TORONTO—LMTM, an investigational tau-aggregation inhibitor, may not benefit patients with Alzheimer’s disease who are receiving standard of care, according to research presented at the Alzheimer’s Association International Conference. As monotherapy, however, the drug may stabilize cognition and reduce brain atrophy, according to Serge Gauthier, MD, Director of the Alzheimer’s Disease Research Unit at McGill University in Montreal.
Serge Gauthier, MD
The aggregation of tau protein is one of the hallmarks of Alzheimer’s disease, but most therapies to date have been designed to reduce the number of amyloid plaques. LMTM is a stabilized, reduced form of the methylthionium moiety. As the oxidized chloride salt (methylthionium chloride or MTC), it is commonly known as methylene blue. LMTM is better absorbed, better tolerated, and can be administered in a broader dose range than MTC. Phase II studies of MTC provided evidence for the treatment’s efficacy as monotherapy, but the drug was poorly absorbed at higher doses. MTC and LMTM block tau aggregation in vitro and in tau transgenic animal models.
An International Trial
Dr. Gauthier and colleagues conducted a 15-month phase III study of LMTM in patients with mild to moderate Alzheimer’s disease. Researchers in 16 countries randomized 891 patients to 8 mg/day, 150 mg/day, or 250 mg/day of LMTM. Like methylene blue, LMTM discolors the urine. Because no dye achieves the same effect, researchers administered 8 mg/day of LMTM as a control dose. This dose is enough to discolor the urine, and thus avoid breaking the blind, but is believed to be pharmacologically inactive.
The primary end point was a composite of cognition, as measured by the Alzheimer’s Disease Assessment Scale-Cognition (ADAS-Cog), and activities of daily living, as measured by the Alzheimer’s Disease Cooperative Study-Activities of Daily Living (ADCS-ADL). The secondary end points were brain volume (ie, lateral ventricular volume) as measured by MRI, Clinical Global Impression of Change, and the Mini-Mental State Examination (MMSE).
The investigators examined the data using a standard, mixed-model, repeated-measure analysis with no imputation for missing data. They included patients’ Alzheimer’s disease treatment status as an additive term in their primary analysis. In addition, they planned a second analysis that used this treatment status as a covariate.
LMTM Failed Primary End Point
Approximately 62% of the population was female, and the population’s mean age was 70.6. About 85% of participants were taking approved treatments for Alzheimer’s disease at baseline. Baseline MMSE score was 18.6, and dementia was of moderate severity in 62% of patients. The study’s retention rate was 69%.
At 15 months, Dr. Gauthier and colleagues found no difference in ADAS-Cog score or ADCS-ADL score between the three treatment arms. Patients who took LMTM as monotherapy, however, had stable scores during the study period, compared with patients who took LMTM and standard treatments for Alzheimer’s disease. ADAS-Cog scores were 5.8 and 6.3 points higher, respectively, in patients taking the two higher doses of LMTM as monotherapy, compared with patients taking LMTM in combination with standard treatments. In addition, the rate of brain atrophy was 33% lower among patients taking LMTM as monotherapy, compared with patients taking LMTM and standard treatments.
Diarrhea was the most common side effect of the 250-mg/day dose of LMTM. This side effect may lead to a reduction of dose or treatment cessation. Dysuria was another adverse event and is explained by the drug effect in the urinary tract, according to the researchers.
What Is the Future of Tau Therapy?
The study results are disappointing, according to David Knopman, MD, Professor of Neurology at the Mayo Clinic College of Medicine in Rochester, Minnesota, who was not involved in the study. “The only thing that really counts is the primary outcome that was prespecified…. It was the group as a whole, and there weren’t any benefits.” Although the secondary results are interesting, secondary analyses are “fraught with interpretive difficulties because of hidden biases,” Dr. Knopman added. “When we’re only looking at a small subset of participants, and 15% were on no drug, I think it becomes difficult to interpret.” In addition, the results may have limited relevance for North American populations, where few people with Alzheimer’s disease are not receiving standard care.
A second, predominantly North American, study of LMTM in 800 patients with mild Alzheimer’s disease will be reported in the fall. In light of LMTM’s lack of efficacy as add-on to existing treatments, the researchers modified the primary analyses of the second study before unblinding to focus on monotherapy. “Tau therapy is a way to go. It’s just maybe more complicated than we thought,” said Dr. Gauthier, who is a member of the scientific advisory board of TauRx, the company that sponsored the study.