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

Background: Tau pathology correlates with and predicts clinical decline in Alzheimer's 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 Alzheimer's 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.

Keywords: Alzheimer’s disease; Immunotherapy; Machine learning; Post-hoc analysis; Tau.

Fig. 1

Diagrams of study design (CONSORT and STARD flowchart). (a) CONSORT flowchart. FAS = full analysis set. NA = patient could not be evaluated by the machine learning algorithm and did not provide CSF. The FAS are all patients who have any post-baseline value for efficacy; completers are FAS patients who have attended the end-of-study visit at week 104. Patients could present with multiple reasons for screening failure. (b) STARD flowchart. Flow diagram of participants and Amyloid/Tau phenotype of participants within the ADNI model development cohort and within the ADAMANT independent validation cohort.

Fig. 2

MMRM analysis of cognitive and functional endpoints. This figure shows the results of a mixed model for repeated measures (MMRM) analysis for CDR-SB and ADCS-ADL endpoints, with p-values derived from estimated marginal means. All models were adjusted for the baseline and time-interaction effects of age, sex, geographical region, baseline MMSE, baseline plasma NF-L, and APOE status. Higher CDR-SB values and lower ADL values indicate worsening. (a and b) Full analysis set (n = 119). (c and d) Analysis of completers (participants who had CDR-SB and ADL evaluated at the final, 104-week study visit). Error bars indicate standard error and the dotted line indicates baseline. The number of participants for at each visit is presented under each figure. These results are also presented in Supplementary Table S4. ∼p < 0.1; ∗p < 0.05.

Fig. 3

MMRM analysis of neurodegeneration endpoints. This figure shows the results of a mixed model for repeated measures (MMRM) analysis for plasma NF-L and MRI (volume of, temporal lobe, and whole cortex) endpoints for the Full Analysis Subset in sub-figures (a–c) (n = 119) and the set of participants who had endpoint evaluations at the final, 104-week study visit in sub-figures (d–f) (completers). p-values are derived from estimated marginal means. All models were adjusted for the baseline and time-interaction effects of age, sex, geographical region, baseline MMSE, and APOE status. Error bars indicate standard error and the dotted line indicates baseline. The number of participants for at each visit is presented under each figure. These results are also presented in Supplementary Table S4. ∗p < 0.05.

Fig. 4

AADvac1-induced anti-tau antibody production versus change in trial endpoints. This figure shows the results of linear regression modelling with AADvac1-induced anti-tau production as independent variable and change from baseline at 104 weeks in trial endpoints (a: CDR-SB, b: ADCS-ADL, c: plasma NF-L, and MRI [volumes of d: lateral ventricles, e and f: hippocampi, g: temporal lobe, and h: whole cortex]) as dependent variables. AADvac1-induced anti-tau antibody production is presented on a natural logarithmic scale and was adjusted for age and sex before analysis. Only participants from the treatment group who completed the 104-week visit were included in the analysis (n = 62). The number of participants for each analysis is presented in the figure sub-headers.