Evaluation of the safety and immunogenicity of synthetic Abeta42 (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 microg) with QS-21 adjuvant (50 or 100 microg) 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 > or =1:1,000). 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.