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

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

doi:10.1038/s41591-023-02326-3

Journal Article

DZNE-2023-00662

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

Mummery, C. J. ; Börjesson-Hanson, A. ; Blackburn, D. J. ; Vijverberg, E. G. B. ; De Deyn, P. P. ; Ducharme, S. ; Jonsson, M. ; Schneider, A.DZNE* ; Rinne, J. O. ; Ludolph, A. C.DZNE* ; Bodenschatz, R. ; Kordasiewicz, H. ; Swayze, E. E. ; Fitzsimmons, B. ; Mignon, L. ; Moore, K. M. ; Yun, C. ; Baumann, T. ; Li, D. ; Norris, D. A. ; Crean, R. ; Graham, D. L. ; Huang, E. ; Ratti, E. ; Bennett, C. F. ; Junge, C. ; Lane, R. M.

2023
Nature America Inc. New York, NY

Nature medicine 29(6), 1437-1447 (2023) [10.1038/s41591-023-02326-3]

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Please use a persistent id in citations: doi:10.1038/s41591-023-02326-3

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 .

Keyword(s): Humans (MeSH) ; tau Proteins: genetics (MeSH) ; Alzheimer Disease: drug therapy (MeSH) ; Alzheimer Disease: genetics (MeSH) ; Alzheimer Disease: cerebrospinal fluid (MeSH) ; Oligonucleotides, Antisense: therapeutic use (MeSH) ; Treatment Outcome (MeSH) ; Double-Blind Method (MeSH) ; tau Proteins ; Oligonucleotides, Antisense ; MAPT protein, human

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ddc:610

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Appears in the scientific report 2023

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