TORONTO – A highly anticipated phase III trial of an anti-tau drug has posted negative topline results, conferring no cognitive or functional benefits when given in conjunction with standard-of-care Alzheimer’s disease medications.
The drug, LMTX (TauRx, Singapore), also did not slow the progression of brain atrophy on imaging in either of two doses tested, according to a company press release.
Although the study didn’t meet its clinical endpoints in the overall cohort of 891 patients with mild-moderate Alzheimer’s disease, TauRx promoted it as “promising,” based on a subgroup analysis of patients who took the drug as monotherapy. None of these patients were taking any standard-of-care Alzheimer’s medications; the press release did not say how many this group comprised. But it did imply that the group was small enough that the treatment effect was diluted in the pooled primary analysis.
In patients who took the drug as monotherapy, LMTX was associated with dose-dependent, statistically significant improvements in the Alzheimer’s Disease Assessment Scale measures of cognition (ADAS-cog) and Alzheimer’s Disease Cooperative Study Activities of Daily Living inventory (ADCS-ADL). The drug was also associated with a slowing of brain ventricular expansion, compared with controls, suggesting that it could be preserving brain mass.
ADAS-cog scores for patients taking LMTX monotherapy 75 mg twice a day declined 6.3 points less than did controls, indicating preserved cognition. Those taking LMTX monotherapy 125 mg twice a day declined 5.8 points less than did controls. On the ADCS-ADL, patients taking 75 mg twice a day scored 6.5 points higher than controls, indicating better function, and those taking 125 mg twice a day scored 6.9 points higher.
Lateral ventricular volume expansion on MRI was significantly less than that seen in controls. For those taking 75 mg twice a day, ventricular expansion was reduced by 38%, and for those taking 125 mg twice a day, expansion was reduced by 33%.
This indicates a decrease in the rate of brain atrophy, the press release said, and the finding was “confirmed by corresponding increases in the whole-brain volumes in the same patient groups.”
The press release also said that the imaging findings offer physiologic confirmation of the cognitive and functional findings. “This is the first treatment in which a clinical effect has been supported by evidence in delay of progression in brain atrophy shown by MRI scans.”
The missing number of patients who took LMTX monotherapy is key, however, in determining whether the positive effects in that group are real or a chance finding, according to Richard J. Caselli, MD, associate director and clinical core director of the Alzheimer’s Disease Center at the Mayo Clinic, Scottsdale, Ariz.
“Were the monotherapy results a fluke that washed out with bigger numbers or a meaningful effect? That needs to be clarified,” he said when asked to comment on the study. “Smaller ‘N’ trials can have skewed results due to random chances that mean nothing, and that is my fear. It’s unproven at this point but the burden of proof will rest on the investigators to replicate the positive outcome.”
The finding of a positive signal in monotherapy only is puzzling and also demands an explanation, said Michael Wolfe, PhD, a professor of neurology at Harvard University, Boston.
LMTX is a purified form of the dye methylene blue. Its method of action in preventing or dissolving tau tangles is not fully elucidated. A 2013 paper in a German chemistry journal, Angewandte Chemie, suggested that it works through oxidation to maintain the tau protein as a monomer, which prevents aggregation into filaments. There is no reason to think this pathway could intersect or interfere with any of the standard-of-care Alzheimer’s medications.
“There’s nothing obvious that comes to mind regarding interaction,” between the drug classes, Dr. Wolfe said in an interview. “We can’t say anything about this mechanistically. Any explanation here is just hand waving, I think.”
Dean Hartley, PhD, director of science initiatives at the Alzheimer’s Association, commented on the trial in a video interview at the Alzheimer’s Association International Conference 2016.
Neither Dr. Caselli nor Dr. Wolfe had relevant disclosures.
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