease.

TauRx Clinical Phase 2 Imaging.

In the images above, created using rCBF SPECT, the central figure demonstrates the locations of tau pathology in Alzheimer’s. The surrounding images show the locations that rember® appears to protect. The areas are the statistically significant regions of difference between the active and control groups.


Wischik CM, Staff RT, Wischik DJ, et al. (2015) Tau aggregation inhibitor therapy: an exploratory phase 2 study in mild or moderate Alzheimer's disease. J Alzheimers Dis 44(2):705-20.

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