Hopes that an alternative to the prevailing beta-amyloid theory of Alzheimer’s could spawn a genuinely disease-modifying therapy have been raised by the results of a Phase II trial with TauRx Therapeutics’ rember, a novel form of methylthioninium chloride (MTC) that targets the neurofibrillary tau tangles in the brain first discovered by Alois Alzheimer in 1907.

In the trial with 321 Alzheimer’s patients reported by scientists from TauRx Therapeutics and the UK’s University of Aberdeen at the Alzheimer’s Association International Conference on Alzheimer’s Disease (ICAD 2008) in Chicago, a 60mg dose of rember was shown to reduce the rate of cognitive decline by 81% over a 50-week period.

A final, 84-week analysis confirmed the long-term effect of the 60mg dose in those Alzheimer’s patients who remained on treatment, with “apparent decline still not significantly different from baseline at the final assessment, whereas there was significant decline at other doses”, the researchers noted, adding: “In essence, TAI [tau aggregation inhibitor] therapy appears to stabilise patients who remain on treatment for at least 19 months”.

The TauRx-Aberdeen University team plans to start a Phase III trial with rember sometime next year. If this confirms the Phase II findings, a new treatment for Alzheimer’s could be on the market by 2012, the researchers believe. At the same time, TauRx continues to work on refining rember, suggesting that restoration of cognitive function may be possible at least during the earlier stages of the disease with improved versions of the drug.

The lesions or tangles – toxic aggregates of abnormal tau protein fibres that form inside nerve cells in the brain – associated with dementia “are already destroying nerve cells in parts of the brain critical for memory in people in their fifties and upwards”, the researchers commented. “The ultimate goal is to develop a product that is convenient for patients that could be widely used at the very earliest stages of the disease, long before patients experience the first symptoms of Alzheimer’s.”

“Unprecedented result”

The demonstrated effects of rember on disease progression were hailed by Professor Claude Wischik, chairman of TauRx Therapeutics and Professor of Psychiatric Geratology and Old Age Psychiatry at the University of Aberdeen’s Institute of Medical Sciences, as “an unprecedented result in the treatment of Alzheimer’s disease”.

The primary objective of the Phase II study reported in Chicago was actually to investigate the effects of oral MTC versus placebo at doses of 30mg, 60mg and 100mg over 24 weeks on cognitive function in patients with mild or moderate Alzheimer’s, as measured by ADAS-cog (Alzheimer’s Disease Assessment Scale cognitive subscale).

The trial conducted at 16 centres in the UK and one in Singapore (where TauRx Therapeutics, a spin-off from Aberdeen University, has its headquarters), involved a 24-week, double-blind, randomised, placebo-controlled phase followed by a 60-week blinded active-treatment extension, in which the control arm received a minimal efficacy dose. In parallel, molecular brain scans (SPECT and PET) were taken from 100 of the mild Alzheimer’s disease (AD) patients after 18 and 24 weeks of treatment.

On the primary outcome measure, the researchers said, treatment with 60mg rember produced clinically relevant, significant benefit compared with the control group at 24 weeks in moderate AD patients (effect size: -5.5 ADAS-cog units; p = 0.0208) and at 50 weeks in both mild and moderate patients (effect size: -6.8 ADAS-cog units; p = < 0.0001). Initial efficacy analysis in mild AD patients over 24 weeks was confounded by the absence of any placebo decline in the control group during this period.

SPECT scan

In the SPECT brain scan, which measures neuronal function indirectly by assessing regional cerebral blood flow (rCBF), 60mg rember was found to alter the trajectory of rCBF decline over six months in mild Alzheimer’s. The efficacy of rember was most pronounced in those regions of the brain characterised by the most severe tau aggregation, namely the hippocampus and the entorhinal cortex.

This finding “raises the possibility that treatment targeting the tau aggregation cascade that underlies Alzheimer’s tangle may be an important component of the long-term management and prevention of Alzheimer’s disease”, the researchers stated.

The UK-based Alzheimer’s Society sounded a note of caution. While this “first modestly sized trial in humans is potentially exciting” and suggests that rember “could be over twice as effective as any treatment that is currently available”, larger-scale trials are needed to confirm the drug’s safety and “establish how far it could benefit the thousands of people living with this devastating disease”, commented director of research Professor Clive Ballard.

The active substance in rember, MTC, has a long history of clinical use in urinary tract infection and methaemoglobinaemia, a condition in which excessive haemoglobin in the blood is converted to methaemoglobin and can no longer deliver oxygen to body tissues.