Hydromethylthionine (TauRx Therapeutics Ltd), an experimental tau inhibitor in development for the treatment of Alzheimer disease (AD), also has significant pharmacologic activity in behavioral variant frontotemporal dementia (bvFTD).
Results of a phase 3 randomized trial showed even at the control dose of 8 mg/day, the drug produced significant concentration-dependent effects on clinical decline and brain atrophy for patients with bvFTD. The drug has also been found to benefit patients with mild to moderate AD at that dosage, as reported by Medscape Medical News.
At the 8 mg/day dose, "hydromethylthione reduced the rate of clinical decline and brain atrophy by almost half in patients with adequate blood levels of the drug compared to the patients who had minimal blood levels of the drug at the same dose," study investigator Claude Wischik, MD, PhD, who is also executive chairman of TauRx Therapeutics and professor of psychiatric gerontology at the University of Aberdeen, United Kingdom, told Medscape Medical News.
"The study showed that it should be possible to achieve even better results at the higher dose of 30 mg/day," Wischik said.
The research was published online May 19 in the Journal of Alzheimer's Disease.
Severely Debilitating, Rapidly Progressive
Although a rare disorder, bvFTD is the second most common cause of dementia in individuals younger than 65 years. The hallmarks of bvFTD are personality changes, apathy, and a progressive decline in socially appropriate behavior, judgment, self-control, and empathy.
Patients with bvFTD often do not recognize the changes in their own behavior or do not exhibit awareness or concern for the effect their behavior has on those around them. Unlike AD, among patients with bvFTD, memory is not as badly affected.
"Although much rarer than AD, bvFTD is a severely debilitating and rapidly progressive disease that is extremely distressing for families. The possibility of a new drug on the horizon in the form of hydromethylthionine for the first time offers a real hope for those affected," study coinvestigator Serge Gauthier, MD, director of the Alzheimer Disease Research Unit, McGill Center for Studies in Aging, Montreal, Canada, said in a news release.
Hydromethylthionine blocks abnormal aggregation of tau protein and TDP-43 protein in the brain. These proteins have been linked to more than 80% of cases of bvFTD.
A phase 3 clinical trial was conducted in 220 patients (mean age, 63 years; 63% men) who met international consensus criteria for bvFTD and who exhibited evidence of brain atrophy.
As in the AD trials, the trial compared a high dose of hydromethylthionine (200 mg/day) against a low dose (8 mg/day) that was intended only as a control to mask the discoloration of urine that may occur with the drug.
In addition, similar to results from the AD studies, there were no significant differences between the high dose and the low dose on any of the efficacy outcomes.
Placebo-Controlled Trial Planned
To further explore the findings in bvFTD, the investigators conducted a pharmacokinetic population analysis using plasma concentration data from 176 of the 220 patients in the trial to determine how blood levels of the drug relate to its effects on the brain.
Using a new sensitive assay, they observed "steep concentration-response relationships" on clinical and MRI outcomes for steady-state plasma levels in the range 0.3 to 0.6 ng/mL on the clinical Addenbrooke's Cognitive Examination–Revised test and the Functional Activities Questionnaire, as well as with respect to whole-brain atrophy, as measured with MRI.
Substantially higher plasma concentrations in the range 7 to 14 ng/mL produced by the 200-mg/day dose were associated with worse outcomes.
These results in bvFTD are in line with the AD trials, which also showed steep concentration-response relationships on cognitive and MRI outcomes for steady-state plasma levels in the range 0.3 to 0.8 ng/mL with the 8-mg/day dose and that higher plasma concentrations produced by higher doses in the range 150 to 250 mg/day provided no additional benefit.
The present results support the idea that hydromethylthionine works similarly in both AD and bvFTD, the researchers note.
"The outcomes and findings from this study have provided valuable information on the optimal dosage and the safety profile of hydromethylthionine in bvFTD," said Wischik.
The analyses suggest that a dose "in the vicinity of 30 mg/day" would be optimal in bvFTD, the researchers write. TauRx Therapeutics now plans to test this dose in a placebo-controlled confirmatory trial.
A Step in the Right Direction
Commenting on the findings for Medscape Medical News, Maria C. Carrillo, PhD, Alzheimer's Association chief science officer, cautioned that the study was relatively small and that the results "are hard to interpret without proper placebo control.
"While the post hoc analysis reported in this paper is pointing in the right direction, this is basically now a new hypothesis, and it needs to be tested in a placebo-controlled trial," she said.
The study was sponsored by TauRx Therapeutics. Several authors are employees of the company or have financial relationships with the company. Carrillo has disclosed no relevant financial relationships.
J Alz Dis. Published online May 19, 2020. Full text
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Cite this: Tau Inhibitor Promising in Rapidly Progressing Dementia Type - Medscape - May 27, 2020.