PMID- 29378651 OWN - NLM STAT- MEDLINE DCOM- 20190916 LR - 20190916 IS - 1758-9193 (Electronic) VI - 10 IP - 1 DP - 2018 Jan 29 TI - Safety, tolerability and immunogenicity of an active anti-Abeta(40) vaccine (ABvac40) in patients with Alzheimer's disease: a randomised, double-blind, placebo-controlled, phase I trial. PG - 12 LID - 10.1186/s13195-018-0340-8 [doi] LID - 12 AB - BACKGROUND: Immunotherapy targeting the amyloid-beta (Abeta) peptide is a promising strategy for the treatment of Alzheimer's disease (AD); however, none of the active or passive vaccines tested have been demonstrated to be effective to date. We have developed the first active vaccine against the C-terminal end of Abeta(40), ABvac40, and assessed its safety and tolerability in a phase I clinical trial. METHODS: A randomised, double-blind, placebo-controlled, parallel-group, phase I study of ABvac40 was conducted with patients aged 50-85 years with mild to moderate AD. Participants were entered into three separate groups according to time of study entry and were randomly allocated to receive ABvac40 or placebo (overall ratio 2:1). The first group received two half-doses of ABvac40 or placebo, whereas the second and third groups received two and three full doses, respectively. All treatments were administered subcutaneously at 4-week intervals. Patients, carers and investigators were blind to treatment allocation throughout the study. The primary objective was to assess the safety and tolerability of ABvac40 by registering all adverse events (AEs). All patients who received at least one dose of treatment were included in the safety analysis. The secondary objective was to evaluate the immunogenicity of ABvac40 by titration of specific anti-Abeta(40) antibodies in plasma. RESULTS: Twenty-four patients were randomly allocated: 16 patients to the ABvac40 group and 8 patients to the placebo group. All randomised patients completed the study, therefore the intention-to-treat and safety populations were identical. Overall, 71 AEs affecting 18 patients were recorded: 11 (69%) in the ABvac40 group and 7 (88%) in the placebo group (p = 0.6214). Neither incident vasogenic oedema nor sulcal effusion (amyloid-related imaging abnormalities corresponding to vasogenic oedema and sulcal effusions) nor microhaemorrhages (amyloid-related imaging abnormalities corresponding to microhaemorrhages and hemosiderin deposits) were detected throughout the study period in the ABvac40-treated patients. Eleven of 12 (~92%) individuals receiving three injections of ABvac40 developed specific anti-Abeta(40) antibodies. CONCLUSIONS: ABvac40 showed a favourable safety and tolerability profile while eliciting a consistent and specific immune response. An ongoing phase II clinical trial is needed to confirm these results and to explore the clinical efficacy of ABvac40. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03113812 . Retrospectively registered on 14 April 2017. FAU - Lacosta, Ana-Maria AU - Lacosta AM AD - Araclon Biotech, Via Hispanidad 21, 50009, Zaragoza, Spain. FAU - Pascual-Lucas, Maria AU - Pascual-Lucas M AD - Araclon Biotech, Via Hispanidad 21, 50009, Zaragoza, Spain. FAU - Pesini, Pedro AU - Pesini P AD - Araclon Biotech, Via Hispanidad 21, 50009, Zaragoza, Spain. ppesini@araclon.com. FAU - Casabona, Diego AU - Casabona D AD - Araclon Biotech, Via Hispanidad 21, 50009, Zaragoza, Spain. FAU - Perez-Grijalba, Virginia AU - Perez-Grijalba V AD - Araclon Biotech, Via Hispanidad 21, 50009, Zaragoza, Spain. FAU - Marcos-Campos, Ivan AU - Marcos-Campos I AD - Araclon Biotech, Via Hispanidad 21, 50009, Zaragoza, Spain. FAU - Sarasa, Leticia AU - Sarasa L AD - Araclon Biotech, Via Hispanidad 21, 50009, Zaragoza, Spain. FAU - Canudas, Jesus AU - Canudas J AD - Araclon Biotech, Via Hispanidad 21, 50009, Zaragoza, Spain. FAU - Badi, Hassnae AU - Badi H AD - Araclon Biotech, Via Hispanidad 21, 50009, Zaragoza, Spain. FAU - Monleon, Inmaculada AU - Monleon I AD - Araclon Biotech, Via Hispanidad 21, 50009, Zaragoza, Spain. FAU - San-Jose, Itziar AU - San-Jose I AD - Araclon Biotech, Via Hispanidad 21, 50009, Zaragoza, Spain. FAU - Munuera, Josep AU - Munuera J AD - Institut de Diagnostic per la Imatge, Hospital Universitari Germans Trias i Pujol, Badalona, Spain. FAU - Rodriguez-Gomez, Octavio AU - Rodriguez-Gomez O AD - Memory Clinic and Research Centre, Fundacio ACE Institut Catala de Neurociencies Aplicades, Barcelona, Spain. FAU - Abdelnour, Carla AU - Abdelnour C AD - Memory Clinic and Research Centre, Fundacio ACE Institut Catala de Neurociencies Aplicades, Barcelona, Spain. FAU - Lafuente, Asuncion AU - Lafuente A AD - Memory Clinic and Research Centre, Fundacio ACE Institut Catala de Neurociencies Aplicades, Barcelona, Spain. FAU - Buendia, Mar AU - Buendia M AD - Memory Clinic and Research Centre, Fundacio ACE Institut Catala de Neurociencies Aplicades, Barcelona, Spain. FAU - Boada, Merce AU - Boada M AD - Memory Clinic and Research Centre, Fundacio ACE Institut Catala de Neurociencies Aplicades, Barcelona, Spain. FAU - Tarraga, Lluis AU - Tarraga L AD - Memory Clinic and Research Centre, Fundacio ACE Institut Catala de Neurociencies Aplicades, Barcelona, Spain. FAU - Ruiz, Agustin AU - Ruiz A AD - Memory Clinic and Research Centre, Fundacio ACE Institut Catala de Neurociencies Aplicades, Barcelona, Spain. FAU - Sarasa, Manuel AU - Sarasa M AD - Araclon Biotech, Via Hispanidad 21, 50009, Zaragoza, Spain. LA - eng SI - ClinicalTrials.gov/NCT03113812 PT - Clinical Trial, Phase I PT - Journal Article PT - Randomized Controlled Trial PT - Research Support, Non-U.S. Gov't DEP - 20180129 PL - England TA - Alzheimers Res Ther JT - Alzheimer's research & therapy JID - 101511643 RN - 0 (Alzheimer Vaccines) RN - 0 (Amyloid beta-Peptides) RN - 0 (Peptide Fragments) RN - 0 (amyloid beta-protein (1-40)) SB - IM MH - Aged MH - Aged, 80 and over MH - Alzheimer Disease/blood/*immunology/*therapy MH - Alzheimer Vaccines/adverse effects/*therapeutic use MH - Amyloid beta-Peptides/*immunology MH - Double-Blind Method MH - Female MH - Follow-Up Studies MH - Humans MH - *Immunogenicity, Vaccine MH - Male MH - Middle Aged MH - Peptide Fragments/*immunology MH - Protein Domains MH - Severity of Illness Index MH - Treatment Outcome PMC - PMC5789644 OTO - NOTNLM OT - ABvac40 OT - Alzheimer's disease OT - Amyloid-beta OT - Abeta OT - Immunotherapy OT - Phase I COIS- ETHICS APPROVAL AND CONSENT TO PARTICIPATE: This study was approved by the independent ethics committee of the Barcelona Hospital Clinic and conducted in accordance with the ethical and scientific principles described in the Declaration of Helsinki and the International Conference on Harmonisation Guideline for Good Clinical Practice (CPMP/ICH/135/95), European guidelines for clinical trials (2001/20/CE), and Spanish legislation (Royal Decree 223/2004 of 6 February, which regulates clinical drug trials). All participants provided written informed consent before enrolment. CONSENT FOR PUBLICATION: Not applicable. COMPETING INTERESTS: AML, MPL, PP, DC, VPG, IMC, LS, JC, HB, IM, ISJ and MS are employees of Araclon Biotech Ltd. ISJ is a shareholder of Araclon Biotech Ltd. MS holds several patents related to Alzheimer's disease diagnosis and treatment, and he is the founder, chief executive officer, chief scientific officer and one of the current shareholders of Araclon Biotech Ltd. AR reports receiving personal fees from Landsteiner Genmed, grants from the Innovative Medicines Initiative (IMI) ADAPTED project (European Commission), the IMI MOPEAD project (European Commission), Instituto de Salud Carlos III (ISCIII; Ministry of Health, Spain), Grifols and Fundacion Bancaria "La Caixa" outside the submitted work. MBo reports receiving grants from the European Foundation for the Study of Diabetes/Lilly Mental Health and Diabetes Program 2014-2015, and IH2020-JTI-IMI2-2015-05 (European Commission) (Eli Lilly and AstraZeneca) MOPEAD project 2016-2018, as well as personal fees from Grifols, Janssen, Eli Lilly, MSD, Nutricia, Roche and Servier, outside the submitted work. JM, ORG, CA, AL, MBu and LT declare that they have no competing interests. PUBLISHER'S NOTE: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. EDAT- 2018/01/31 06:00 MHDA- 2019/09/17 06:00 PMCR- 2018/01/29 CRDT- 2018/01/31 06:00 PHST- 2017/09/04 00:00 [received] PHST- 2018/01/11 00:00 [accepted] PHST- 2018/01/31 06:00 [entrez] PHST- 2018/01/31 06:00 [pubmed] PHST- 2019/09/17 06:00 [medline] PHST- 2018/01/29 00:00 [pmc-release] AID - 10.1186/s13195-018-0340-8 [pii] AID - 340 [pii] AID - 10.1186/s13195-018-0340-8 [doi] PST - epublish SO - Alzheimers Res Ther. 2018 Jan 29;10(1):12. doi: 10.1186/s13195-018-0340-8.