How LMTM works
LMTM’s full chemical name is leuco-methylthioninium bis(hydromethanesulphonate). It is a derivative of methylthioninium chloride, a dye also known as methylene blue. The dye has long been used in research and for the treatment of malaria and other conditions. More recently, it has attracted attention for its potential to slow the progression of Alzheimer’s disease.
LMTM replaces TauRx’s earlier therapy Rember, another formulation of methylene blue that was tested in Phase 2 clinical trials. Compared with its predecessor, LMTM is better absorbed and has improved safety and tolerability, according to TauRx.
LMTM in clinical trials
TauRx has completed two Phase 3 clinical trials of LMTM for the treatment of Alzheimer’s.
The first Phase 3 trial (NCT01689246) included 891 participants with mild to moderate Alzheimer’s disease at 115 centers in 16 countries. Participants received 125 mg twice daily or 75 mg twice daily of LMTM in tablet form, while a control group received 4 mg twice daily.
A low dose of LMTM was used as a control. Because LMTM causes the urine to turn blue, using a control that didn’t color the urine would reveal which participants were in the control group, and the study would not be “blind.”
Researchers found no significant difference in cognitive scores or ability to perform activities of daily life between the treatment and control groups.
But when investigators looked at a subset of patients who were not taking other treatment for Alzheimer’s disease, a benefit was seen for higher doses of LMTM compared to the control dose. The low dose of 4 mg twice a day, which had been used as the control, appeared to benefit patients who were taking it as their only treatment (monotherapy), compared to participants who took LMTM as an add-on to another therapy.
Some scientists not involved in the LMTM study said that the results from the monotherapy subset were encouraging, but because of the small number of participants in that group, further research was needed. Others questioned the validity of the subset analysis.
TauRx’s second Phase 3 trial (NCT01689233) of LMTM as an Alzheimer’s treatment seemed to confirm the findings seen in the monotherapy subset group in the first trial. Participants who took LMTM at a dose of 100 mg twice a day as their only Alzheimer’s therapy scored significantly better on cognitive and functional tests than a group taking a lower dose of 4 mg twice a day.
The trial enrolled 800 patients with mild Alzheimer’s disease, but only 79 participants in the 100 mg twice daily group were taking LMTM as a monotherapy. The lower dose of 4 mg twice a day, which was originally intended as a control, appeared to provide benefit as a monotherapy compared to when it was used as an add-on therapy.
In addition, TauRx is conducting a Phase 3 open-label extension trial (NCT02245568) for LMTM. The trial is open to participants in the company’s previous two Phase 3 trials for Alzheimer’s disease, as well as participants in a trial of LMTM as a treatment for a different condition known as behavioral variant frontotemporal dementia.
The study will follow approximately 1,000 participants who will take LMTM at a starting dose of 100 mg twice a day. They will be monitored for adverse events, changes in blood chemistry or vital signs, quality of life, and their use of healthcare.
TauRx said in a press release that its next step would be to conduct randomized controlled studies of LMTM in Alzheimer’s patients in which the 4 mg twice daily dose would be compared with placebo in monotherapy participants; that is, those who are not receiving other treatments for Alzheimer’s, such as cholinesterase inhibitors or memantine.
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