Add-on anti-tau aggregation therapy fails to slow AD progression
medwireNews: Phase III trial results suggest there is no benefit to adding tau-aggregation inhibitor therapy to standard treatment in patients with mild to moderate Alzheimer’s disease (AD).
The selective inhibitor tested – leuco-methylthioninium bis(hydromethanesulfonate) (LMTM) – is a stable reduced form of the methylthioninium moiety, which enables it to be given at high doses but still be effectively absorbed.
At doses of 75 mg or 125 mg twice a day, LMTM was no more effective than 4 mg of the drug (control) in reducing disease progression, as measured on the Alzheimer’s Disease Assessment Scale–Cognitive Subscale (ADAS-Cog) and Alzheimer’s Disease Co-operative Study–Activities of Daily Living Inventory (ADCS-ADL).
The 531 patients assigned to treatment and the 354 to control were aged a mean of 71 years. They were permitted to continue taking any standard AD medications during the 15-month trial, Claude Wischik (University of Aberdeen, UK) and co-workers report in The Lancet.
Scores on the ADAS-Cog increased by an average of 6.32 points for patients in the control group and there was only a 0.02-point and 0.43-point improvement on this for patients taking LMTM 75 mg and 125 mg, respectively, reflecting nonsignificant differences in both cases. Similarly, average scores on the ADCS-ADL fell by 8.22 points for the control group and only a further 0.93 and 0.34 points for those taking LMTM 75 mg and 125 mg, respectively.
There was also no benefit to LMTM add-on for the secondary outcomes of ADCS–Clinical Global Impression of Change scale and the Mini-Mental State Examination.
Interpreting the findings in a related comment, Michael Rafii (University of California, San Diego, USA), says that the “patients taking LMTM as an add-on to approved medications for Alzheimer’s disease continued to decline in a manner indistinguishable for the control group.”
However, findings from a prespecified post-hoc analysis suggested a significant benefit on all treatment outcomes and brain atrophy for patients receiving LMTM as monotherapy, with no difference between treatment doses, compared with those receiving it as an add-on.
But Rafii comments: “Although these results are intriguing, the trial was not, as the authors note, designed to test the efficacy of LMTM as monotherapy.”
He points out that only 74 patients received LMTM monotherapy, which represented about 15% of the participants enrolled.
LMTM was generally well tolerated; the most common adverse events, and reasons for discontinuing, affected the gastrointestinal and urinary tracts. There were nine deaths, none of which were considered related to treatment.
Rafii believes that “this study, albeit negative, is an important step in anti-tau drug development.”
With additional results from two other phase III trials of LMTM in AD and frontal temporal dementia still awaited and more regular use of combined tau and amyloid positron emission tomography imaging in trials, he grows optimistic that “we have the right tools in place to assess compounds that might halt, or even prevent, Alzheimer’s disease.”
By Lucy Piper
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