Tau-targeting antisense oligonucleotide MAPTRx in mild Alzheimer’s disease: a phase 1b, randomized, placebo-controlled trial

Catherine J. Mummery, Anne Börjesson-Hanson, Daniel J. Blackburn, Everard G. B. Vijverberg, Peter Paul de Deyn, Simon Ducharme, Michael Jonsson, Anja Schneider, Juha O. Rinne, Albert C. Ludolph, Ralf Bodenschatz, Holly Kordasiewicz, Eric E. Swayze, Bethany Fitzsimmons, Laurence Mignon, Katrina M. Moore, Chris Yun, Tiffany Baumann, Dan Li, Daniel A. NorrisRebecca Crean, Danielle L. Graham, Ellen Huang, Elena Ratti, C. Frank Bennett, Candice Junge, Roger M. Lane

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70 Citations (Scopus)

Abstract

Tau plays a key role in Alzheimer’s disease (AD) pathophysiology, and accumulating evidence suggests that lowering tau may reduce this pathology. We sought to inhibit MAPT expression with a tau-targeting antisense oligonucleotide (MAPTRx) and reduce tau levels in patients with mild AD. A randomized, double-blind, placebo-controlled, multiple-ascending dose phase 1b trial evaluated the safety, pharmacokinetics and target engagement of MAPTRx. Four ascending dose cohorts were enrolled sequentially and randomized 3:1 to intrathecal bolus administrations of MAPTRx or placebo every 4 or 12 weeks during the 13-week treatment period, followed by a 23 week post-treatment period. The primary endpoint was safety. The secondary endpoint was MAPTRx pharmacokinetics in cerebrospinal fluid (CSF). The prespecified key exploratory outcome was CSF total-tau protein concentration. Forty-six patients enrolled in the trial, of whom 34 were randomized to MAPTRx and 12 to placebo. Adverse events were reported in 94% of MAPTRx-treated patients and 75% of placebo-treated patients; all were mild or moderate. No serious adverse events were reported in MAPTRx-treated patients. Dose-dependent reduction in the CSF total-tau concentration was observed with greater than 50% mean reduction from baseline at 24 weeks post-last dose in the 60 mg (four doses) and 115 mg (two doses) MAPTRx groups. Clinicaltrials.gov registration number: NCT03186989.
Original languageEnglish
Pages (from-to)1437-1447
Number of pages11
JournalNature medicine
Volume29
Issue number6
Early online date2023
DOIs
Publication statusPublished - Jun 2023

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