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Antisense Oligonucleotide Reduces Tau Levels in Patients With Mild Alzheimer Disease
A tau-targeting antisense oligonucleotide (MAPTRx) reduced cerebrospinal fluid total-tau concentration more than 50%, on average, 6 months after the last dose in patients with mild Alzheimer disease. Researchers published their findings online ahead of print in Nature Medicine.
“Given the important role of tau in Alzheimer’s disease pathophysiology and the accumulating evidence that lowering tau may reduce this pathological effect, we sought to inhibit MAPT expression and thus reduce tau levels, directly targeting a key disease effector mechanism in patients with Alzheimer’s disease,” wrote corresponding author Catherine J. Mummery, MD, PhD, of the Dementia Research Centre at the University College London in the United Kingdom, and an international team of coauthors.
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The first-in-human phase 1b trial looked at safety, pharmacokinetics, and target engagement of MAPTRx in patients with mild Alzheimer disease. The double-blind study randomly assigned patients 3:1 to intrathecal bolus administrations of MAPTRx or placebo over 13 weeks. Four cohorts were included: a 10-mg monthly cohort, a 30-mg monthly cohort, a 60-mg monthly cohort D, and a 115-mg quarterly (total of two doses) cohort.
Of the 46 patients enrolled, 34 received MAPTRx and 12 received placebo. The study’s primary endpoint was safety.
According to the findings, no serious adverse events were reported in any patients who received MAPTRx either during the 13-week treatment period or the 23-week post-treatment period.
“The proportion of participants experiencing adverse events was greater in those receiving MAPTRx versus placebo (94% versus 75%, respectively), and this was mainly due to an increased incidence of mild adverse events in the MAPTRx treatment group (62% versus 42% in placebo),” researchers reported.
Patients who received MAPTRx showed dose- and time-dependent drops in the concentration of cerebrospinal fluid t-tau and p-tau181, the study found. At 24 weeks after the last dose, patients in the 60-mg (4 doses) and 115-mg (2 doses) MAPTRx groups showed a greater than 50% mean reduction in cerebrospinal fluid total-tau concentration from baseline.
“These results demonstrate that antisense-mediated suppression of tau protein synthesis in the cerebrospinal fluid of participants with mild Alzheimer’s disease is possible,” researchers wrote, “and warrant further evaluation of the effect of MAPTRx on the clinical course of patients with Alzheimer’s disease and in other tauopathies.”
Ionis Pharmaceuticals and Biogen funded the study.
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