Alzheimer's drug development

Behind the Headlines

Wednesday July 30 2008

Professor Claude Wischik with Dr Dave Horsley

Professor Claude Wischik with Dr Dave Horsley. Courtesy of the University of Aberdeen.

Extensive news coverage has been given to a new Alzheimer’s treatment which has been hailed as a “major break through”. The Daily Mail quoted it as being the “biggest breakthrough against disease for 100 years” while The Daily Telegraph called it a “drug that could bring the brain back to life”. The newspapers said that the drug – Rember – can slow the progression of the disease by as much as 81%, making it more than twice as effective as other treatments.

The news stories are based on a presentation at this year’s International Conference on Alzheimer’s Disease in Chicago. As reported in the news, the results are from early trials of Rember, claimed to be the first drug that acts on tau protein – a protein found in the characteristic brain tangles of Alzheimer’s. These phase II trials have given some indication of the drug’s actions and safety. While encouraging, the results from larger phase III trials are required to get a clearer picture of its benefits in a larger population for a longer period of time.

Where did the story come from?

The study was presented at the International Conference on Alzheimer’s Disease (ICAD) 2008, which was held this month in Chicago, Illinois. This appraisal is based on a press release from the ICAD conference, and one from the University of Aberdeen. The research was led 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. It was carried out by teams from the University of Aberdeen and TauRx Therapeutics, a company based in Singapore.


What kind of scientific study was this?

The study that the newspapers reported on was a phase II trial of methylthioninium chloride (MTC). The brand name of the drug is Rember. The press release said that this was a double-blind, randomised, dose-ranging, parallel design trial of MTC monotherapy. The aim of the trial was to investigate the effects of the drug at different doses compared to a placebo, and to look at the drug’s potential at altering the development of Alzheimer's over a 19-month period. Rember is a tau aggregation inhibitor therapy which targets the neurofibrillary tangles that develop in Alzheimer’s.


Alzheimer’s is an increasingly common condition of unknown cause in which there is characteristic memory loss in addition to problems with speech and language, difficulty in planning and carrying out normal tasks and activities of daily life, as well as problems with recognition of people or things. People are diagnosed with Alzheimer’s through their clinical history, an examination and suggestive neurological features on CT or MRI scans, and the absence of any identifiable medical cause. At present, it is only at autopsy that diagnosis can be made for certain, but neurological imaging is improving and enabling more accurate detection of the brain plaques and tangles that are hallmarks of the condition. Plaques are deposits of beta amyloid protein which accumulate around the nerve cells affecting brain communication.

Tau is the protein within nerve cells which has been found to accumulate and twist in Alzheimer’s, resulting in neurofibrillary tangles which affect the function of the cells. Rember has been demonstrated in the laboratory to dissolve the tau tangle filaments, and prevent their accumulation, and to improve cognition and behaviour in animal models.

In this 84-week trial, 321 people with mild-moderate Alzheimer’s disease from 17 centres across the UK and Singapore were randomly allocated to orally receive Rember (in either a 30, 60, or 100mg dose) or a placebo, three times a day for 24 weeks. After this period, the patients could continue to receive blinded treatment for a further 60 weeks. The researchers examined the effect on cognitive function, using a validated scale. Changes in the brain were examined using brain scans taken at the beginning of the trial, and after 24 weeks and up to 60 weeks later.

What were the results of the study?

Rember at the 60mg dose significantly improved cognition in people compared to the placebo. The effect at 50 weeks was greater than that seen at 24 weeks, which the researchers say suggests an improvement in the rate of cognitive decline. Analyses confirmed that cognitive decline was slowed by a rate of 81% over a year with the drug.

Rember was also seen on brain imaging to reduce the decline in blood flow in certain areas of the brain which are first and most severely affected by tau aggregates (the hippocampus and the entorhinal cortex), also indicating that the drug may stabilise progression of the disease. By 84 weeks, the participants who remained on the 60mg dose of Rember still had not experienced significant cognitive decline, while those in the other study groups had. It was not clear from the press release whether this included those on other doses of Rember.

What interpretations did the researchers draw from these results?

Professor Claude Wischik of the University of Aberdeen, who led the Rember trial and is chairman of the company that developed the drug and funded the trial said in the press release: “This is the first instance of disease-modifying Alzheimer’s therapy that has attained its primary, pre-specified cognitive efficacy target in clinical trial….We now need to confirm this in a larger phase III trial.”

Also in the press release, the chair of the Alzheimer’s Association’s Medical and Scientific Advisory Council, Dr Samuel Gandy, said that while treatments targeting amyloid are being pursued, other potential avenues of treatment must be investigated in order to help solve the growing burden of this highly prevalent condition. He said that while currently approved treatments may offer some symptomatic relief, they do not alter the underlying course of the disease. He went on to say it is hoped that disease-modifying treatments will be developed to prevent or slow the progression of brain cell death and loss of function, thereby preventing the development of Alzheimer’s in millions of people.

What does the NHS Knowledge Service make of this study?

The results reported in this press release are encouraging and demonstrate how treatments for Alzheimer’s are currently developing in many areas. Rember appears to show some promise. However, it must be pointed out that these are early trials, and further research is needed before it is possible to be sure about its efficacy and safety.

The press release announces that phase III trials are now being planned and should begin in 2009. These trials will give a clearer picture of the drug’s effectiveness and safety if they confirm this most recent study’s findings.

As the methods and results of the current study have not yet been fully published in a medical journal, it is not possible to comment on particular strengths or weaknesses that the study may have that would affect the interpretation of its results. The current situation is probably best summed up by the head of research for the Alzheimer’s Society Professor Clive Ballard, ‘… We are not there yet. Larger scale trials are now needed to confirm the safety of this drug and establish how far it could benefit the thousands of people living with this devastating disease.’

Sir Muir Gray adds...

Presentations at scientific meetings can be ignored, lets wait for publication of the report.

Analysis by Bazian

Edited by NHS Choices


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