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

Neurology. 2005 May 10;64(9):1553-62. doi: 10.1212/01.WNL.0000159740.16984.3C.

Abstract

Background: AN1792 (beta-amyloid [Abeta]1-42) immunization reduces Abeta 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 microg plus the adjuvant QS-21 50 microg (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 Abeta42) was assessed in anti-AN1792 antibody responder patients (immunoglobulin G titer > or = 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 Abeta immunotherapy may be useful in Alzheimer disease.

Publication types

  • Clinical Trial, Phase II
  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Aged, 80 and over
  • Alzheimer Disease / drug therapy*
  • Alzheimer Disease / immunology
  • Alzheimer Disease / physiopathology
  • Amyloid beta-Peptides / antagonists & inhibitors*
  • Amyloid beta-Peptides / immunology
  • Amyloid beta-Peptides / metabolism
  • Antibodies / blood
  • Antibodies / immunology
  • Brain / drug effects*
  • Brain / immunology
  • Brain / pathology
  • Cognition Disorders / drug therapy
  • Cognition Disorders / immunology
  • Cognition Disorders / physiopathology
  • Double-Blind Method
  • Drug Administration Schedule
  • Female
  • Humans
  • Immunotherapy, Active / adverse effects*
  • Immunotherapy, Active / methods
  • Injections, Intramuscular
  • Magnetic Resonance Imaging
  • Male
  • Meningoencephalitis / chemically induced*
  • Meningoencephalitis / immunology
  • Meningoencephalitis / physiopathology
  • Middle Aged
  • Neuropsychological Tests
  • Peptide Fragments / antagonists & inhibitors*
  • Peptide Fragments / immunology
  • Peptide Fragments / metabolism
  • Placebos
  • Treatment Outcome
  • Vaccines / administration & dosage
  • Vaccines / adverse effects*
  • Vaccines / immunology

Substances

  • Amyloid beta-Peptides
  • Antibodies
  • Peptide Fragments
  • Placebos
  • Vaccines
  • amyloid beta-protein (1-42)