Aims

The DIAN-TU Tau NexGen Platform trial will assess the safety, tolerability, biomarker, and cognitive efficacy of anti-tau therapies before and after tangle formation in dominantly inherited AD (DIAD) using a staggered, adaptive design with shared controls across treatment arms.

Tau species, including MTBR-tau which aggregate in tau tangles, increase in CSF and blood more than 10 years before tangles are detected by PET, and are closely associated with progression of Alzheimer pathology. This trial will investigate whether the monoclonal antibody, E2814, which targets soluble MTBR-tau, can limit disease progression in DIAD. To assure comparable background therapy, the anti-amyloid antibody lecanemab will be administered to participants.

The trial will enroll separate DIAD cohorts of pre-tangle, asymptomatic (CDR=0) and post-tangle, symptomatic (CDR=0.5-1.0) participants, randomizing each to E2814 or placebo. Lecanemab will be administered after E2814 in the asymptomatic cohort and before E2814 in the symptomatic cohort. Outcomes include clinical and cognitive measures, and biomarkers.

For the pre-tangle, asymptomatic cohort, CSF ptau217/tau217 at 4 years is the endpoint. For the post-tangle, symptomatic cohort, tau-PET at 2 and 4 years is primary endpoint. Target engagement will be assessed by CSF MTBR-tau and downstream effects on soluble t-tau, p-tau and MTBR tau; neurodegeneration by CSF and blood NfL and structural MRI; metabolism by FDG-PET; and amyloid-beta 42/40 by CSF and blood and amyloid-PET.

This is the first trial designed to assess if and when an anti-MTBR tau antibody, with background anti-amyloid antibody, will exert its targeted biomarker and clinical effects through disease progression in DIAD.