How LMTX works
Alzheimer’s disease is a progressive neurodegenerative disorder, where nerve cell death in the brain results in reduced memory and cognitive function in patients. One of the hallmarks of Alzheimer’s disease is the formation of protein structures called amyloid plaques and tau tangles in the brain, which may contribute to the progression of the disease.
The tau protein is essential for normal nerve cell function and survival in the brain. In Alzheimer’s patients, tau misfolds or becomes fragmented resulting in its aggregation and spread, eventually contributing to the death of nerve cells.
LMTX is a tau aggregation inhibitor (TAI), which aims to reduce levels of the abnormal tau protein. The active component of LMTX, methylthioninium chloride (MTC), binds preferentially to the abnormal tau and removes the damaging tau tangles. Through this mechanism, LMTX aims to potentially slow the progression of the disease by reducing the tau-mediated damage in the brain.
LMTX in clinical trials
TauRx initiated a Phase 2 study (NCT01626391) in 2012 to look at 250 mg oral tablets of LMTX a day versus a placebo that contained 4 mg of LMTX. The study was terminated in 2013 due to administrative issues, however.
A phase 3 study (NCT02245568) to investigate LMTX in Alzheimer’s and behavioral-variant frontotemporal dementia (bvFTD) was initiated in 2014 but was also terminated in May of 2017. No reason was given for the termination of the study despite recruiting 913 patients prior to its end. No results have been posted.
TauRx has successfully completed two Phase 3 trials investigating the safety and efficacy of LMTX in mild to moderate Alzheimer’s disease patients, called TRx-015 and TRx-005, however. These trials allowed patients to take other therapies alongside LMTX.
The open-label, randomized, double-blind, placebo-controlled TRx-015 trial (NCT01689246) assessed the safety and efficacy of LMTX in 891 mild to moderate Alzheimer’s disease patients at a low (150mg/day), high (250mg/day), or control (8mg/day) dose for 15 months. LMTX is a modified version of methylene blue which can turn urine and feces blue. To keep patients from knowing if they were taking the placebo or the drug, a very small dosage of LMTX was given as a placebo to still cause the same coloration response. The trial was carried out at 116 sites across North America, Australia, Europe, and Asia.
The open-label, randomized, double-blind, placebo-controlled TRx-005 trial (NCT01689233) assessed an intermediate dosage of LMTX (200mg/day) versus a control dosage (8mg/day) in 800 mild Alzheimer’s disease patients for 18 months. The trial took place at 98 sites in North America, Europe, and Australia.
The main measures of efficacy for both trials was the change in performance on two scales: the Alzheimer’s disease assessment scale-cognitive subscale (ADAS-cog11) and the modified Alzheimer’s disease cooperative study–activities of daily living (ACDS-ADL). Secondary outcomes involved measuring changes in brain volume by MRI and changes in brain glucose uptake, a measure of brain activity. This aimed to assess the potential effect of LMTX on slowing neurodegeneration.
Overall, both trials failed to meet their primary endpoints. The initial results for TRx-015, published in The Lancet, suggested that there was no benefit of LMTX as an add-on treatment in Alzheimer’s disease and the results for TRx-005 were similar.
However, further analysis of the results of TRx-015 suggested that a subset of patients who were taking LMTX as a monotherapy showed a significant decrease in the rate of disease progression compared to the placebo. Furthermore, the level of brain atrophy slowed down by 33 to 38 percent in the LMTX group compared to the placebo. Similar results were also seen in TRx-005 and were published in the Journal of Alzheimer’s Disease.
Both trials also determined that the benefit of the 8mg/day dose, originally intended to be a control, was similar to the higher doses and had fewer side effects. To confirm whether there is a benefit to LMTX as a monotherapy, TauRx is currently running another Phase 2/3 trial (NCT03446001) called LUCIDITY to investigate two low doses (8 mg and 16mg) of LMTX vs. placebo. The trial is looking to recruit 375 participants with early Alzheimer’s disease. The primary outcomes of the study include changes in brain function using imaging techniques, changes in cognitive performance, and the number and types of adverse events. Results of the study are expected in December 2020.
TauRx also has an Expanded Access Program (NCT03539380) that provides access to the drug for patients who are still interested in taking LMTX after their participation in a study has ended.
LMTX was granted orphan drug designation by the US Food and Drug Administration (FDA) in 2018 for the treatment of frontotemporal dementia.
Last updated: Aug. 25, 2019
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