Synonyms: AIP 001
Therapy Type: Immunotherapy (active) (timeline)
Target Type: Amyloid-Related (timeline)
Condition(s): Alzheimer's Disease
U.S. FDA Status: Alzheimer's Disease (Discontinued)
Company: Janssen, Pfizer
Approved for: None
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).
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).
Clinical Trial Timeline
- Phase 2
- Study completed / Planned end date
- Planned end date unavailable
- Study aborted
Last Updated: 28 Oct 2012
- Nicoll JA, Wilkinson D, Holmes C, Steart P, Markham H, Weller RO. Neuropathology of human Alzheimer disease after immunization with amyloid-beta peptide: a case report. Nat Med. 2003 Apr;9(4):448-52. PubMed.
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- Vellas B, Black R, Thal LJ, Fox NC, Daniels M, McLennan G, Tompkins C, Leibman C, Pomfret M, Grundman M. Long-term follow-up of patients immunized with AN1792: reduced functional decline in antibody responders. Curr Alzheimer Res. 2009 Apr;6(2):144-51. PubMed.
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- Maarouf CL, Daugs ID, Kokjohn TA, Kalback WM, Patton RL, Luehrs DC, Masliah E, Nicoll JA, Sabbagh MN, Beach TG, Castaño EM, Roher AE. The biochemical aftermath of anti-amyloid immunotherapy. Mol Neurodegener. 2010;5:39. PubMed.
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- Koepsell TD, Chi YY, Zhou XH, Lee WW, Ramos EM, Kukull WA. An alternative method for estimating efficacy of the AN1792 vaccine for Alzheimer disease. Neurology. 2007 Nov 6;69(19):1868-72. PubMed.
- Bombois S, Maurage CA, Gompel M, Deramecourt V, Mackowiak-Cordoliani MA, Black RS, Lavielle R, Delacourte A, Pasquier F. Absence of beta-amyloid deposits after immunization in Alzheimer disease with Lewy body dementia. Arch Neurol. 2007 Apr;64(4):583-7. PubMed.
- Fox NC, Black RS, Gilman S, Rossor MN, Griffith SG, Jenkins L, Koller M. Effects of Abeta immunization (AN1792) on MRI measures of cerebral volume in Alzheimer disease. Neurology. 2005 May 10;64(9):1563-72. PubMed.
- Kokjohn TA, Roher AE. Antibody responses, amyloid-beta peptide remnants and clinical effects of AN-1792 immunization in patients with AD in an interrupted trial. CNS Neurol Disord Drug Targets. 2009 Apr;8(2):88-97. PubMed.
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