FUNDAMANT: an interventional 72-week phase 1 follow-up study of
AADvac1, an active immunotherapy against tau protein pathology
in Alzheimer’s disease

J 2018

FUNDAMANT: an interventional 72-week phase 1 follow-up study of AADvac1, an active immunotherapy against tau protein pathology in Alzheimer’s disease

NOVÁK, Petr, Reinhold SCHMIDT, Eva KONTSEKOVA, Branislav KOVACECH, Tomas SMOLEK et. al.

Základní údaje

Originální název

FUNDAMANT: an interventional 72-week phase 1 follow-up study of AADvac1, an active immunotherapy against tau protein pathology in Alzheimer’s disease

Název anglicky

FUNDAMANT: an interventional 72-week phase 1 follow-up study of AADvac1, an active immunotherapy against tau protein pathology in Alzheimer’s disease

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Vydání

Alzheimer’s Research Therapy, Springer, 2018, 1758-9193

Další údaje

Typ výsledku

Článek v odborném periodiku

Utajení

není předmětem státního či obchodního tajemství

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URL

Impakt faktor

Impact factor: 6.142

DOI

http://dx.doi.org/10.1186/s13195-018-0436-1

UT WoS

000448240400001

Změněno: 5. 3. 2020 13:01, Mgr. Marie Šípková, DiS.

Anotace

V originále

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. 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. 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. 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.

Citovat

NOVÁK, Petr, Reinhold SCHMIDT, Eva KONTSEKOVA, Branislav KOVACECH, Tomas SMOLEK, Stanislav KATINA, Lubica FIALOVÁ, Michal PRCINA, Vojtech PARRAK, Peter DAL-BIANCO, Martin BRUNNER, Wolfgang STAFFEN, Michael RAINER, Matej ONDRUŠ, Stefan ROPELE, Miroslav SMIŠEK, Roman SIVÁK, Norbert ŽILKA, Bengt WINBLAD a Michal NOVÁK. 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. Springer, 2018, roč. 10, č. 108, s. 1-16. ISSN 1758-9193. Dostupné z: https://dx.doi.org/10.1186/s13195-018-0436-1.

@article{1456917,
   author = {Novák, Petr and Schmidt, Reinhold and Kontsekova, Eva and Kovacech, Branislav and Smolek, Tomas and Katina, Stanislav and Fialová, Lubica and Prcina, Michal and Parrak, Vojtech and DalandBianco, Peter and Brunner, Martin and Staffen, Wolfgang and Rainer, Michael and Ondruš, Matej and Ropele, Stefan and Smišek, Miroslav and Sivák, Roman and Žilka, Norbert and Winblad, Bengt and Novák, Michal},
   article_number = {108},
   doi = {http://dx.doi.org/10.1186/s13195-018-0436-1},
   issn = {1758-9193},
   journal = {Alzheimer’s Research Therapy},
   note = {Žádný z autorů nemá afiliaci k MU, nelze tedy výsledek přenášet do RIV.},
   title = {FUNDAMANT: an interventional 72-week phase 1 follow-up study of AADvac1, an active immunotherapy against tau protein pathology in Alzheimer’s disease},
   url = {https://alzres.biomedcentral.com/articles/10.1186/s13195-018-0436-1},
   volume = {10},
   year = {2018}
}

TY  - JOUR
ID  - 1456917
AU  - Novák, Petr - Schmidt, Reinhold - Kontsekova, Eva - Kovacech, Branislav - Smolek, Tomas - Katina, Stanislav - Fialová, Lubica - Prcina, Michal - Parrak, Vojtech - Dal-Bianco, Peter - Brunner, Martin - Staffen, Wolfgang - Rainer, Michael - Ondruš, Matej - Ropele, Stefan - Smišek, Miroslav - Sivák, Roman - Žilka, Norbert - Winblad, Bengt - Novák, Michal
PY  - 2018
TI  - FUNDAMANT: an interventional 72-week phase 1 follow-up study of AADvac1, an active immunotherapy against tau protein pathology in Alzheimer’s disease
JF  - Alzheimer’s Research Therapy
VL  - 10
IS  - 108
SP  - 1-16
EP  - 1-16
PB  - Springer
SN  - 17589193
N1  - Žádný z autorů nemá afiliaci k MU, nelze tedy výsledek přenášet do RIV.
UR  - https://alzres.biomedcentral.com/articles/10.1186/s13195-018-0436-1
N2  - 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. 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. 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. 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.
ER  -

NOVÁK, Petr, Reinhold SCHMIDT, Eva KONTSEKOVA, Branislav KOVACECH, Tomas SMOLEK, Stanislav KATINA, Lubica FIALOVÁ, Michal PRCINA, Vojtech PARRAK, Peter DAL-BIANCO, Martin BRUNNER, Wolfgang STAFFEN, Michael RAINER, Matej ONDRUŠ, Stefan ROPELE, Miroslav SMIŠEK, Roman SIVÁK, Norbert ŽILKA, Bengt WINBLAD a Michal NOVÁK. FUNDAMANT: an interventional 72-week phase 1 follow-up study of AADvac1, an active immunotherapy against tau protein pathology in Alzheimer’s disease. \textit{Alzheimer’s Research Therapy}. Springer, 2018, roč.~10, č.~108, s.~1-16. ISSN~1758-9193. Dostupné z: https://dx.doi.org/10.1186/s13195-018-0436-1.

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