Background

AN-1792 was the first active immunotherapy strategy for Alzheimer's disease. AN-1792 consists of synthetic full-length Aβ peptide with QS-21 adjuvant. The rationale was that AN-1792 would induce an immune response that would remove brain amyloid deposition. Extensive preclinical evidence showed that immunization with Aβ1-42 peptide can prevent or reverse the development of the neuropathological hallmarks of Alzheimer's disease, including  amyloid plaque formation, neuritic dystrophy, synaptic loss, gliosis, and impaired performance in behavioral assays (e.g. Schenk et al., 1999).

Findings

Dosing in a 372-patient, multinational Phase 2a trial in people with mild to moderate AD was suspended when four treated patients developed brain inflammation that later proved to be aseptic meningoencephalitis. Altogether, six percent of patients came down with this side effect. In 2002, development of AN-1792 was terminated, but follow-up assessment of treated patients continued.

Postmortem pathology examination of patients who had received AN-1792 in Phase 1 or 2a showed that the vaccine had markedly cleared plaque from the brain.  It did not clear neurofibrillary tangles. Postmortem pathology also showed T cell infiltration and inflammation around leptomeningeal blood vessels, especially near vascular amyloid (e.g. Nicoll et al., 2003). Only a minority of patients treated with AN-1792 mounted a significant antibody response, primarily with antibodies directed against the N-terminus of Aβ (see Lee et al., 2005). Eight responders from the Phase 1 trial were reported to have died from end-stage Alzheimer's disease despite brain amyloid clearance (see Holmes et al., 2008). In contrast, a 4.6 year follow up of 159 patients from the Phase 2a trial reported functional benefit in responders (see Vellas et al., 2009). Biomarker analysis in the AN-1792 program was limited. CSF assays reported a trend toward reduction in CSF phospho-tau concentrations in responders, and subsequent phospho-tau analysis of postmortem brain tissue reported a reduction of aggregated tau in neuronal processes (Boche et al., 2010). MRI scans at baseline and after treatment showed a transient increase in brain atrophy in responders, considered paradoxical at the time (see Jul 2004 conference story).

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