Details

Autor(en) / Beteiligte

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

Titel

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

Ist Teil von

• Nature medicine, 2023-06, Vol.29 (6), p.1437

Ort / Verlag

United States

Erscheinungsjahr

2023

Quelle

MEDLINE

Beschreibungen/Notizen

• 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 (MAPT ) 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 MAPT . Four ascending dose cohorts were enrolled sequentially and randomized 3:1 to intrathecal bolus administrations of MAPT 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 MAPT 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 MAPT and 12 to placebo. Adverse events were reported in 94% of MAPT -treated patients and 75% of placebo-treated patients; all were mild or moderate. No serious adverse events were reported in MAPT -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) MAPT groups. Clinicaltrials.gov registration number: NCT03186989 .