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

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.

Exploratory Tau Biomarker Results From a Multiple Ascending-Dose Study of BIIB080 in Alzheimer Disease

“…To evaluate proof of mechanism of the study drug, levels of t-tau and p-tau181 in the CSF were evaluated. Results from the placebo-controlled MAD study have been previously reported . Briefly, the placebo group maintained stable levels of both analytes throughout the duration of the MAD period, in line with prior natural history studies, whereas the BIIB080-treated groups demonstrated dose-dependent decreases in both analytes during the 13-week treatment period (Figure 2, eTables 6 and 7, and eFigure 2 in Supplement 3).…”

“…5 Clinically, a multiple ascending-dose (MAD) phase 1b study was completed in participants with mild AD, with the primary objective of evaluating the safety and tolerability of BIIB080. As previously published, 6 BIIB080 was generally well tolerated. The majority of adverse events were mild or moderate in severity, of which the most common were headache, back pain, and post-lumbar puncture syndrome.…”

“…Volumetric MRI results from the placebo-controlled MAD period have been previously reported . Briefly, at week 25, the mean change in lateral ventricular volume as a percentage of total intracranial volume was greater in the participants receiving active treatment than in those receiving placebo.…”

“…Volumetric MRI results from the placebo-controlled MAD period have been previously reported. 6 Briefly, at week 25, the mean change in lateral ventricular volume as a percentage of total intracranial volume was greater in the participants receiving active treatment than in those receiving placebo. At week 25, whole-brain volume decreased slightly from baseline in all groups and did not differ between Effect of BIIB080 on levels of t-tau (A) and p-tau181 (B) in the CSF during MAD and LTE.…”

Personalised Regional Modelling Predicts Tau Progression in the Human Brain

“…If AD is a consequence of first tau spread and then production, it will be crucial for these immunotherapies to be administered early in the AD process to halt the widespread transmission of tau before accelerated local production can occur. In contrast, therapies that act to reduce intracellular tau concentration should be effective in slowing AD progression across the AD continuum, regardless of whether widespread tau transmission has occurred [53].…”