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

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 μ g plus the adjuvant QS-21 50 μ g (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 Aβ 42) 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.