Efficacy assessment of an active tau immunotherapy in Alzheimers disease patients with amyloid and tau pathology: a post hoc analysis of the ADAMANT randomised, placebo-controlled, double-blind, multi-centre, phase 2 clinicaltrial.

BACKGROUND: Tau pathology correlates with and predicts clinical decline in Alzheimers disease. Approved tau-targeted therapies are not available. METHODS: ADAMANT, a 24-month randomised, placebo-controlled, parallel-group, double-blinded, multicenter, Phase 2 clinical trial (EudraCT2015-000630-30, NCT02579252) enrolled 196 participants with Alzheimers disease; 119 are included in this post-hoc subgroup analysis. AADvac1, active immunotherapy against pathological tau protein. A machine learning model predicted likely Amyloid+Tau+participants from baseline MRI. STATISTICAL METHODS: MMRM for change from baseline in cognition, function, and neurodegeneration; linear regression for associations between antibody response and endpoints. RESULTS: The prediction model achieved PPV of 97.7% for amyloid, 96.2% for tau. 119 participants in the full analysis set (70 treatment and 49 placebo) were classified as A+T+. A trend for CDR-SB 104-week change (estimated marginal means [emm]=-0.99 points, 95% CI [-2.13, 0.13], p=0.0825]) and ADCS-MCI-ADL (emm=3.82 points, CI [-0.29, 7.92], p=0.0679) in favour of the treatment group was seen. Reduction was seen in plasma NF-L (emm=-0.15 log pg/mL, CI [-0.27,-0.03], p=0.0139). Higher antibody response to AADvac1 was related to slowing of decline on CDR-SB (rho=-0.10, CI [-0.21, 0.01], p=0.0376) and ADL (rho=0.15, CI [0.03, 0.27], p=0.0201), and related to slower brain atrophy (rho=0.18-0.35, p<0.05 for temporal volume, whole cortex, and right and left hippocampus). CONCLUSIONS: In the subgroup of ML imputed or CSF identified A+T+, AADvac1 slowed AD-related decline in an antibody-dependent manner. Larger anti-tau trials are warranted. FUNDING: AXON Neuroscience SE.