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. 2025 Sep 18:120:105940.
doi: 10.1016/j.ebiom.2025.105940. Online ahead of print.

Safety and immunogenicity of two Tau-targeting active immunotherapies, ACI-35.030 and JACI-35.054, in participants with early Alzheimer's disease: a phase 1b/2a, multicentre, double-blind, randomised, placebo-controlled study

Olivier Sol  1 , Julien Mermoud  2 , Merja Hallikainen  3 , Sudhir Kurl  3 , Juha Rinne  4 , Paul Dautzenberg  5 , Everard G B Vijverberg  6 , Catherine Mummery  7 , Anne Börjesson-Hanson  8 , Michael Jonsson  9 , Craig Ritchie  10 , Catherine Pennington  10 , Marija Vukicevic  2 , Eva Gollwitzer  2 , Emma Fiorini  2 , David T Hickman  2 , Valérie Hliva  2 , Julian Gray  2 , Viktoriia Gerasymchuk  2 , Jonathan Wagg  2 , Nicolas Fournier  2 , Bénédicte Lê  2 , Iva Kezic  11 , Lennert Steukers  11 , Gallen Triana-Baltzer  12 , Clara Theunis  11 , Johannes Streffer  13 , Marie Kosco-Vilbois  2 , Andrea Pfeifer  2 , Philip Scheltens  6
Affiliations

Safety and immunogenicity of two Tau-targeting active immunotherapies, ACI-35.030 and JACI-35.054, in participants with early Alzheimer's disease: a phase 1b/2a, multicentre, double-blind, randomised, placebo-controlled study

Olivier Sol et al. EBioMedicine. .

Abstract

Background: Active immunotherapies targeting C-terminal phosphorylated Tau species have the potential to efficiently reduce Tau spreading. ACI-35.030, a SupraAntigen®-based liposome, and JACI-35.054, a CRM197 carrier-protein conjugate, share the same immunogenic pTau sequence and were assessed to determine the best formulation for preferential activation of B cells specific to pathological Tau forms.

Methods: Individuals with early AD were enrolled in this randomised, double-blind, placebo-controlled study (NCT04445831). Participants were randomly assigned to 2 cohorts (ACI-35.030 at 300, 900, 1800 μg or placebo; and JACI-35.054 at 15, 60 μg or placebo) and received 4 intramuscular injections over 48 weeks, followed up to week 74. Participants receiving at least one dose of study drug were included in the intention-to-treat analysis. The primary objectives were safety, tolerability and immunogenicity.

Findings: Among the 57 randomised participants, 41 were assigned to the ACI-35.030 cohort and 16 to the JACI-35.054 cohort. The most frequent adverse events observed consistently in both active groups were injection site reactions (16.7%-100%) and headaches (16.7%-50%). No relevant MRI findings and no adverse events leading to study discontinuation were reported. ACI-35.030 required only one injection to induce anti-pTau IgG titres in all participants and consistently boosted levels with subsequent immunisations. JACI-35.054 raised a strong but more heterogenous anti-pTau IgG response and required multiple administrations to reach consistent titres in all participants. ACI-35.030 induced a robust polyclonal antibody response binding enriched PHF from AD brain tissue while concurrently sparing the response to non-phosphorylated Tau. A post-hoc statistical analysis revealed statistically significant differences between some randomised actively treated groups and the pooled placebo group on plasma pTau217 and brain-derived Tau changes from baseline.

Interpretation: ACI-35.030 and JACI-35.054 were well tolerated. ACI-35.030 induced a more rapid and sustained antibody response selective to p-Tau species with evidence of altering AD-related plasma biomarkers and was selected for testing in the ongoing Phase 2b trial.

Funding: AC Immune SA and Johnson & Johnson Innovative Medicine.

Keywords: Active immunotherapy; Alzheimer's disease; Immunogenicity; Paired helical filament; Tau; Vaccine; phosphoTau.

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Conflict of interest statement

Declaration of interests OS, JM, MV, EG, EF, DTH, VH, VG, JW, NF, BL, MKV, and AP, who is the CEO, are full-time employees and shareholders of AC Immune SA. JS was a full-time employee and shareholder of AC Immune SA at the time of study conduct. JG received consulting fees as a clinical advisor of AC Immune SA. IK is a full-time employee and shareholder of Johnson & Johnson Innovative Medicine, she is also the co-holder of patent JPI6073USPSP2. LS is a full-time employee and shareholder of Johnson & Johnson Innovative Medicine, he is also the co-holder of patents JPl6059OMPCT1 and JPl6073USPSP2. GTB is a full-time employee and shareholder of Johnson & Johnson Innovative Medicine, he is also the co-holder of patents JAB6123USPSP2, JAB7064USPSP2, JAB7165USPSP2, and JAB721SUSPSP2. CT is a full-time employee and shareholder of Johnson & Johnson Innovative Medicine, she is also the co-holder of patents PCT/US2022/074902 and PCT/US2024/052885. JR was study investigator and fees related to the conduct of the study were paid to his institution, he had also academic research grants from Sigrid Juselius Foundation that were received by his institution and also from the Finnish Governmental Research Funding (VTR) that were received by Turku University Hospital. MH, SK, PD, EGBV, and ABH were study investigators and fees related to the conduct of the study were paid to their respective institutions. MJ was study investigator and fees related to the conduct of the study were paid to his institution, he received compensation for advisory board attendance with Biogen, Eli Lilly, Eisai, and BioArctic. CM was study investigator and fees related to the conduct of the study were paid to her institution, she was granted award for investigator led trial of ultrafast MRI in dementia with Biogen, she received compensation for advisory board attendance with Roche, Eli Lilly, Eisai, Novartis, Neurimmune, MSD, and GSK, she received honorarium for lecturing at sponsored symposium with Eli Lilly and Eisai, she received payments from Biogen, Eisai, Roche, and Alector for travel and accommodation for advisory board meetings held at different scientific conferences, she received compensation as DSMB chair from Imperial and Immunobrain, and she is also Director of NIHR UK Dementia Trials Network. CR was study investigator and fees related to the conduct of the study were paid to his institution, he is also the Founder, CEO, and majority shareholder of Scottish Brain Sciences, he received consulting fees from Biogen, Eisai, MSD, Actinogen, Roche, Eli Lilly, and Novo Nordisk, he received payment or honoraria for lectures and presentations from Roche, Eisai, and Eli Lilly, and he also received compensation from Novo Nordisk for advisory board attendance. CP was study investigator and fees related to the conduct of the study were paid to her institutions. PS is Professor Emeritus at Amsterdam UMC, is a DSMB member at Immunobrain Checkpoint and at Johnson & Johnson Innovative Medicine, is a co-chair at the steering committee of EVOKES studies at Novo-Nordisk, is a full-time employee of EQT Life Sciences and, as the ACI-35-1802 study coordinating investigator, he received consulting fees that were paid to Amsterdam UMC.

Figures

Fig. 1
Fig. 1
Trial profile.1A participant was considered to have completed the study treatment if he or she had reached the end of the treatment period (Visit 9 Week 50) and had received all planned injections (4 successive IM immunisations with IP). 2A participant was considered to have not completed the study treatment if he or she had reached the end of the treatment period (Visit 9 Week 50) and had not received all planned IP injections. 3Participants discontinuing study due to participant withdrawal are the same participants who discontinued IP. 4A participant was considered to have completed the study if he or she had completed the safety follow-up period. eCRF = electronic case report form; IM = intramuscular; IP = investigational product.
Fig. 2
Fig. 2
Geometric mean of the anti-pTau, anti-ePHF, and anti-Tau IgG responses with active immunotherapies. Plots of the geometric mean of anti-pTau (a, b), anti-ePHF (c, d), and anti-Tau IgG (e, f) responses versus nominal study visit time (in weeks) for active immunotherapy with ACI-35.030 (a, c, e) or JACI-35.054 (b, d, f). Error bars denote standard errors of the geometric means. Geometric means and standard errors are plotted by study arm and nominal study visit time. Sample sizes for plotted geometric means and standard errors are tabulated below each graph. The four vertical arrows at the top of each graph denote nominal study visit times for administration of ACI-35.030 or JACI-35.054.
Fig. 3
Fig. 3
Arithmetic mean change from baseline of plasma pTau217 and plasma brain derived (BD) Tau with active immunotherapy. Plots of the mean change from baseline of plasma pTau217 (a, b) and plasma brain derived (BD) Tau (c, d) concentrations (pg/mL) versus nominal study visit time (in weeks) for active immunotherapy with ACI-35.030 (a, c) or JACI-35.054 (b, d). Error bars denote standard errors of the means. Means and standard errors are plotted by study arm and nominal study visit time. Sample sizes for plotted means and standard errors are tabulated below each graph. Stars denote a statistically significant (p < 0.05) difference from placebo group based on the post-hoc statistical analysis (Linear Mixed Model analysis, contrasts using Satterthwaite's degrees of freedom; see Supplementary Material for full details). The four vertical arrows at the top of each graph denote nominal study visit times for administration of ACI-35.030 or JACI-35.054.
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