Safety, tolerability, immunogenicity, and efficacy of ABvac40 active immunotherapy against Aβ40 in patients with mild cognitive impairment or very mild Alzheimer's disease: A randomized, double-blind, placebo-controlled phase 2 study

Abstract

Introduction: ABvac40 is an investigational active immunotherapy (vaccine) targeting Aβ40. This study assessed the safety and immunogenicity of ABvac40 in patients with amnestic mild cognitive impairment or very mild Alzheimer's disease.

Methods: AB1601 was a multicenter, randomized, double-blind, placebo-controlled phase 2 study. Patients (n = 124) received five monthly injections plus a 10-month booster of ABvac40 or placebo, with 18-24 months of follow-up. Primary endpoints included safety, tolerability, and immunogenicity. Secondary endpoints assessed immune response, neuropsychological changes, and disease biomarkers.

Results: Treatment-emergent adverse events (TEAEs) and serious TEAEs were comparable between ABvac40 (90.6% and 26.6%) and placebo (93.3% and 26.7%). Amyloid-related imaging abnormalities-hemorrhage (ARIA-H) were similar (12.5% ABvac40; 15.0% placebo), with no ARIA-edema (ARIA-E) or meningoencephalomyelitis. ABvac40 induced a specific, sustained immune response in plasma, with detectable antibodies in CSF.

Discussion: These findings support further investigation of ABvac40 as a potential disease-modifying therapy.

Clinical trial registration number: NCT03461276 (ClinicalTrials.gov) HIGHLIGHTS: ABvac40 was safe and well-tolerated in early-stage Alzheimer's disease patients. No amyloid-related imaging abnormalities-edema (ARIA-E) or encephalitis observed; ARIA-hemorrhage (ARIA-H) rates were similar across groups. Specific, sustained immune response to ABvac40 in plasma, with cerebrospinal fluid (CSF) antibody penetration. Cognitive scales and magnetic resonance imaging (MRI) volumetric data favored ABvac40 over placebo. Results support further development of ABvac40 as a disease-modifying therapy.

Keywords: ABvac40; Alzheimer's disease; Aβ40; active immunotherapy; amyloid‐β 40; cerebral amyloid angiopathy; clinical trial; disease‐modifying therapy; phase 2; randomized trial; vaccine.

FIGURE 1

Patient disposition. ^aTwo patients were randomized to placebo but inadvertently received one dose of ABvac40; therefore, these two patients were summarized for the safety population in the ABvac40 arm. ITT, intent‐to‐treat; mITT, modified intent‐to‐treat; PP, per‐protocol; PPc, per‐protocol cognition.

FIGURE 2

Immunogenicity of ABvac40. (A) Average MΔ of anti‐Aβ40 antibody signal in plasma (optical density in ELISA) from baseline (mITT population). MΔ for each participant was defined as the maximum change from baseline in anti‐Aβ40 antibody signal across all post‐baseline visits. The line represents the median (horizontal line), and the error bars indicate the IQR. Individual values are also shown. Group differences were assessed using the Mann–Whitney U test. ***p < 0.001. (B) (C) Anti‐Aβ40 antibody concentrations in CSF (B) and plasma (C) for ABvac40 and placebo groups (ITT population). Plasma values are presented as mean ± 95% CI, while CSF values are shown as median and IQR. In the CSF graph, two outliers from the ABvac40 group at 12 months (219.28 ng/mL and 119.10 ng/mL) are excluded for visualization but included in median and IQR calculations. (D) Frequency of memory B cells in blood (ITT population). Values are presented as mean ± 95% CI. Aβ, amyloid‐beta; CI, confidence interval; CSF, cerebrospinal fluid; IQR, interquartile range; ITT, intent‐to‐treat; MΔ, maximal increment; mITT, modified intent‐to‐treat; n, number of participants; PBMC, peripheral blood mononuclear cells; SFU, spot‐forming units. Syringe symbol: time points of product administration.

FIGURE 3

Performance in neuropsychological tests (PPc population). (A) MMSE; (B) RBANS; (C) TMT‐A; (D) CDR‐SB; (E) ADCS‐ADL MCI. Plots show the LS‐mean change from baseline and 95% CI based on an MMRM analysis. *p < 0.05. ADCS‐ADL MCI, Alzheimer's Disease Cooperative Study–Activities of Daily Living, Mild Cognitive Impairment; CDR‐SB, Clinical Dementia Rating Sum of Boxes; CI, confidence interval; LS, least squares; MMRM, mixed model for repeated measures; MMSE, Mini‐Mental State Examination; n, number of participants; PPc, per‐protocol cognition; RBANS, Repeatable Battery for the Assessment of Neuropsychological Status; TMT‐A, Trail Making Test A. Syringe symbol: time points of product administration.

FIGURE 4

Brain imaging assessments (PP population). Volumetric MRI measures of whole brain (A) and hippocampal atrophy (B) (left hippocampus) and (C) (right hippocampus). (D) Rate of amyloid deposition as measured by amyloid‐PET. Plots show the LS‐mean change from baseline and 95% CI based on an MMRM analysis. *p < 0.05. CI, confidence interval; LS, least squares; MMRM, mixed model for repeated measures; MRI, magnetic resonance imaging; n, number of participants; PET, positron emission tomography; PP, per‐protocol. Syringe symbol: time points of product administration.

FIGURE 5

Plasma levels of Aβ40 peptide measured by (A) mass spectrometry‐based assay (total levels) or (B) immunoassay (free levels) (PP population). Plots shows LS‐mean change from baseline and 95% CI based on a MMRM analysis. *p < 0.05; **p < 0.01; ***p < 0.001. Aβ, amyloid‐beta; CI, confidence interval; LS, least squares; MMRM, mixed model for repeated measures; n, number of participants; PP, per‐protocol. Syringe symbol: time points of product administration.

FIGURE 6

Reactivity of ABvac40‐induced antibodies on paraffin‐embedded occipital brain sections from patients with AD and concomitant CAA. IHC was performed using plasma (A–C) and CSF (D–F) samples from ABvac40‐treated patients as primary antibodies. The images show specific labeling of vascular amyloid deposits in the walls of blood vessels throughout the brain, including leptomeningeal and penetrating arteries (A, D), arterioles (some of which also exhibit amyloid aggregates in the surrounding neuropil) (B, E), and capillaries (C, F). AD, Alzheimer's disease; CAA, cerebral amyloid angiopathy; CSF, cerebrospinal fluid; IHC, immunohistochemistry.