TY - JOUR
T1 - Tau-targeting antisense oligonucleotide MAPTRx in mild Alzheimer’s disease
T2 - a phase 1b, randomized, placebo-controlled trial
AU - Mummery, Catherine J.
AU - Börjesson-Hanson, Anne
AU - Blackburn, Daniel J.
AU - Vijverberg, Everard G. B.
AU - de Deyn, Peter Paul
AU - Ducharme, Simon
AU - Jonsson, Michael
AU - Schneider, Anja
AU - Rinne, Juha O.
AU - Ludolph, Albert C.
AU - Bodenschatz, Ralf
AU - Kordasiewicz, Holly
AU - Swayze, Eric E.
AU - Fitzsimmons, Bethany
AU - Mignon, Laurence
AU - Moore, Katrina M.
AU - Yun, Chris
AU - Baumann, Tiffany
AU - Li, Dan
AU - Norris, Daniel A.
AU - Crean, Rebecca
AU - Graham, Danielle L.
AU - Huang, Ellen
AU - Ratti, Elena
AU - Bennett, C. Frank
AU - Junge, Candice
AU - Lane, Roger M.
N1 - Funding Information:
We thank the participants and their companions who participated in the study; the sites, study teams from Ionis Pharmaceuticals, Biogen and Syneos for executing the study; N. Fox and I. Malone (University College London Dementia Research Centre, London, UK) for their collaboration on analyses and interpretation of the MRI volumetric data; and J. Matthews (Ionis) and J. Allison (Immunologix, Tampa, FL) for exploratory biomarker analysis support. The study was funded by Ionis Pharmaceuticals and Biogen.
Funding Information:
We thank the participants and their companions who participated in the study; the sites, study teams from Ionis Pharmaceuticals, Biogen and Syneos for executing the study; N. Fox and I. Malone (University College London Dementia Research Centre, London, UK) for their collaboration on analyses and interpretation of the MRI volumetric data; and J. Matthews (Ionis) and J. Allison (Immunologix, Tampa, FL) for exploratory biomarker analysis support. The study was funded by Ionis Pharmaceuticals and Biogen.
Publisher Copyright:
© 2023, The Author(s).
PY - 2023/6
Y1 - 2023/6
N2 - 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.
AB - 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.
UR - https://www.scopus.com/pages/publications/85153371450
U2 - 10.1038/s41591-023-02326-3
DO - 10.1038/s41591-023-02326-3
M3 - Article
C2 - 37095250
SN - 1078-8956
VL - 29
SP - 1437
EP - 1447
JO - Nature medicine
JF - Nature medicine
IS - 6
ER -