Clinical effects of Abeta immunization (AN1792) in patients with AD in an interrupted trial.

Abstract

BACKGROUND:

AN1792 (beta-amyloid [Abeta]1-42) immunization reduces Abeta plaque burden and preserves cognitive function in APP transgenic mice. The authors report the results of a phase IIa immunotherapy trial of AN1792(QS-21) in patients with mild to moderate Alzheimer disease (AD) that was interrupted because of meningoencephalitis in 6% of immunized patients.

METHODS:

This randomized, multicenter, placebo-controlled, double-blind trial of IM AN1792 225 microg plus the adjuvant QS-21 50 microg (300 patients) and saline (72 patients) included patients aged 50 to 85 years with probable AD, Mini-Mental State Examination (MMSE) 15 to 26. Injections were planned for months 0, 1, 3, 6, 9, and 12. Safety and tolerability were evaluated, and pilot efficacy (AD Assessment Scale-Cognitive Subscale [ADAS-Cog], MRI, neuropsychological test battery [NTB], CSF tau, and Abeta42) was assessed in anti-AN1792 antibody responder patients (immunoglobulin G titer > or = 1:2,200).

RESULTS:

Following reports of meningoencephalitis (overall 18/300 [6%]), immunization was stopped after one (2 patients), two (274 patients), or three (24 patients) injections. Of the 300 AN1792(QS-21)-treated patients, 59 (19.7%) developed the predetermined antibody response. Double-blind assessments were maintained for 12 months. No significant differences were found between antibody responder and placebo groups for ADAS-Cog, Disability Assessment for Dementia, Clinical Dementia Rating, MMSE, or Clinical Global Impression of Change, but analyses of the z-score composite across the NTB revealed differences favoring antibody responders (0.03 +/- 0.37 vs -0.20 +/- 0.45; p = 0.020). In the small subset of subjects who had CSF examinations, CSF tau was decreased in antibody responders (n = 11) vs placebo subjects (n = 10; p < 0.001).

CONCLUSION:

Although interrupted, this trial provides an indication that Abeta immunotherapy may be useful in Alzheimer disease.

• Authors: S Gilman, M Koller, R S Black, L Jenkins, S G Griffith, N C Fox, L Eisner, L Kirby, M Boada Rovira, F Forette, J-M Orgogozo, AN1792(QS-21)-201 Study Team
• Journal: Neurology (Neurology) Vol. 64 Issue 9 Pg. 1553-62 (May 10 2005) ISSN: 1526-632X [Electronic] United States
• PMID: 15883316 (Publication Type: Clinical Trial, Phase II, Journal Article, Multicenter Study, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)

Chemical References

• Amyloid beta-Peptides
• Antibodies
• Peptide Fragments
• Placebos
• Vaccines
• amyloid beta-protein (1-42)

Topics

• Aged
• Aged, 80 and over
• Alzheimer Disease (drug therapy, immunology, physiopathology)
• Amyloid beta-Peptides (antagonists & inhibitors, immunology, metabolism)
• Antibodies (blood, immunology)
• Brain (drug effects, immunology, pathology)
• Cognition Disorders (drug therapy, immunology, physiopathology)
• Double-Blind Method
• Drug Administration Schedule
• Female
• Humans
• Immunotherapy, Active (adverse effects, methods)
• Injections, Intramuscular
• Magnetic Resonance Imaging
• Male
• Meningoencephalitis (chemically induced, immunology, physiopathology)
• Middle Aged
• Neuropsychological Tests
• Peptide Fragments (antagonists & inhibitors, immunology, metabolism)
• Placebos
• Treatment Outcome
• Vaccines (administration & dosage, adverse effects, immunology)