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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.
Address correspondence and reprint requests to Dr. S. Gilman, Department of Neurology, University of Michigan, 300 N. Ingalls 3D15, Ann Arbor, MI 48109-0489; e-mail: sgilman{at}umich.edu
Background: AN1792 (beta-amyloid [Aß]1–42) immunization reduces Aß 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 Aß42) 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 Aß immunotherapy may be useful in Alzheimer disease.
Additional material related to this article can be found on the Neurology Web site. Go to www.neurology.org and scroll down the Table of Contents for the May 10 issue to find the title link for this article.
See also page 1563
*Members of the AN1792(QS-21)-201 Study Team are listed in the Appendix.
Sponsored by Elan Pharmaceuticals, Inc. and Wyeth Research. N.C.F. holds a Medical Research Council Senior Clinical Fellowship.
Drs. Fox, Forette, and Orgogozo have received honoraria (in excess of $10,000 for Dr. Orgogozo only) from Wyeth Research. Drs. Fox and Orgogozo have also received honoraria from Elan Pharmaceuticals, Inc. Dr. Orgogozo is a consultant for Elan Pharmaceuticals, Inc. and Wyeth Research. Dr. Kirby has received grants in excess of $10,000 from Elan Pharmaceuticals, Inc. Dr. Gilman served as Chair of the Safety Monitoring Committee for the trial and received payment from Elan Pharmaceuticals, Inc., only for his time reviewing safety data. Drs. Griffith and Koller are employees of Elan Pharmaceuticals, Inc., and hold equity in excess of $10,000 in its parent company, Elan Corporation, plc. Drs. Jenkins and Black are employees of, hold equity in excess of $10,000, and have received honoraria in excess of 10,000 from Wyeth Research.
Presented in part at the 9th International Conference on AD; July 17–22, 2004; Philadelphia, PA.
Received August 12, 2004. Accepted in final form January 31, 2005.
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