A new pharmacokinetic population analysis of hydromethylthionine (TauRx, Aberdeen, Scotland) has been published in the Journal of Alzheimer's Disease. The study used plasma concentration data from 1,162 participants in previous clinical trials of hydromethylthionine for treatment of mild to moderate Alzheimer’s disease (AD). The study measured how blood levels of the drug relate to its effects on the brain.
Using a new assay, it was found that the effects of hydromethylthionine at the 8 mg/day dose were determined by the blood level, and that the majority of participants had high enough blood levels of the drug at this dose to produce meaningful reductions in cognitive decline and brain atrophy. The study authors concluded that a slightly higher dose of hydromethylthionine of 16 mg/day would ensure that all participants would have the blood levels needed to maximize the drug's activity, because its effects plateau at higher concentrations and doses. The pharmacokinetic profile they found, typical of many drugs, now explains why the pharmacologic effects of hydromethylthionine at the high doses tested in the trials were no better than those seen in participants with blood levels at the 8 mg/day dose.
The analysis also showed that although hydromethylthionine has a similar concentration-response profile in participants taking the drug as an add-on therapy to the routinely used symptomatic treatments in AD, the maximum effect in these participants was reduced by half. This finding supports the hypothesis that symptomatic drugs for this condition interfere with the disease-modifying treatment effects of hydromethylthionine. This hypothesis was initially proposed on the basis of the drug's phase 3 trial results.
"Since we already have a substantial database supporting the safety and tolerability of hydromethylthionine in clinical trials of patients with mild-to-moderate AD, the additional results of this analysis have given us the confidence to expand the scope of the new TauRx Lucidity clinical trial to confirm the potential efficacy of the hydromethylthionine 16 mg/day dose in these types of patients," said professor Claude Wischik, of Aberdeen University and executive chairman of TauRx Therapeutics.
"In addition to the reduction in brain atrophy, we were surprised to see the large cognitive effects of treatment in the patient group with the higher blood levels of hydromethylthionine at the 8 mg daily dose," he added. "According to scores from the Alzheimer's Disease Assessment Scale–cognitive subscale (ADAS-Cog) scale, the effect was around 7.5 points, or 3 times that seen from current routine AD treatments, and would be equivalent to an 85% reduction in cognitive decline over 65 weeks."
Hydromethylthionine blocks abnormal aggregation of tau. In phase 3 clinical trials conducted in almost 1,700 participants with mild-to-moderate AD between 2012 and 2016, hydromethylthionine was tested at doses of 150 to 250 mg/day against a low dose of 8 mg/day, which was intended only as a control to mask the discoloration of urine that can sometimes occur with the drug. The study designs were based on the findings from an earlier trial that used a different variant of the drug.
Chen Zhao, MD; Claire Flaherty, PhD; Paul J. Eslinger, PhD; and Krishnankutty Sathian, MBBS, PhD
Stephen M. Gollomp, MD, and Paul G. Mathew, MD, DNBPAS, FAAN, FAHS
Brad Klein, MD, MBA, FAAN, FAHS, FAANEM, and Raissa Villanueva MD, MPH, FAAN