Alzheimer’s disease is a degenerative and terminal brain disorder affecting millions of people around the world. During the course of the disease’s progress, lesions called plaques and tangles are built up in the brain. The tangles, aggregates of abnormal fibers of a protein called tau, were discovered by Alois Alzheimer in 1907. These aggregates form inside nerve cells in the brain, destroy neurons essential for memory and, at later stages of the disease, neurons in other parts of the brain.
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 and his team have found that tangles’ clumping is highly correlated with the progression of Alzheimer’s, while development of plaques (accumulations of the beta-amyloid protein), which has been the main focus of research so far, is more characteristic of normal aging and is poorly correlated with dementia. Therefore, the team has been working with methylthioninium chloride, a chemical that was unintentionally found by Wischik, to dissolve the tau protein fibers.
TauRx Therapeutics and the University of Aberdeen (UK) developed Rember – a novel form of the chemical- which is the first treatment specifically designed to target the tau tangles. They tested the drug in a phase 2 clinical trial involving 321 patients with mild and moderate Alzheimer’s disease who were given 30, 60, or 100mg doses of the drug or a placebo. There was no significant decline in mental function in patients treated with Rember either at one year or at their final assessment at 19 months. Brain scans at the beginning of the study and after 25 weeks indicate that the greatest effect of the treatment was in the memory-critical brain regions, where the density of Alzheimer tangles is often the greatest. The control group, on the other hand, showed a significant decline from the starting score in cognitive testing and on brain scans.
“We did an analysis of the effect size at 24 weeks and at 50 weeks compared to the average effect size of the current treatments and it was about two and a half times better,” noted Professor Wischik. He added that this is the first trial of an Alzheimer’s disease modifying drug which actually hit its primary pre-specified efficacy target, and that “this result now validates our pipeline capability for development of second and third generation disease modifying treatments in this space.”
If the larger, phase 3 trial planned to be initiated in 2009 confirms the phase 2 findings, the drug could be available by 2012. The researchers are also investigating whether the drug has a role in prevention of the disease in the first place. As tangles may destroy nerve cells in parts of the brain critical for memory in people in their fifties and upwards, the researchers are refining the Rember treatment with the ultimate goal of developing a product that is convenient for wide use by patients at the very earliest stages of the disease, long before they experience the first symptoms of Alzheimer’s. World Health Organization (WHO) figures indicate that there will be more than one billion people aged 65 and over by 2050, of whom we calculate about half will have tau tangles in their brains. “This makes it particularly important to develop new treatments to halt and prevent tangles forming in the brain” commented Professor Wischik.
Alzheimer’s experts are optimistic about the results. They say that by being the first realistic evidence that a new drug can improve cognition in people with Alzheimer’s by targeting the protein tangles that cause brain cell death; these results represent a major new development in the fight against dementia. However, they all agree that larger human trials were now needed.
TFOT recently covered another phase 2 pivotal trial of a potential treatment for Alzheimer’s disease. Although the mechanism of action in this drug, called Dimebon, is not fully known, it has achieved statistically significant improvements over placebo in cognitive and overall functions.
More information on Rember is available in this webpage of the University of Aberdeen.