Background: AN1792 (beta-amyloid [Aβ]1–42) immunization reduces Aβ 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 Aβ42) 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 Aβ immunotherapy may be useful in Alzheimer disease.