Tau-targeting antisense oligonucleotide MAPTRx in mild Alzheimer's disease: a phase 1b, randomized, placebo-controlled trial
Mummery CJ, Börjesson-Hanson A, Blackburn DJ, Vijverberg EGB, De Deyn PP, Ducharme S, Jonsson M, Schneider A, Rinne JO, Ludolph AC, Bodenschatz R, Kordasiewicz H, et al.. Nature Medicine, 2023-04-24
Topic: Amyloid, tau and blood-test diagnosis
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 Rx ) 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 Rx . Four ascending dose cohorts were enrolled sequentially and randomized 3:1 to intrathecal bolus administrations of MAPT Rx 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 Rx 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 Rx and 12 to placebo. Adverse events were reported in 94% of MAPT Rx -treated patients and 75% of placebo-treated patients; all were mild or moderate. No serious adverse events were reported in MAPT Rx -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 Rx groups. Clinicaltrials.gov registration number: NCT03186989 .
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APA 7th
Mummery, C. J., Börjesson-Hanson, A., Blackburn, D. J., Vijverberg, E. G. B., De Deyn, P. P., Ducharme, S., et al. (2023). Tau-targeting antisense oligonucleotide MAPTRx in mild Alzheimer's disease: a phase 1b, randomized, placebo-controlled trial. Nature Medicine. https://doi.org/10.1038/s41591-023-02326-3
Vancouver
Mummery CJ, Börjesson-Hanson A, Blackburn DJ, Vijverberg EGB, De Deyn PP, Ducharme S, et al. Tau-targeting antisense oligonucleotide MAPTRx in mild Alzheimer's disease: a phase 1b, randomized, placebo-controlled trial. Nature Medicine. 2023. doi:10.1038/s41591-023-02326-3. PMID: 37095250.
BibTeX
@article{mummery2023-37095250,
author = {Mummery, C. J. and Börjesson-Hanson, A. and Blackburn, D. J. and Vijverberg, E. G. B. and De Deyn, P. P. and Ducharme, S. and Jonsson, M. and Schneider, A. and Rinne, J. O. and Ludolph, A. C. and Bodenschatz, R. and Kordasiewicz, H. and others},
title = {{Tau-targeting antisense oligonucleotide MAPTRx in mild Alzheimer's disease: a phase 1b, randomized, placebo-controlled trial}},
journal = {Nature Medicine},
year = {2023},
doi = {10.1038/s41591-023-02326-3},
pmid = {37095250},
url = {https://doi.org/10.1038/s41591-023-02326-3}
}
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Key findings
- Tau plays a key role in Alzheimer's disease (AD) pathophysiology, and accumulating evidence suggests that lowering tau may reduce this pathology.
Why it matters
In this phase 1b trial, an antisense oligonucleotide targeting tau was given to 46 patients with mild Alzheimer's disease and reduced cerebrospinal fluid total-tau in a dose-dependent way. Adverse events were mild or moderate and no serious adverse events occurred in treated patients, but this early trial was designed mainly to test safety, not whether it helps symptoms.
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Study details
- Study designphase-1-trial
- Participants46
- Effect sizeGreater than 50% mean reduction in CSF total tau at 24 weeks post-last dose in the two highest-dose groups
- Evidence strengthEarly
Limitations
Small phase 1 sample (n = 46); whether a ~50% CSF tau reduction is clinically beneficial requires larger controlled trials; exploratory biomarker changes were not dose-responsive or concordant; participants were relatively young with mild AD, so results may not represent late-onset disease; CSF tau indexes target engagement only indirectly.
How this study scored 71/100
Published in a top-tier journal. Scored zero for study design because the record does not state it. We have no data on free to read, so that was left out: it earned 70 of the 98 points we could judge it on, which is 71 out of 100.
| Component | Points | Why |
|---|---|---|
| Journal tier | 10 / 10 | Tier 1 — top-tier general journal (Nature Medicine) |
| Journal's citation record | 4 / 4 | Nature Medicine: journal h-index 763 (OpenAlex, 2026-10-29) |
| Study design | 0 / 12 | Design recorded as “phase-1-trial”, which our rubric does not rank (not stated in the record — scored 0) |
| Strength of evidence | 2 / 5 | Rated “early” in our summary |
| Peer-review validation | 10 / 10 | Peer-reviewed. Published as an article in a named peer-reviewed journal. |
| How recent | 3 / 5 | 2023 — within 6 year(s) of the newest study here |
| Sample size | 1 / 4 | 46 participants |
| Effect reported | 2 / 3 | Effect reported as a number, without an interval or test |
| Studied in people | 3 / 3 | Studied in people (participant count stated) |
| Randomised / blinded | 2 / 2 | Randomised and blinded or placebo-controlled (as stated in the record) |
| Times cited | 6 / 7 | Cited 343 times (OpenAlex, 2026-10-10) |
| Citations per year | 5 / 5 | 68.6 citations a year over 5 year(s) since 2023 |
| Impact for its field and year | 6 / 6 | Cited 50.3× the average for papers of its field and year (OpenAlex FWCI) |
| Cited by studies here | 3 / 6 | Cited by 16 other studies in this library |
| Still being cited | 4 / 4 | Cited 304 times in 2024–2026 (2026 still in progress; OpenAlex) |
| Senior author's track record | 2 / 4 | Last-listed author Roger M. Lane: h-index 47 (OpenAlex, whole career) |
| Institution's track record | 2 / 3 | University College London: institution h-index 2,029 (OpenAlex) |
| Multi-centre collaboration | 3 / 3 | OpenAlex lists 24 institution(s) in 7 countries |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 37095250) |
| Free to read | — / 2 | Access not recorded — left out of this score |
| Points | 70 / 98 | Scored on 19 of 20 parts. We have no data for the rest, so they are left out: 70 of the 98 points we could judge it on is 71 out of 100. |
| Total | 71 / 100 | — |
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