Abstract
Alzheimer’s disease (AD) pathology is partly characterized by accumulation of aberrant forms of tau protein. Here we report the results of ADAMANT, a 24-month double-blinded, parallel-arm, randomized phase 2 multicenter placebo-controlled trial of AADvac1, an active peptide vaccine designed to target pathological tau in AD (EudraCT 2015-000630-30). Eleven doses of AADvac1 were administered to patients with mild AD dementia at 40 μg per dose over the course of the trial. The primary objective was to evaluate the safety and tolerability of long-term AADvac1 treatment. The secondary objectives were to evaluate immunogenicity and efficacy of AADvac1 treatment in slowing cognitive and functional decline. A total of 196 patients were randomized 3:2 between AADvac1 and placebo. AADvac1 was safe and well tolerated (AADvac1 n = 117, placebo n = 79; serious adverse events observed in 17.1% of AADvac1-treated individuals and 24.1% of placebo-treated individuals; adverse events observed in 84.6% of AADvac1-treated individuals and 81.0% of placebo-treated individuals). The vaccine induced high levels of IgG antibodies. No significant effects were found in cognitive and functional tests on the whole study sample (Clinical Dementia Rating-Sum of the Boxes scale adjusted mean point difference −0.360 (95% CI −1.306, 0.589)), custom cognitive battery adjusted mean z-score difference of 0.0008 (95% CI −0.169, 0.172). We also present results from exploratory and post hoc analyses looking at relevant biomarkers and clinical outcomes in specific subgroups. Our results show that AADvac1 is safe and immunogenic, but larger stratified studies are needed to better evaluate its potential clinical efficacy and impact on disease biomarkers.
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Data availability
Raw data for figures are available as supplementary materials.
The data that support the findings of this study are available from the corresponding author upon reasonable request.
Antibodies utilized in this study are available from the corresponding author upon reasonable request.
Code availability
The R-code is deposited on GitHub: https://doi.org/10.5281/zenodo.3862685.
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Acknowledgements
The study was funded by AXON Neuroscience SE. The authors thank the patients and their caregivers and the ADAMANT investigators (Supplementary Section 13).
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Contributions
P.N. developed the study design and SAP, performed data analysis and interpretation and manuscript preparation. B.K. led investigational medicinal product (IMP) design, and contributed to data analysis and interpretation and manuscript preparation. S.K. developed the SAP and conducted data analysis, data interpretation and manuscript preparation. R. Schmidt was coordinating investigator and performed data acquisition and study design. P.S. conducted data interpretation and manuscript review for intellectual content. E.K. led immunogenicity assessments, data analysis and interpretation. S.R. performed MRI and DTI evaluation. L. Fialova conducted immunogenicity assessments. M.K. performed data acquisition and manuscript review for intellectual content. N.P.I. conducted immunogenicity assessments. M. Smisek evaluated MRI scans. J.Hanes, E.S., V.P., M.P., J.G., M.C., T.H., P.F. and A.K. performed fluid biomarker analysis. S.S. performed data acquisition and manuscript review for intellectual content. P.K. and M. Samcova undertook safety analysis. J.P. prepared and verified datasets for extended analyses. C.P.G. undertook cognitive assessments. R. Sivak designed the study design and interpreted data. L. Froelich conducted data acquisition and manuscript review for intellectual content. M.F. performed study design, data interpretation, manuscript review for intellectual content. M.R. conducted data acquisition and manuscript review for intellectual content. J. Harrison undertook cognitive assessment and manuscript review for intellectual content. J. Hort undertook data acquisition, manuscript review for intellectual content. M. Otto performed data acquisition, manuscript review for intellectual content. D.T. carried out biomarker prediction via MRI algorithm. M. Ondrus carried out study design, study oversight, SAP, data interpretation and manuscript preparation. B.W. conducted study design, data interpretation, manuscript review for intellectual content. M.N. carried out study design, data analysis and interpretation, manuscript review for intellectual content. N.Z. conducted study design, data analysis and interpretation and manuscript preparation.
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All authors affiliated with AXON Neuroscience SE, AXON Neuroscience R&D Services SE or AXON Neuroscience CRM Services SE (P.N., B.K., S.K., E.K., L. Fialova, N.P.-I, M. Smisek, J. Hanes, E. S., A. K., V. P., P. K., M. P., J. G., M. C., P. F., J. P., M. Samcova, C. P.-G., R. Sivak, M. F., M. Ondrus, M. N. and N. Z.) receive salary from the respective companies. T.H. receives salary from AXON Neuroscience R&D services SE. R. Schmidt and S.R. have received personal fees and honoraria for image analyses from AXON Neuroscience. The investigators’ institutions have received payments on a per-patient per-visit basis. P. S. has received consultancy/speaker fees (paid to the institution) from AXON, Biogen, People Bio, Roche (Diagnostics) and Novartis Cardiology. He is Principal Investigator of studies with Vivoryon, IONIS, CogRx, AC Immune and Toyama. He serves on the DSMB of Genentech anti-tau study. M. Otto reports personal fees from AXON Neuroscience. The investigator’s institution has received payments on a per-patient per-visit basis. B.W. reports personal fees from AXON Neuroscience. The investigator’s institution has received payments on a per-patient per-visit basis. J. Hort reports personal fees from AXON Neuroscience. The investigator’s institution has received payments on a per-patient per-visit basis. L. Froelich reports personal fees from AXON Neuroscience. The investigator’s institution has received payments on a per-patient per-visit basis. M.K.’s institution has received payments on a per-patient per-visit basis. M.R.’s institution has received payments on a per-patient per-visit basis. S.S.’s institution has received payments on a per-patient per-visit basis. J. Harrison reports receipt of personal fees in the past 2 years from AlzeCure, Aptinyx, Astra Zeneca, Athira Therapeutics, AXON Neuroscience, Axovant, Biogen Idec, BlackThornRx, Boehringer Ingelheim, Cerecin, Cognition Therapeutics, Compass Pathways, CRF Health, Curasen, EIP Pharma, Eisai, Eli Lilly, FSV7, G4X Discovery, GfHEU, Heptares, Ki Elements, Lundbeck, Lysosome Therapeutics, MyCognition, Neurocentria, Neurocog, Neurodyn Inc., Neurotrack, Novartis, Nutricia, Probiodrug, Regeneron, Rodin Therapeutics, Samumed, Sanofi, Servier, Signant, Syndesi Therapeutics, Takeda, Vivoryon Therapeutics, vTv Therapeutics and Winterlight Labs. Additionally, he holds stock options in Neurotrack Inc. and is a joint holder of patents with MyCognition Ltd. D.T.’s institution received payments from AXON Neuroscience for image processing during the conduct of the study.
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Extended data
Extended Data Fig. 1 CSF biomarker baseline values.
For pT217, values of 92 pg/mL indicate values < LLOQ. Error bars denote geometric mean and 95% CI. Full analysis set, patients who provided CSF at baseline (n = 46, except for pT217, where 3 patients were not evaluated due to sample depletion).
Extended Data Fig. 2 The association between IgG levels and patient age is fairly loose.
Simple linear regression line and 95% confidence bands are shown. FAS, AADvac1-treated completers shown (n = 99, AUC not calculated in one patient due to missing sample). Pearson r –0.2335 (95% CI –0.4119, –0.03785), p = 0.0200.
Extended Data Fig. 3 CSF versus serum antibodies.
Overall correlation (above) Spearman r= 0.9351, 95% CI (0.8806, 0.9652), P (two-tailed) <0.0001. Correlation by visit (below): V11 Spearman r = 0.9112, 95% CI (0.7853, 0.9647), p < 0.0001; V16 Spearman r = 0.9341, 95% CI (0.8417, 0.9734), p < 0.0001. Simple linear regression line and 95% confidence bands are shown. FAS, AADvac1-treated patients who provided CSF at V11 and/or V16 (n = 21 and 22, respectively).
Extended Data Fig. 4 IgG isotype profile following 4-5 doses of AADvac1.
Immunization with AADvac1 predominantly stimulates production antibodies of IgG1 isotype. Values were obtained after 4-5 doses of AADvac1 (n = 13, randomly selected). Thick vertical lines and error bars indicate geometric mean and 95% CI. Boxes indicate median and quartiles. Whiskers indicate 1.5× IQR.
Extended Data Fig. 5 Changes in CSF tau biomarkers in a subset of placebo- and AADvac1-treated patients across the duration of the trial.
Changes in CSF tau biomarkers in a subset of placebo- and AADvac1-treated patients across the duration of the trial Absolute and baseline-adjusted average changes in CSF pT181 phospho-tau (95% CI –17.9080, 1.6567; t-statistic –1.7144; df = 24; p = 0.09935; Cohen’s d –0.5749) (a and b), CSF pT217 phospho-tau (95% CI –119.1822, –19.3229; t-statistic –2.8692; df = 23; p = 0.00867; Cohen’s d –0.9474) (c and d) and CSF total tau (95% CI –1148.1889, 4.5162; t-statistic –1.9418; df = 24; p = 0.06399; Cohen’s d –0.8963) (t-tau; e and f) in a subset of placebo- and AADvac1-treated patients during the 104 weeks of the trial (ANCOVA, adjusted for baseline). On the left are shown the absolute measurements for all individuals (dashed lines) and their mean per group (solid lines). On the right are shown the average baseline-adjusted changes (mean, 95% CI of mean) in the two groups. FAS, AADvac1-treated patients who provided CSF at baseline and end of study shown. pT181, AADvac1 n = 20, placebo n = 7; pT217 phospho-tau, AADvac1 n = 19, placebo n = 7; t-tau, AADvac1 n = 20, placebo n = 7.
Extended Data Fig. 6 CSF tau biomarker changes by APOE4 genotype.
Both APOE4- and APOE4 + AADvac1-treated patients contribute to the difference from placebo. Error bars denote mean change and 95% CI of mean. FAS, patients with both baseline and end-of-study values (placebo n = 7, all APOE4 positive; AADvac1 APOE4 positive n = 10, APOE4 negative n = 10 for pT181 and total tau, and n = 9 for pT217 tau).
Extended Data Fig. 7 CSF amyloid and neurogranin.
a, Individual patient courses of CSF neurogranin levels. b, Both AADvac1 and placebo group showed decrease in neurogranin. (95% CI –48.913, 14.194; t-statistic –1.1355; df = 24; p = 0.26738; Cohen’s d –0.3154) Change from baseline (mean, 95% CI of mean shown). c, The decrease in CSF Aβ40 in AADvac1 and placebo patients is almost universal. d, Both treatment and placebo group showed decrease in Aβ40. (95% CI –2056.972, 280.813; t-statistic –1.5681; df = 24; p = 0.12996; Cohen’s d –0.3679) Change from baseline (mean, 95% CI of mean shown). e, Individual patient courses of CSF Aβ42 levels. f, Both treatment and placebo group showed decrease in Aβ42. (95% CI –47.001, 45.385; t-statistic –0.0361; df = 24; p = 0.97151, Cohen’s d –0.0228) Change from baseline (mean, 95% CI of mean shown). FAS, patients who provided baseline and end-of-study CSF samples, AADvac1 n = 20, placebo n = 7.
Extended Data Fig. 8 Effects of AADvac1 treatment on white matter integrity.
a–d, Fornix integrity is preserved by treatment a, Fractional anisotropy, individual patient courses. Group means shown in bold. b, Fractional anisotropy, change from baseline (95% CI 0.0294,0.1277; t-statistic 3.3739; df = 17, p = 0.00361, Cohen’s d = 1.9261). c, Mean diffusivity, individual patient courses. Group means shown in bold. d, Mean diffusivity, change from baseline (95% CI –0.637, 0.041; p = 0.08135, t-statistic –1.8528; df = 17, Cohen’s d = –1.3254). e–h, Corpus callosum (genu) integrity on AADvac1 vs. placebo treatment. e, Fractional anisotropy, individual patient courses. Group means shown in bold. f, Fractional anisotropy, change from baseline (95% CI –0.008, 0.055; t-statistic 1.5769; df = 17; p = 0.13324, Cohen’s d = 0.9732). g, Mean diffusivity, individual patient courses. Group means shown in bold. h, Mean diffusivity, change from baseline (95% CI –0.11, 0.005; t-statistic –1.9262; df = 17; p = 0.07097; Cohen’s d –1.0913). FAS, patients who had both baseline and end of study DTI sequences (AADvac1 n = 13, placebo n = 7). Panels b,d,f,h show mean and 95% CI of mean change.
Extended Data Fig. 9 DTI changes by APOE4 genotype. Both APOE4– and APOE4 + AADvac1-treated patients contribute to the difference from placebo.
Error bars denote mean change and 95% CI of mean (for APOE4– placebo, only the mean is shown). FAS, patients who had DTI sequences at baseline and end of study (n = 20). AADvac1: APOE4 neg. n = 6, APOE4 pos. n = 7. Placebo: APOE4 neg. n = 2, APOE4 pos. n = 5.
Supplementary information
Supplementary Information
Supplementary Tables 6–27; commentary on some extended figures; administrative details; CONSORT checklist; site and investigator list; verbatim eligibility criteria; detailed AE listings; and subgroup demographics.
Supplementary Data 1
Combined document with clinical trial protocol and SAP.
Source data
Source Data Fig. 2
Titers and quantity of IgG antibodies to Axon Peptide 108.
Source Data Fig. 3
Raw baseline NfL values and change from baseline values.
Source Data Extended Data Fig. 1
CSF biomarker baseline values.
Source Data Extended Data Fig. 2
Age and cumulative IgG amount data (area under curve).
Source Data Extended Data Fig. 3
CSF versus serum antibody quantities.
Source Data Extended Data Fig. 4
IgG isotype values
Source Data Extended Data Fig. 5
CSF tau biomarker data (absolute values, change from baseline).
Source Data Extended Data Fig. 6
CSF tau biomarker changes by APOE genotype.
Source Data Extended Data Fig. 7
CSF amyloid and neurogranin biomarker data (absolute values, change from baseline).
Source Data Extended Data Fig. 8
DTI (FA, MD) absolute and change from baseline values.
Source Data Extended Data Fig. 9
DTI changes by APOE genotype.
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Novak, P., Kovacech, B., Katina, S. et al. ADAMANT: a placebo-controlled randomized phase 2 study of AADvac1, an active immunotherapy against pathological tau in Alzheimer’s disease. Nat Aging 1, 521–534 (2021). https://doi.org/10.1038/s43587-021-00070-2
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DOI: https://doi.org/10.1038/s43587-021-00070-2
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