144 Current Alzheimer Research, 2009, 6, 144-151 Long-Term Follow-Up of Patients Immunized Functional Decline in Antibody Responders with AN1792: Reduced Bruno Vellas*, R. Black, Leon J. Thal, Nick C. Fox, M. Daniels, G. McLennan, C. Tompkins, C. Leibman, M. Pomfret, Michael Grundman; for the AN1792 (QS-21)-251 Study Team# Department of Geriatrics INSERM U 558, Toulouse University Hospital Center, Toulouse, France (BV); Wyeth Re- search, Philadelphia, Pennsylvania (RB, MP); University of California, San Diego, California (LT-deceased); Institute of Neurology, University College London, UK (NF); Elan Pharmaceuticals, South San Francisco, California (MD, MG, GMcL, CT, CL), USA Abstract: Background: Immunization of patients with Alzheimer’s disease (AD) with synthetic amyloid- peptide (A 42) (AN1792) was previously studied in a randomized, double-blind, placebo-controlled phase 2a clinical trial, Study AN1792(QS-21)-201. Treatment was discontinued following reports of encephalitis. One year follow-up revealed that AN1792 antibody responders showed improvements in cognitive measures as assessed by the neuropsychological test bat- tery (NTB) and a decrease in brain volume compared with placebo. Methods: A follow-up study, Study AN1792(QS-21)-251, was conducted to assess the long-term functional, psychomet- ric, neuroimaging, and safety outcomes of patients from the phase 2a study 4.6 years after immunization with AN1792. The results were analyzed by comparing patients originally identified as antibody responders in the AN1792 phase 2a study with placebo-treated patients. Results: One hundred and fifty-nine patients/caregivers (30 placebo; 129 AN1792) participated in this follow-up study. Of the 129 AN1792-treated patients, 25 were classified in the phase 2a study as anti- body responders (anti-AN1792 titers 1:2,200 at any time after the first injection). Low but detectable, sustained anti- AN1792 titers were found in 17 of 19 samples obtained from patients classified as antibody responders in the phase 2a study. No detectable anti-AN1792 antibodies were found in patients not classified as antibody responders in the phase 2a study. Significantly less decline was observed on the Disability Assessment for Dementia scale among antibody respond- ers than placebo-treated patients (p=0.015) after 4.6 years. Significant differences in favor of responders were also ob- served on the Dependence Scale (p=0.033). Of the small number of patients who underwent a follow-up MRI, antibody responders showed similar brain volume loss during the follow-up period subsequent to the AN1792 phase 2a study com- pared with placebo-treated patients. Conclusions: Approximately 4.6 years after immunization with AN1792, patients defined as responders in the phase 2a study maintained low but detectable, sustained anti-AN1792 antibody titers and demonstrated significantly reduced func- tional decline compared with placebo-treated patients. Brain volume loss in antibody responders was not significantly dif- ferent from placebo-treated patients approximately 3.6 years from the end of the original study. No further cases of en- cephalitis were noted. These data support the hypothesis that A immunotherapy may have long-term functional benefits. Keywords: Alzheimer’s disease, Immunotherapy, A , amyloid, NTB. INTRODUCTION Alzheimer’s disease (AD) is a neurodegenerative disor- der that represents the leading cause of dementia in the eld- erly, with approximately 27 million AD patients worldwide. The global prevalence of AD is expected to quadruple to approximately 106 million patients by 2050 [1]. Treatment options to delay or halt the progression of AD to dementia are highly desirable. Immunotherapy with human amyloid- (A ) 1-42 peptide (AN1792) stimulated the clearance of amyloid plaques and prevented AD-associated cognitive *Address correspondence to this author at the Department of Geriatrics INSERM U 558, Toulouse University Hospital Center, Toulouse, (BV), France; E-mail: vellas.b@chu-toulouse.fr #Members of the AN1792 (QS-21)-251 Study Team are listed in the Appen- dix; Sponsored by Elan Pharmaceuticals, Inc. and Wyeth Research. decline in a mouse model of AD [2]. Efficacy observed after immunization with AN1792 in the mouse model led to the strategy of targeted A immunotherapy for removal and clearance of A from the brains of AD patients. Preclinical studies in several species demonstrated the safety, tolerability, and activity of AN1792 in combination with the adjuvant QS-21 [2-6]. Phase 1 studies demonstrated that the optimal dose combination for eliciting an anti- AN1792 antibody response was AN1792 225 g and QS-21 50 g [7]. Accordingly, a double-blind, placebo-controlled, multi-center phase 2a study (Study 201) was initiated to evaluate the safety, tolerability, and pilot efficacy of AN1792 in patients with mild-to-moderate AD. Study drug administration was discontinued in January 2002 after the first reports of meningoencephalitis [8]. The protocol was amended to monitor all patients for 12 months from the first dose of drug, while maintaining the study blind to determine 1567-2050/09 $55.00+.00 ©2009 Bentham Science Publishers Ltd.