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.

1st Department of Neurology Faculty of Medicine Comenius University and University Hospital Bratislava Slovakia

Alzheimer Center Amsterdam University Medical Centers Amsterdam the Netherlands

AXON Neuroscience CRM Services SE Bratislava Slovakia

AXON Neuroscience R and D Services SE Bratislava Slovakia

AXON Neuroscience SE Larnaca Cyprus

Clinical Division of General Neurology Department of Neurology Medical University Graz Graz Austria

Clinical Division of Neurogeriatrics Department of Neurology Medical University Graz Graz Austria

Department of Geriatric Psychiatry Zentralinstitut für Seelische Gesundheit Medical Faculty Mannheim University of Heidelberg Heidelberg Germany

Department of Neurological Diseases University Medical Centre Maribor Maribor Slovenia

Department of Neurology Ulm University Hospital Ulm Germany

Department of Neurology University Medical Centre Ljubljana Ljubljana Slovenia

Department of Radiology and Biomedical Imaging University of California San Francisco CA USA

Division of Neurogeriatrics Center for Alzheimer Research Karolinska Institutet Solna Sweden

Institute of Neuroimmunology Slovak Academy of Sciences Bratislava Slovakia

Memory Clinic Department of Neurology Charles University 2nd Faculty of Medicine and Motol University Hospital Prague Czech Republic

Theme Inflammation and Aging Karolinska University Hospital Huddinge Sweden

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Nat Aging. 2021 Jun;1(6):493-495. doi: 10.1038/s43587-021-00076-w. PubMed

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Post hoc analysis of ADAMANT, a phase 2 clinical trial of active tau immunotherapy with AADvac1 in patients with Alzheimer's disease, positive for plasma p-tau217

NMR Studies of Tau Protein in Tauopathies

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EudraCT
2015-000630-30