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.

introductionABvac40 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.

methodsAB1601 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.

resultsTreatment-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.