by Isabella Colonna
For May we selected 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, Swayze EE, Fitzsimmons B, Mignon L, Moore KM, Yun C, Baumann T, Li D, Norris DA, Crean R, Graham DL, Huang E, Ratti E, Bennett CF, Junge C, Lane RM. Tau-targeting antisense oligonucleotide MAPTRx in mild Alzheimer’s disease: a phase 1b, randomized, placebo-controlled trial. Nat Med. 2023 Apr 24. doi: 10.1038/s41591-023-02326-3. Epub ahead of print. PMID: 37095250.
Growing evidence indicates that aggregated, hyperphorylated tau plays an important role in the neurodegeneration observed in Alzheimer’s Disease (AD). Preclinical studies have shown that MAPTRx, an antisense oligonucleotide conceived to reduce the concentration of MAPT messenger RNA which is responsible for the coding of tau protein, has been associated with decreased tau levels and improved disease-associated phenotypes in mouse models of tauopathy.
Our paper of the month is a phase 1b, randomised, multicentre, placebo-controlled trial, which aims to investigate the safety, pharmacokinetics, and effects of MAPTRx in patients with mild AD. In the first part of the study, patients were randomised to receive intrathecal administration of a placebo (n=12) or of MAPTRx (n=34). In the interventional group, individuals received four monthly doses at 10mg (n=6), 30mg (n=6) or 60mg (n=9), or two quarterly doses at 115mg (n=13). Successively, there was a 23-week post-treatment period during which patients did not receive any study drug. Participants who completed this first part of the trial were eligible to participate in the second part of the study, which was an open-label long-term extension.
In patients receiving MAPTRx, there were dose- and time-dependent decreases in the CSF levels of total tau, which also continued in the post-treatment period. At eight weeks after the last dose, the mean percentage change from baseline was -30%, -40%, -49% and -42% in the groups receiving MAPTRx at 10mg, 30mg and 60mg monthly and 115mg quarterly, respectively. Furthermore, in the last two groups, which entered seamlessly into the long-term extension, authors found a decline in total-tau levels greater than 50% from baseline at 24 weeks after the last dose. Similar results were found for the CSF concentrations of pospho-tau181. The incidence of mild adverse events (AE) was greater in the interventional group, while no differences between groups were found in the incidence of moderate AE. No severe or serious AE occurred during the 13-week treatment period as well as the 23-week post-treatment period.
The results of this phase 1b trial indicate that an antisense-mediated reduction of CSF tau protein levels in patients with mild AD is possible; however, larger trials are needed in order to further investigate the effect of MAPTRx on the clinical course of AD and other taupathies.