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

Abstract

ImportanceAccumulation of hyperphosphorylated, tangled microtubule-associated protein tau (MAPT) is a pathological hallmark of Alzheimer disease (AD) associated with disease progression and cognitive decline.ObjectiveTo evaluate the effect of tau synthesis reduction on tau biomarkers in patients with mild AD.Design, Setting, and ParticipantsThis 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.InterventionIntrathecal 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 MeasuresThe 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.ResultsOf 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 RelevanceIn 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 RegistrationClinicalTrials.gov Identifier: NCT03186989

Considerations for biomarker strategies in clinical trials investigating tau-targeting therapeutics for Alzheimer’s disease

“…In a similar manner, antisense oligonucleotide approaches that reduce tau expression would be expected to slow the longitudinal progression of tau pathology, as measured by PET, but remain unlikely to drastically affect established tangles. However, in a phase 1b trial investigating the antisense oligonucleotide termed BIIB080 in subjects with mild AD, a significant reduction of tau PET below baseline was observed in a small imaging cohort ( n = 12) at week 100, likely through reducing the amount of tau protein that can be recruited in the modest ability of turnover in tangles [ 90 , 91 ]. Furthermore, an immunotherapeutic approach targeting an epitope within tau tangles may aim to acutely reduce tau PET signal below that of baseline under the context of target engagement, but it should be noted that extracellular tangles are a small and limited population to target.…”

Novel Therapeutic Strategies in Alzheimer’s Disease: Pitfalls and Challenges of Anti-Amyloid Therapies and Beyond

“…The trial results were recently published [ 209 ], showing a CSF total tau and p-181 tau reduction by 60 percent for six months in the higher-dose cohorts. Also, imaging results were promising, with reduced tau aggregates below baseline levels in all brain regions examined with tau PET [ 210 ]. Phase 2 is ongoing (NCT05399888).…”

Excitoprotective effects of conditional tau reduction in excitatory neurons and in adulthood

“…Drugs targeting microtubule-associated protein tau, the primary component of neurofibrillary tangles found in AD, are excellent candidates. Tau reduction using antisense oligonucleotides improved tau biomarkers in a Phase 1 clinical trial (Mummery et al, 2023;Edwards et al, 2023) and a Phase 2 trial is underway (NCT05399888).…”