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


CONCLUSIONS
Although interrupted, this trial provides an indication that Abeta immunotherapy may be useful in Alzheimer disease.
Gilman
S
S
Department of Neurology, University of Michigan, 300 N. Ingalls 3D15, Ann Arbor, MI 48109-0489, USA. sgilman@umich.edu
Koller
M
M
Black
R S
RS
Jenkins
L
L
Griffith
S G
SG
Fox
N C
NC
Eisner
L
L
Kirby
L
L
Rovira
M Boada
MB
Forette
F
F
Orgogozo
J-M
JM
D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000188:drug therapy* / Q000276:immunology / Q000503:physiopathology; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors* / Q000276:immunology / Q000378:metabolism; D000906:Antibodies / Q000097:blood / Q000276:immunology; D001921:Brain / Q000187:drug effects* / Q000276:immunology / Q000473:pathology; D003072:Cognition Disorders / Q000188:drug therapy / Q000276:immunology / Q000503:physiopathology; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D016233:Immunotherapy, Active / Q000009:adverse effects* / Q000379:methods; D007273:Injections, Intramuscular; D008279:Magnetic Resonance Imaging; D008297:Male; D008590:Meningoencephalitis / Q000139:chemically induced* / Q000276:immunology / Q000503:physiopathology; D008875:Middle Aged; D009483:Neuropsychological Tests; D010446:Peptide Fragments / Q000037:antagonists & inhibitors* / Q000276:immunology / Q000378:metabolism; D010919:Placebos; D016896:Treatment Outcome; D014612:Vaccines / Q000008:administration & dosage / Q000009:adverse effects* / Q000276:immunology
D016229:Amyloid beta-Peptides; D000906:Antibodies; D010446:Peptide Fragments; D010919:Placebos; D014612:Vaccines; C075222:amyloid beta-protein (1-42)