Abstract
Background
Hydromethylthionine mesylate (HMTM) is a potent oral tau aggregation inhibitor. Recent results from Study TRx-237-039 (LUCIDITY) suggest strong effects on cognitive and functional decline and progression of brain atrophy. We investigated the effect of HMTM on change in the plasma biomarker neurofilament light chain (NfL) in LUCIDITY. NfL is a clinically accessible and established biomarker for neurodegeneration that is known to be correlated with measures of clinical decline and brain atrophy in AD and MCI due to AD (MCI-AD).
Method
LUCIDITY is a double-blind randomised controlled Phase 3 clinical trial comparing change over 12 months in cognitive, functional and brain atrophy outcomes at HMTM doses of 16 mg/day, 8 mg/day and methylthioninium chloride (MTC) at a dose of 4 mg twice weekly as a control in a 4:1:4 randomisation, with a subsequent 12 month blinded open-label extension phase in which all participants received 16 mg/day.
Result
Baseline and 12-month NfL plasma levels were available as randomised in 161/185 participants receiving HMTM 16 mg/day, 38/48 receiving HMTM 8 mg/day and 136/185 receiving MTC 8 mg/week. The corresponding prespecified analysis model showed a 93% reduction in the change in NfL levels relative to control for HMTM 16 mg/day overall (p = 0.0278). Reduction in NfL change in the MCI-AD subgroup was significant also at HMTM 8 mg/day (p = 0.0242). In the AD subgroup, there were directional dose-dependent trends that did not reach statistical significance. Change in NfL level at 12 months was significantly correlated with change in ADAS-cog11 (p = 0.0038) and whole brain volume (p = 0.0359) over 24 months.
Conclusion
These results demonstrate that the orally administered tau aggregation-inhibitor, HMTM, is able to produce a significant dose-dependent reduction in neurodegeneration in AD as measured by change in plasma NfL levels.
Hydromethylthionine mesylate (HMTM) is a potent oral tau aggregation inhibitor. Recent results from Study TRx-237-039 (LUCIDITY) suggest strong effects on cognitive and functional decline and progression of brain atrophy. We investigated the effect of HMTM on change in the plasma biomarker neurofilament light chain (NfL) in LUCIDITY. NfL is a clinically accessible and established biomarker for neurodegeneration that is known to be correlated with measures of clinical decline and brain atrophy in AD and MCI due to AD (MCI-AD).
Method
LUCIDITY is a double-blind randomised controlled Phase 3 clinical trial comparing change over 12 months in cognitive, functional and brain atrophy outcomes at HMTM doses of 16 mg/day, 8 mg/day and methylthioninium chloride (MTC) at a dose of 4 mg twice weekly as a control in a 4:1:4 randomisation, with a subsequent 12 month blinded open-label extension phase in which all participants received 16 mg/day.
Result
Baseline and 12-month NfL plasma levels were available as randomised in 161/185 participants receiving HMTM 16 mg/day, 38/48 receiving HMTM 8 mg/day and 136/185 receiving MTC 8 mg/week. The corresponding prespecified analysis model showed a 93% reduction in the change in NfL levels relative to control for HMTM 16 mg/day overall (p = 0.0278). Reduction in NfL change in the MCI-AD subgroup was significant also at HMTM 8 mg/day (p = 0.0242). In the AD subgroup, there were directional dose-dependent trends that did not reach statistical significance. Change in NfL level at 12 months was significantly correlated with change in ADAS-cog11 (p = 0.0038) and whole brain volume (p = 0.0359) over 24 months.
Conclusion
These results demonstrate that the orally administered tau aggregation-inhibitor, HMTM, is able to produce a significant dose-dependent reduction in neurodegeneration in AD as measured by change in plasma NfL levels.
| Original language | English |
|---|---|
| Article number | e083153 |
| Journal | Alzheimer's Dementia |
| Volume | 19 |
| Issue number | S24 |
| Early online date | 25 Dec 2023 |
| DOIs | |
| Publication status | Published - Dec 2023 |