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Tau-targeting antisense oligonucleotide MAPTRx in mild Alzheimer's disease: a phase 1b, randomized, placebo-controlled trial
Catherine J Mummery 1, Anne Börjesson-Hanson 2, Daniel J Blackburn 3, Everard G B Vijverberg 4, Peter Paul De Deyn 5, Simon Ducharme 6, Michael Jonsson 7, Anja Schneider 8, Juha O Rinne 9, Albert C Ludolph 10, Ralf Bodenschatz 11, Holly Kordasiewicz # 12, Eric E Swayze # 12, Bethany Fitzsimmons # 12, Laurence Mignon # 12, Katrina M Moore # 12, Chris Yun # 12, Tiffany Baumann # 12, Dan Li # 12, Daniel A Norris # 12, Rebecca Crean # 12, Danielle L Graham # 13, Ellen Huang # 13, Elena Ratti # 13, C Frank Bennett # 12, Candice Junge 12, Roger M Lane 12
...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 .