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First Evidence of Potential Efficacy of Tau Aggregation Inhibitor Therapy in Alzheimer's Disease

Product could be on the market by 2017

The Journal of Alzheimer’s Disease has published the results of the first clinical trial of a tau aggregation inhibitor in patients with Alzheimer’s disease (AD).

The phase II, double-blind, dose-finding study involved 321 patients at centers in the United Kingdom and Singapore, and tested three doses of the drug. The study met its predefined primary efficacy endpoint at 24 weeks on the Alzheimer’s Disease Assessment Scale – Cognitive Subscale (ADAS-cog), the tool most commonly used to measure cognitive decline in clinical trials, at a dosage of 138 mg/day. The effect sizes were statistically significant and clinically meaningful in subjects with moderate AD at 24 weeks. The clinical results were also supported by brain-scan evidence of the arrest of decline over the same period in subjects with mild AD at the same dosage. The treatment’s beneficial effect was sustained to 50 weeks in both mild and moderate AD at this dosage, with a 90% overall reduction in the rate of cognitive decline.

According to the drug’s developer (TauRx Therapeutics), this is the first clinical trial that attempted to target directly the hallmark neurofibrillary tangle pathology of AD. Tangles were originally discovered by Alois Alzheimer in 1906, and his discovery gave the disease its name. In 1988, Professor Clause Wiscik and his colleagues in Cambridge, U.K., found that tangles were composed of abnormal filaments largely made up of a short fragment of the tau protein.

The spread and density of tangles in the brain are known to be highly correlated with the clinical severity of dementia. They are also correlated with the extent of abnormal aggregation of tau proteins and with the loss of neuronal function seen on brain scans in those brain regions where tangles typically form.

Wiscik and his colleagues went on to report in 1996 that the chemical substance methylthioninium (MT), used in medicine for the last 100 years, dissolves tangle filaments isolated from the human brain by selectively blocking a critical step in the process required to form the rogue filaments.

The encouraging efficacy signals seen in the new phase II study at the minimum effective dosage of 138 mg/day were first announced in a preliminary form at the Alzheimer’s Association International Conference on Alzheimer’s Disease in Chicago, Illinois, in July 2008. However, the surprising observation that the top dosage of 228 mg/day had reduced efficacy took scientists an additional 4 years to unravel. The results of these studies were reported in the Journal of Pharmacology and Experimental Therapeutics.

The form of MT that has been used in medicine for the last century (a chloride salt of the oxidized MT+ form of the molecule, commonly known as MTC or “methylene blue”) is poorly tolerated without food, so taking it with food has been recommended traditionally. However, scientists discovered that MTC shows dose-dependent impairment in absorption when taken with food. This is because the oxidized MT+ form needs to be actively converted to the reduced form leucomethylthioninium (LMT) in the gut before it can be absorbed as LMT. In other words, MTC is a pro-drug for LMT, and food interferes with the conversion and absorption process.

Since MTC was given with food in the phase II trial to maximize tolerability for patients, only 109 mg/day of the intended 228-mg dose was available for absorption. Therefore, the minimum effective dosage of 138 mg/day identified in the study was the highest available dose tested.

To proceed with phase III testing, scientists at TauRx Therapeutics have developed a new form of the molecule, termed LMTX, which keeps MT in the LMT form, thereby allowing it to be absorbed directly without the need for active conversion in the gut. This has enabled phase III trials to test whether even greater efficacy can be achieved without significant loss of tolerability and safety. The ongoing studies are testing MT delivered as LMTX in the dosage range of 150 to 250 mg/day.

If phase III clinical trials confirm a level of efficacy and safety similar to that seen in the recent phase II study, a treatment targeting the tau aggregation pathology of AD could be on the market as early as 2017, TauRx predicts.

Source: TauRx Therapeutics; January 20, 2015.

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