Treatment to target tangles

TauRx demonstrates potential efficacy of tau aggregation inhibitor therapy in Alzheimer’s disease

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SINGAPORE—Tangles of neuronal fibers are correlated with abnormalities in brain scans of patients with Alzheimer’s disease (AD), but nobody has an approved treatment to target the tangles at the moment, according to Dr. Claude Wischik, co-founder of TauRx Therapeutics Ltd.
Part of the reason for that, he believes, is that a huge investment of money and people’s careers has gone into approaching AD with amyloid therapy. Clearly, that approach is not working. While current treatments for AD are only able to ease symptoms temporarily, tau-based vaccines may offer a new and more effective way to treat AD in the early course of the disease, says an analyst with research and consulting firm GlobalData. The market could be worth upwards of $10 billion.
“It takes an upstart biotech company like us to break the mold and show that a different approach is viable,” Wischik says.
TauRx Therapeutics is a spin-out company from the University of Aberdeen in Scotland, established in Singapore in 2002 to develop new treatments and diagnostics for a range of neurodegenerative diseases. The company’s tau aggregation inhibitor, LMTX, which is currently in global Phase 3 clinical trials for Alzheimer’s and frontotemporal dementia, targets aggregates of abnormal fibers of tau protein that form inside nerve cells in the brain, giving rise to tau tangles.
Recently, The Journal of Alzheimer’s Disease published the results of the first clinical trial of a Tau Aggregation Inhibitor (TAI) in AD. This Phase 2 clinical trial, conducted by TauRx, provided the basis and rationale for subsequent Phase 3 clinical trials of a TAI in AD currently in progress.
“We believe that we can arrest disease progression, hit the pause button and possibly even use the treatment preventatively,” explains Wischik. “It’s a completely different kind of treatment that acts on neurodegeneration.”
Tangles were originally discovered by Alois Alzheimer in 1906, and this discovery gave the disease its name. Tangles were found to be composed of abnormal filaments largely made up of a short fragment of the protein tau in 1988 by Wischik and his colleagues. Using Heiko Braak’s system for staging tangle pathology, the TauRx team has seen that the process of developing tangles begins in a person’s fifties or earlier, and spreads from one region of the brain to another. The progression of the disease goes through six stages with a decline in mental function.
The double-blind dose-finding Phase 2 clinical trial with the TAI, which involved 321 patients in 16 clinical research centers in the United Kingdom and one center in Singapore, tested three doses of the drug. The study met its predefined primary efficacy endpoint at 24 weeks on the standard scale most commonly used to measure cognitive decline in clinical trials (ADAS-cog) at the 138 mg/day dose. The primary result was also supported by benefit on two other clinical scales. The effect sizes seen were statistically significant and clinically meaningful in moderate subjects at 24 weeks. The clinical results were also supported by brain scan evidence of arrest of decline over the same period in mild subjects at the same dose. The beneficial effect was sustained to 50 weeks in both mild and moderate subjects at this dose, with 90-percent reduction in the rate of cognitive decline overall.
However, the surprising observation that the top dose of 228 mg/day had reduced efficacy has taken TauRx scientists four more years to unravel. They discovered that the original formulation suffers from dose-dependent impairment in absorption when taken with food and developed an entirely new form of the molecule that enables direct absorption without need for active conversion in the gut. It is better absorbed, better tolerated and has fewer side effects, according to Wischik, thus enabling Phase 3 trials to test whether an even higher level of efficacy can be achieved without significant loss of tolerability and safety. The ongoing trials are testing LMTX in the dosage range of 150 to 250 mg/day.
First results from the clinical trials are expected in the first half of 2016. If the Phase 3 clinical trials confirm a level of efficacy and safety similar to that seen in the Phase 2 trial reported in the Journal of Alzheimer’s Disease, a treatment targeting the Tau aggregation pathology of AD could be on the market as early as 2017.

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