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

Abstract

<h3>Background</h3><p>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.</p><h3>Methods</h3><p>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.</p><h3>Findings</h3><p>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.</p><h3>Interpretation</h3><p>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. </p>