United States – Treatment with an experimental orally administered tau protein aggregation inhibitor, hydromethylthionine mesylate (HMTM), resulted in a statistically significant reduction in an established biomarker of neurodegeneration in Alzheimer’s disease. Alzheimer’s, as part of the LUCIDITY phase 3 trial.
Neurofilament light chain (NfL) blood concentrations showed a 93% reduction over 12 months in participants receiving HMTM at the target dose of 16 mg/day compared to the control group, which correlates significantly with a biomarker of tau (p-tau 181) in the blood and a change in the results of cognitive tests.
“This is the first tau protein aggregation inhibitor to reach Phase 3 development and produce such results,” said Claude Wischik, PhD, executive chairman of TauRx Therapeutics, which is developing the drug, during from an interview with Medscape Medical News.
It is the first tau protein aggregation inhibitor to reach phase 3 development and produce such results. Claude Wischik
“NfL is one of the best-studied biomarkers in this field, as it is deregulated in a range of neurodegenerative disorders. In Alzheimer’s disease, it correlates with the severity of the disease and parallels the ongoing damage to neurons,” Wischik explained.
Orally administered HMTM was designed to reduce tau pathology in AD, and the observed changes in NfL concentration by HMTM indicate a “direct impact on disease pathology,” said Claude Wischik.
The results, from a prespecified analysis of blood biomarkers from the Phase 3 LUCIDITY trial, were presented at the Alzheimer’s Association International Conference (AAIC) 2023.
Significant reduction in NfL
Early results from the LUCIDITY study showed improved cognition over 18 months in participants with mild cognitive impairment (MCI) due to Alzheimer’s disease treated with a 16 mg/day dose of HMTM.
However, strangely, participants in the control group who received a low dose of methylthioninium chloride (MTC) also showed cognitive improvement.as previously reported Medscape Medical News.
Therefore, HMTM 16 mg/day did not meet its two primary endpoints – Change from Baseline Alzheimer’s Disease Cognitive Subscale (ADAS-Cog11) and Alzheimer’s Disease Inventory. Activities of Daily Living from the Alzheimer’s Disease Cooperative Study (ADCS-ADL23) – compared to control group receiving MTC.
This is likely because treatment with MTC, which is a variant of HMTM, unexpectedly achieved blood levels of the active drug above the threshold needed to produce a clinical effect.
Regarding the pre-specified biomarker analysis presented at AAIC 2023, plasma NfL concentrations at baseline and at 12 months were available in 161 of 185 participants receiving HMTM 16 mg/day, 38 of 48 receiving HMTM 8 mg/day and 136 of 185 receiving MTC at 8 mg/week.
Blood NfL concentrations showed a statistically significant reduction of 93% over 12 months in participants receiving HMTM at a dose of 16 mg/day compared to the control group (p=0.0278), reported Claude Wischik.
Furthermore, the increase in p-tau 181 over 12 months “tailed to zero” with HMTM 16 mg/day and there was a significant correlation between the change in NfL and the p-tau concentration. 181, he noted.
Reductions in NfL were significantly correlated with change in ADAS-Cog11 (p=0.0038) and whole brain volume (p=0.0359) over 24 months.
“Exciting” data on biomarkers
Commenting on the new data, Christopher Weber, PhD, director of global science initiatives at the Alzheimer’s Association, told Medscape Medical News that LUCIDITY Phase 3 results “suggest that HMTM could be a potential treatment to slow down neurodegenerative processes in Alzheimer’s disease.”
“Plasma NfL is an interesting biomarker that is increasingly being used in clinical trials because it is non-invasive, accessible, and can help diagnose and monitor disease in the early stages. Elevated levels of NfL suggest that neurons are affected in the brain, which could indicate the presence or progression of Alzheimer’s disease,” said Christopher Weber.
He added that the biomarker data from the LUCIDITY study was “exciting”.
“However, due to the relatively small sample size, we look forward to further research on HMTM in larger and even more diverse cohorts to better understand the performance of this treatment and the role of NfL in the Alzheimer’s disease,” said Christopher Weber.
We look forward to further research on HMTM in larger and even more diverse cohorts. Christopher Weber
Howard Fillit, MD and Founding Executive Director of the Alzheimer’s Drug Discovery Foundation (ADDF), also provided an outside perspective, noting that currently “a lot of effort is being made to try to treat tau abnormalities that occur in Alzheimer’s disease”.
LUCIDITY biomarker data shows that HMTM “appears to markedly decrease the amount of NfL in plasma and has some correlation with cognitive scores.” The most obvious unknown is whether these changes in plasma NfL “will predict clinical benefit,” Dr. Fillit told Medscape Medical News.
“This is an oral drug with a good safety profile and a logical mechanism of action, but we need to see the clinical data,” Dr. Fillit said.
Final two-year data from the LUCIDITY trial is expected to be released later this year.
In the UK, TauRx has entered an accelerated approval process for the drug, and the company said it expects to seek regulatory approval in the US and Canada this year.
It is an oral drug with a good safety profile and a logical mechanism of action, but we need to see the clinical data. Howard Fillit
The study was funded by TauRx Therapeutics. Wischik is an employee of the University of Aberdeen, Aberdeen, Scotland, and TauRx Therapeutics. Christopher Weber and Howard Fillit report no relevant financial relationship.
The article was originally published on Medscape.com under the title Oral Tau Inhibitor Continues to Show Promise in Alzheimer’s. Edited by Stephanie Lavaud.
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2023-08-07 07:53:01
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