Efficacy assessment of an active tau immunotherapy in Alzheimer’s disease patients with amyloid and tau pathology: a post hoc analysis of the “ADAMANT” randomised, placebo-controlled, double-blind, multi-centre, phase 2 clinical trial

Abstract

BackgroundTau pathology correlates with and predicts clinical decline in Alzheimer’s disease. Approved tau-targeted therapies are not available. MethodsADAMANT, a 24-month randomised, placebo-controlled, parallel-group, double-blinded, multicenter, Phase 2 clinical trial (EudraCT2015-000630-30, NCT02579252) enrolled 196 participants with Alzheimer’s disease; 119 are included in this post-hoc subgroup analysis. InterventionAADvac1, 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. FindingsThe 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). InterpretationIn 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. FundingAXON Neuroscience SE