FUNDAMANT: an interventional 72-week phase 1 follow-up study of AADvac1, an active immunotherapy against tau protein pathology in Alzheimer’s disease
Abstract Background Neurofibrillary pathology composed of tau protein is closely correlated with severity and phenotype of cognitive impairment in patients with Alzheimer’s disease and non-Alzheimer’s tauopathies. Targeting pathological tau proteins via immunotherapy is a promising strategy for dise...
| Main Authors: | , , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
BMC
2018-10-01
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| Series: | Alzheimer’s Research & Therapy |
| Subjects: | |
| Online Access: | http://link.springer.com/article/10.1186/s13195-018-0436-1 |
| _version_ | 1818700772080091136 |
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| author | Petr Novak Reinhold Schmidt Eva Kontsekova Branislav Kovacech Tomas Smolek Stanislav Katina Lubica Fialova Michal Prcina Vojtech Parrak Peter Dal-Bianco Martin Brunner Wolfgang Staffen Michael Rainer Matej Ondrus Stefan Ropele Miroslav Smisek Roman Sivak Norbert Zilka Bengt Winblad Michal Novak |
| author_facet | Petr Novak Reinhold Schmidt Eva Kontsekova Branislav Kovacech Tomas Smolek Stanislav Katina Lubica Fialova Michal Prcina Vojtech Parrak Peter Dal-Bianco Martin Brunner Wolfgang Staffen Michael Rainer Matej Ondrus Stefan Ropele Miroslav Smisek Roman Sivak Norbert Zilka Bengt Winblad Michal Novak |
| author_sort | Petr Novak |
| collection | DOAJ |
| description | Abstract Background Neurofibrillary pathology composed of tau protein is closely correlated with severity and phenotype of cognitive impairment in patients with Alzheimer’s disease and non-Alzheimer’s tauopathies. Targeting pathological tau proteins via immunotherapy is a promising strategy for disease-modifying treatment of Alzheimer’s disease. Previously, we reported a 24-week phase 1 trial on the active vaccine AADvac1 against pathological tau protein; here, we present the results of a further 72 weeks of follow-up on those patients. Methods We did a phase 1, 72-week, open-label study of AADvac1 in patients with mild to moderate Alzheimer’s disease who had completed the preceding phase 1 study. Patients who were previously treated with six doses of AADvac1 at monthly intervals received two booster doses at 24-week intervals. Patients who were previously treated with only three doses received another three doses at monthly intervals, and subsequently two boosters at 24-week intervals. The primary objective was the assessment of long-term safety of AADvac1 treatment. Secondary objectives included assessment of antibody titres, antibody isotype profile, capacity of the antibodies to bind to AD tau and AADvac1, development of titres of AADvac1-induced antibodies over time, and effect of booster doses; cognitive assessment via 11-item Alzheimer’s Disease Assessment Scale cognitive assessment (ADAS-Cog), Category Fluency Test and Controlled Oral Word Association Test; assessment of brain atrophy via magnetic resonance imaging (MRI) volumetry; and assessment of lymphocyte populations via flow cytometry. Results The study was conducted between 18 March 2014 and 10 August 2016. Twenty-six patients who completed the previous study were enrolled. Five patients withdrew because of adverse events. One patient was withdrawn owing to noncompliance. The most common adverse events were injection site reactions (reported in 13 [50%] of vaccinated patients). No cases of meningoencephalitis or vasogenic oedema were observed. New micro-haemorrhages were observed only in one ApoE4 homozygote. All responders retained an immunoglobulin G (IgG) antibody response against the tau peptide component of AADvac1 over 6 months without administration, with titres regressing to a median 15.8% of titres attained after the initial six-dose vaccination regimen. Booster doses restored previous IgG levels. Hippocampal atrophy rate was lower in patients with high IgG levels; a similar relationship was observed in cognitive assessment. Conclusions AADvac1 displayed a benign safety profile. The evolution of IgG titres over vaccination-free periods warrants a more frequent booster dose regimen. The tendency towards slower atrophy in MRI evaluation and less of a decline in cognitive assessment in patients with high titres is encouraging. Further trials are required to expand the safety database and to establish proof of clinical efficacy of AADvac1. Trial registration The studies are registered with the EU Clinical Trials Register and ClinicalTrials.gov: the preceding first-in-human study under EudraCT 2012-003916-29 and NCT01850238 (registered on 9 May 2013) and the follow-up study under EudraCT 2013-004499-36 and NCT02031198 (registered 9 Jan 2014), respectively. |
| first_indexed | 2024-12-17T15:10:15Z |
| format | Article |
| id | doaj.art-0a507430e9e248e6b42f67da7fb4aa06 |
| institution | Directory Open Access Journal |
| issn | 1758-9193 |
| language | English |
| last_indexed | 2024-12-17T15:10:15Z |
| publishDate | 2018-10-01 |
| publisher | BMC |
| record_format | Article |
| series | Alzheimer’s Research & Therapy |
| spelling | doaj.art-0a507430e9e248e6b42f67da7fb4aa062022-12-21T21:43:42ZengBMCAlzheimer’s Research & Therapy1758-91932018-10-0110111610.1186/s13195-018-0436-1FUNDAMANT: an interventional 72-week phase 1 follow-up study of AADvac1, an active immunotherapy against tau protein pathology in Alzheimer’s diseasePetr Novak0Reinhold Schmidt1Eva Kontsekova2Branislav Kovacech3Tomas Smolek4Stanislav Katina5Lubica Fialova6Michal Prcina7Vojtech Parrak8Peter Dal-Bianco9Martin Brunner10Wolfgang Staffen11Michael Rainer12Matej Ondrus13Stefan Ropele14Miroslav Smisek15Roman Sivak16Norbert Zilka17Bengt Winblad18Michal Novak19Axon Neuroscience CRM Services SEClinical Division of Neurogeriatrics and Division of General Neurology, Department of Neurology, Medical University GrazAxon Neuroscience R&D Services SEAxon Neuroscience R&D Services SEAxon Neuroscience R&D Services SEAxon Neuroscience CRM Services SEAxon Neuroscience R&D Services SEAxon Neuroscience R&D Services SEAxon Neuroscience R&D Services SEUniversity Clinic of Neurology, Medical University of ViennaUniversity Clinic of Clinical Pharmacology, Medical University of ViennaUniversity Clinic of Neurology, Christian-Doppler-ClinicSocial and Medical Centre East, Danube Hospital, Karl Landsteiner Institute for Memory and Alzheimer ResearchAxon Neuroscience CRM Services SEClinical Division of Neurogeriatrics and Division of General Neurology, Department of Neurology, Medical University GrazAxon Neuroscience CRM Services SEAxon Neuroscience CRM Services SEAxon Neuroscience R&D Services SEDivision of Neurogeriatrics, Department NVS Clinical Trial Unit, Karolinska Institute Alzheimer Disease Research Centre, Geriatric Clinic, Karolinska University HospitalAxon Neuroscience SE, 4, Arch. Makariou & KalogreonAbstract Background Neurofibrillary pathology composed of tau protein is closely correlated with severity and phenotype of cognitive impairment in patients with Alzheimer’s disease and non-Alzheimer’s tauopathies. Targeting pathological tau proteins via immunotherapy is a promising strategy for disease-modifying treatment of Alzheimer’s disease. Previously, we reported a 24-week phase 1 trial on the active vaccine AADvac1 against pathological tau protein; here, we present the results of a further 72 weeks of follow-up on those patients. Methods We did a phase 1, 72-week, open-label study of AADvac1 in patients with mild to moderate Alzheimer’s disease who had completed the preceding phase 1 study. Patients who were previously treated with six doses of AADvac1 at monthly intervals received two booster doses at 24-week intervals. Patients who were previously treated with only three doses received another three doses at monthly intervals, and subsequently two boosters at 24-week intervals. The primary objective was the assessment of long-term safety of AADvac1 treatment. Secondary objectives included assessment of antibody titres, antibody isotype profile, capacity of the antibodies to bind to AD tau and AADvac1, development of titres of AADvac1-induced antibodies over time, and effect of booster doses; cognitive assessment via 11-item Alzheimer’s Disease Assessment Scale cognitive assessment (ADAS-Cog), Category Fluency Test and Controlled Oral Word Association Test; assessment of brain atrophy via magnetic resonance imaging (MRI) volumetry; and assessment of lymphocyte populations via flow cytometry. Results The study was conducted between 18 March 2014 and 10 August 2016. Twenty-six patients who completed the previous study were enrolled. Five patients withdrew because of adverse events. One patient was withdrawn owing to noncompliance. The most common adverse events were injection site reactions (reported in 13 [50%] of vaccinated patients). No cases of meningoencephalitis or vasogenic oedema were observed. New micro-haemorrhages were observed only in one ApoE4 homozygote. All responders retained an immunoglobulin G (IgG) antibody response against the tau peptide component of AADvac1 over 6 months without administration, with titres regressing to a median 15.8% of titres attained after the initial six-dose vaccination regimen. Booster doses restored previous IgG levels. Hippocampal atrophy rate was lower in patients with high IgG levels; a similar relationship was observed in cognitive assessment. Conclusions AADvac1 displayed a benign safety profile. The evolution of IgG titres over vaccination-free periods warrants a more frequent booster dose regimen. The tendency towards slower atrophy in MRI evaluation and less of a decline in cognitive assessment in patients with high titres is encouraging. Further trials are required to expand the safety database and to establish proof of clinical efficacy of AADvac1. Trial registration The studies are registered with the EU Clinical Trials Register and ClinicalTrials.gov: the preceding first-in-human study under EudraCT 2012-003916-29 and NCT01850238 (registered on 9 May 2013) and the follow-up study under EudraCT 2013-004499-36 and NCT02031198 (registered 9 Jan 2014), respectively.http://link.springer.com/article/10.1186/s13195-018-0436-1TauAlzheimer’s diseaseVaccineImmunotherapyActive immunotherapyClinical trial |
| spellingShingle | Petr Novak Reinhold Schmidt Eva Kontsekova Branislav Kovacech Tomas Smolek Stanislav Katina Lubica Fialova Michal Prcina Vojtech Parrak Peter Dal-Bianco Martin Brunner Wolfgang Staffen Michael Rainer Matej Ondrus Stefan Ropele Miroslav Smisek Roman Sivak Norbert Zilka Bengt Winblad Michal Novak FUNDAMANT: an interventional 72-week phase 1 follow-up study of AADvac1, an active immunotherapy against tau protein pathology in Alzheimer’s disease Alzheimer’s Research & Therapy Tau Alzheimer’s disease Vaccine Immunotherapy Active immunotherapy Clinical trial |
| title | FUNDAMANT: an interventional 72-week phase 1 follow-up study of AADvac1, an active immunotherapy against tau protein pathology in Alzheimer’s disease |
| title_full | FUNDAMANT: an interventional 72-week phase 1 follow-up study of AADvac1, an active immunotherapy against tau protein pathology in Alzheimer’s disease |
| title_fullStr | FUNDAMANT: an interventional 72-week phase 1 follow-up study of AADvac1, an active immunotherapy against tau protein pathology in Alzheimer’s disease |
| title_full_unstemmed | FUNDAMANT: an interventional 72-week phase 1 follow-up study of AADvac1, an active immunotherapy against tau protein pathology in Alzheimer’s disease |
| title_short | FUNDAMANT: an interventional 72-week phase 1 follow-up study of AADvac1, an active immunotherapy against tau protein pathology in Alzheimer’s disease |
| title_sort | fundamant an interventional 72 week phase 1 follow up study of aadvac1 an active immunotherapy against tau protein pathology in alzheimer s disease |
| topic | Tau Alzheimer’s disease Vaccine Immunotherapy Active immunotherapy Clinical trial |
| url | http://link.springer.com/article/10.1186/s13195-018-0436-1 |
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