Bayer, A. J. et al. Evaluation of the safety and immunogenicity of synthetic A42 (AN1792) in patients with AD. Neurology 64, 94-101

University Department of Geriatric Medicine, Academic Centre, University of Wales College of Medicine, Llandough Hospital, Penarth Road, Cardiff, South Glamorgan, CF64 2XX, UK.
Neurology (Impact Factor: 8.29). 01/2005; 64(1):94-101. DOI: 10.1212/01.WNL.0000148604.77591.67
Source: PubMed


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.
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.
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.
AN1792 + QS-21 elicited a positive antibody response to Abeta42 in more than half of this elderly study population.

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    • "The number of responders was higher in the phase I trial (56.9% of patients who entered the protocol extension likely because addition of polysorbate 80) compared with the phase IIa trial (19.7%) which may have occurred because patients received up to eight doses of AN-1792 in the phase I trial, whereas no patient received more than three doses in the phase IIa trial [42] [58] [64] [65]. Although, data demonstrated significant individual variability of humoral immune responses in trial subjects, it was shown that relatively high anti-Ab antibody titers correlated with a reduction in AD brain pathology in patients that later came to autopsy [52] [54] [55], suggesting a possible therapeutic benefit of the AN-1792 vaccine [58] [64] [65]. Of note, some AD patients with high anti-Ab antibody titers also showed a trend toward slowing of cognitive decline [68], improvement in the memory domain of the neuropsychologic test battery, and decreased cerebrospinal fluid (CSF) tau levels [58]. "
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