Evaluation of the safety and immunogenicity of synthetic Aβ42 (AN1792) in patients with AD

Background: Abeta42-immunization reduces plaque burden and improves cognition in transgenic mouse models of Alzheimer disease (AD). This phase 1 study evaluated the safety, tolerability, and immunogenicity of AN1792 (human aggregated Abeta42) in patients with mild to moderate AD. Methods: Twenty patients were enrolled into each of four dose groups and randomly assigned to receive IM AN1792 (50 or 225 mug) with QS-21 adjuvant (50 or 100 mug) or QS-21 only ( control) in a 4:1 active: control ratio on day 0 and at weeks 4, 12, and 24. Patients could receive up to four additional injections of a polysorbate 80 modified formulation at weeks 36, 48, 60, and 72. Safety, tolerability, immunogenicity, and exploratory evidence of efficacy were evaluated. Results: Treatment-related adverse events were reported in 19 (23.8%) patients, but no relationship was observed between AN1792 dose and incidence. One patient developed meningoencephalitis that was diagnosed after death ( not directly related to study treatment) and 219 days after discontinuing from the study. Five deaths occurred during the study follow-up, but none was considered to be directly related to study treatment. During the period of the first four injections, 23.4% of AN1792-treated patients had a positive anti-AN1792 antibody titer (an anti-AN1792 antibody titer of greater than or equal to1:1,000). This increased to 58.8% after additional injections with the modified formulation. Disability Assessment for Dementia scores showed less decline among active compared with control patients at week 84 (p = 0.002). No treatment differences were observed in three other efficacy measures. Conclusions: AN1792 + QS-21 elicited a positive antibody response to Abeta42 in more than half of this elderly study population.