Exploratory Tau Biomarker Results From a Multiple Ascending-Dose Study of BIIB080 in Alzheimer Disease: A Randomized Clinical Trial

Abstract

Importance: Accumulation of hyperphosphorylated, tangled microtubule-associated protein tau (MAPT) is a pathological hallmark of Alzheimer disease (AD) associated with disease progression and cognitive decline.

Objective: To evaluate the effect of tau synthesis reduction on tau biomarkers in patients with mild AD.

Design, setting, and participants: This randomized clinical trial was a double-blind, placebo-controlled 36-week multiple-ascending dose (MAD) phase 1b trial (October 2017 to September 2020), followed by a 64- or 71-week open-label long-term extension (LTE) (October 2019 to May 2022). After being assessed for eligibility at 12 sites in Canada and Europe, participants with mild AD and confirmed amyloid pathology were randomized 3:1 (BIIB080:placebo) in 4 dose cohorts.

Intervention: Intrathecal administration of BIIB080, a MAPT-targeting antisense oligonucleotide, or placebo. Active dose arms included 10 mg every 4 weeks, 30 mg every 4 weeks, 60 mg every 4 weeks, and 115 mg every 12 weeks during the MAD period and 60 mg every 12 weeks or 115 mg every 12 weeks during the LTE.

Main outcome and measures: The original primary end point was safety. Additionally, BIIB080, total tau (t-tau), and phosphorylated tau 181 (p-tau181) cerebrospinal fluid (CSF) concentrations were evaluated. Tau positron emission tomography (PET) was collected in a substudy, and standard uptake value ratios (SUVRs) were calculated in a priori-defined composite regions of interest.

Results: Of 102 participants assessed for eligibility, 46 participants with mild AD were enrolled; 23 (50%) were female, and mean (SD) age was 65.8 (5.70) years. BIIB080 was generally well tolerated and was associated with a dose-dependent reduction in CSF t-tau and p-tau181 in the MAD period (56% reduction; 95% CI, 50% to 62%; and 51% reduction; 95% CI, 38% to 63%, of CSF t-tau in the 2 higher-dose cohorts) that continued and/or was maintained through quarterly dosing in the LTE. Tau PET demonstrated reduced accumulation vs placebo at week 25 (n = 13). At week 100, tau PET showed a reduction from baseline across all regions assessed (n = 12), with the largest reductions from baseline observed in the temporal composite (-0.71 SUVR; 95% CI, -1.40 to -0.02). A moderate correlation was observed between model-predicted cumulative CSF drug exposure and tau PET change.

Conclusions and relevance: In this randomized clinical trial, BIIB080 reduced tau biomarkers, including CSF t-tau, CSF p-tau181, and tau PET, which is associated with cognitive decline, in participants with mild AD. Effects of BIIB080 on biomarkers and clinical outcomes are being further evaluated in a phase 2 trial.

Trial registration: ClinicalTrials.gov Identifier: NCT03186989.

Figure 1.. Patient Flow During the Multiple-Ascending Dose (MAD) and Long-Term Extension (LTE) Periods

Eligible patients were randomly assigned in a 3:1 ratio to receive BIIB080 or placebo in all cohorts of the MAD period. Participants in cohorts A, B, and C who transitioned to the LTE all received BIIB080, 60 mg, every 12 weeks, while participants in cohort D who transitioned to the LTE all received BIIB080, 115 mg, every 12 weeks.

Figure 2.. Effect of BIIB080 on Change From Baseline in Cerebrospinal Fluid (CSF) Total Tau (t-tau) and CSF Phosphorylated Tau 181 (p-tau181) in the Multiple-Ascending Dose (MAD) and Long-Term Extension (LTE) Periods

Effect of BIIB080 on levels of t-tau (A) and p-tau181 (B) in the CSF during MAD and LTE. To best summarize the full data set, all patients have been aligned on the same axis from 0 to 96 weeks. However, there was a variable gap between the end of the MAD and beginning of the LTE for cohorts A and B, and available visits at the end of the MAD and the beginning of the LTE have been collapsed into a single data point. For cohorts C and D, for which there was a seamless transition from the MAD to the LTE, no gap period exists. For visualization of the data set with chronologically accurate axes, see eFigure 2 in Supplement 3. Note that participants treated with placebo in cohorts A, B, and C were combined for analysis. Participants in the MAD cohorts A, B, and C who transitioned to the LTE all received BIIB080, 60 mg, every 12 weeks, while participants in cohort D who transitioned to the LTE all received BIIB080, 115 mg, every 12 weeks. A full table indicating the number of participants analyzed at each time point is presented in eTable 5 in Supplement 3. Full summary statistics for each time point are presented in eTables 6 and 7 in Supplement 3. Error bars represent SE.

Figure 3.. Effect of BIIB080 on Change From Baseline in Tau Positron Emission Tomography (PET) in the Multiple-Ascending Dose (MAD) and Long-Term Extension (LTE) Periods

Bar plots show adjusted mean standard uptake value ratio (SUVR) change from baseline at week 25 (A) and week 100 in the LTE (B) for each treatment group. The adjusted mean SUVR change was estimated using an analysis of covariance model with fixed effects of treatment group and baseline SUVR value. Error bars represent SE. Circles represent the individual unadjusted tau PET SUVR change from baseline for each participant. Regimen details for the cohorts shown in each panel from left to right are as follows: orange, placebo cohort D, placebo → 115 mg every 12 weeks; blue, intervention cohort D, 115 mg every 12 weeks → 115 mg every 12 weeks; and green, intervention cohort C, 60 mg every 4 weeks → 60 mg every 12 weeks. Full summary statistics for the unadjusted tau PET SUVR change from baseline are presented in eTables 8 and 9 in Supplement 3.

Figure 4.. Tau Positron Emission Tomography (PET) Image Examples From All Participants With Available Longitudinal Tau PET Data

The selected coronal slice shows temporal and parietal regions associated with tau pathology in Alzheimer disease. SUVR indicates standard uptake value ratio.