In July 2008, results from several clinical trials of novel Alzheimer’s Disease treatments were presented at the Alzheimer’s Association International Conference on Alzheimer’s Disease (ICAD 2008) in Chicago. Among these results was an 84-week phase II trial of TauRx’s Rember. Almost immediately, the mainstream media was reporting the most critical breakthrough in the history of Alzheimer’s Disease. This enthusiasm may be premature, however, and more research is needed on this new treatment option.

Methylthioninium chloride, marketed as Rember, is more commonly recognized as methylene blue. It is a chemical compound that has been around for generations and is used most commonly as a chemical indicator in laboratory experiments. However, it is also used to treat urinary tract infections, make inks, dye blue jeans, and even add color to blueberry pies. In the current trial, researchers found that methylene blue targets and dissolves tau protein aggregates in nerve cells of Alzheimer’s patients. These tau “tangles” were discovered by Alois Alzheimer over 100 years ago and are a hallmark of what we now call Alzheimer’s Disease. These tangles are present in the brain long before any symptoms are clinically apparent, but are highly correlated with increasing dementia. Tau tangles first destroy nerve cells responsible for memory and later destroy neurons in other areas of the brain as the disease progresses. Methylene blue is able to dissolve these tau tangles and has produced cognitive and behavioral benefits in animal studies.

Rember is a product of TauRx Therapeutics Ltd, a Singapore-based company aimed at developing treatments for neurodegenerative conditions. TauRx’s cofounder, Claude Wischik, a professor at the University of Aberdeen in Scotland, is the lead researcher for Rember’s clinical trials. He conducted a 24-week randomized, double-blind, placebo-controlled trial of Rember in 321 Alzheimer’s patients throughout the United Kingdom and Singapore. This was followed by a 60-week blinded trial extension. He reported that treatment with 60 mg of Rember three times daily produced significantly less cognitive decline that treatment with placebo.

Patients receiving 30 mg of Rember three times daily did not experience the same pronounced effects, and patients receiving 100 mg three times daily did not receive any benefit, but did experience gastrointestinal side effects. At the end of 19 months, patients receiving Rember did not experience significant decline in mental function. These data suggest that Rember may be twice as effective as current treatment options that are available, most of which target symptoms of Alzheimer’s disease, but cannot alter the disease progression.

Rember is the first Alzheimer’s drug that targets tau protein. Most research is currently focused on destroying amyloid plaques present in the brains of Alzheimer’s patients. These plaques are caused by a buildup of waste protein in the brain and are not as highly correlated with dementia as tau tangles, but may be more related to normal aging processes. If Rember is able to not only dissolve already-formed tau tangles but also prevent the formation of new ones, it could also be a key to Alzheimer’s Disease prevention.

Researchers and practitioners agree that the new data produced by Rember is impressive, but there are several limitations to the results. First, the research was conducted and presented by the pharmaceutical company’s cofounder and current chair. Second, and perhaps foremost, is that fact that no data has yet been published regarding the new findings. Dr. Wischik reportedly plans to publish 3 papers, but will not do so until the United States FDA gives its approval for TauRx to conduct a phase III trial of Rember. TauRx hopes to begin a phase III trial with more than 1000 participants in 2009. TauRx hopes that Rember will be on the market by 2012. Phase II trials are designed to examine dosing and toxicity. Phase III trials are designed to examine efficacy. Until large-scale phase III trials are conducted, and the findings are published in a peer-reviewed journal, the data is preliminary at best.

The Alzheimer’s Association estimates that the number of people living with Alzheimer’s disease will exceed 100 million by 2050, translating to 1 out of every 85 people worldwide. New research focused on modifying the course of Alzheimer’s Disease is exciting and deserves attention, but we will have to wait and see whether or not Rember is the magic bullet that it claims to be.

References

Atamna, H., Nguyen, A., Schultz, C., Boyle, K., Newberry, J., Kato, H., Ames, B.N. (2007). Methylene blue delays cellular senescence and enhances key mitochondrial biochemical pathways. The FASEB Journal, 22(3), 703-712. DOI: 10.1096/fj.07-9610com

Wischik, C.M. (1996). Selective inhibition of Alzheimer disease-like tau aggregation by phenothiazines. Proceedings of the National Academy of Sciences, 93(20), 11213-11218. DOI: 10.1073/pnas.93.20.11213