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immunization (AN1792) in patients with AD in an interrupted trial
From the Department of Neurology (Dr. Gilman), University of Michigan, Ann Arbor; Elan Pharmaceuticals (Drs. Koller and Griffith), San Diego, CA; Wyeth Pharmaceuticals (Drs. Black and Jenkins), Collegeville, PA; Dementia Research Centre (Dr. Fox), Institute of Neurology, Queen Square, London, UK; Baumel-Eisner Neuromedical Institute (Dr. Eisner), Fort Lauderdale, FL; Pivotal Research Centers (Dr. Kirby), Peoria, AZ; Fundació ACE (Dr. Boada Rovira), Institut Català de Neurociències Aplicades, Barcelona, Spain; Hôpital BROCA La Rochefoucauld (Dr. Forette), Paris, France; and Department of Neurology (Dr. Orgogozo), Université de Bordeaux 2, CHU Pellegrin, Bordeaux, France.
* To whom correspondence should be addressed. E-mail: sgilman{at}umich.edu.
Abstract-- Background: AN1792 (beta-amyloid [A
]1-42) immunization reduces A 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 µg plus the adjuvant QS-21 50 µg (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 A42) was assessed in anti-AN1792 antibody responder patients (immunoglobulin G titer 
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 A immunotherapy may be useful in Alzheimer disease.
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|
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|
|
|
|
|
|
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|
|
|
|
 |
|
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|
|
|
|
|
|
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|
|
|
|
|
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|
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|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
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|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
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|
|
|
|
 |
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
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|
|
|
|
 |
|
 D. Milne Alzheimer's Vaccine Trial Gets Second Life Psychiatr News, June 3, 2005; 40(11): 1 - 36. [Full Text]
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