Elan Corporation plc and Wyeth Pharmaceuticals announced several key findings from their phase IIa clinical trial of an investigational Alzheimer's disease (AD) treatment, AN-1792, which were presented in Philadelphia at the 9th International Conference on Alzheimer's Disease and Related Disorders.
AN-1792 is a synthetic form of the beta amyloid peptide that pathologically builds up in the brains of persons with AD. Although dosing with AN-1792 was halted in January 2002 after reports of encephalitis in a subset of patients, the trial remained blinded and the patients were followed in the study until December 2002.
While clinical development of AN-1792 has been terminated, the results presented support the beta amyloid immunotherapy approach, which is thought to treat Alzheimer's disease using an immunologic approach to clear beta amyloid from the brain. The results include less worsening on a neuropsychological test battery, including the memory component at 12 months in patients who developed an antibody response to AN-1792 compared to the placebo group. In addition, in three autopsy examinations of patients treated with AN-1792, reduction of beta amyloid plaque was observed, the company release said.
"These results are significant because they suggest that it may be possible to reduce plaque buildup in the brain and alter the pathologic findings of patients with Alzheimer's disease," said Dale Schenk, senior vice president and chief scientific officer, Elan. "These data offer hope that beta amyloid immunotherapy may be able to make a meaningful difference for these patients," he added.
A number of clinical endpoints were examined in this interrupted trial. Though primary cognitive endpoints did not demonstrate improvement in those treated with AN-1792, a composite neuropsychological performance measure, including the memory component, improved at 12 months in anti beta amyloid antibody responders compared to placebo-treated patients.
Evidence of beta amyloid plaque reduction was observed in three autopsy cases that have been examined from the Phase I and IIa AN-1792 trials. The observed plaque clearance is consistent with those findings of numerous laboratories investigating beta amyloid immunotherapy in animal models of Alzheimer's disease. An analysis is in progress of a fourth autopsy case showing evidence of active plaque removal.
Levels of tau protein in cerebral spinal fluid (CSF), a marker known to be elevated in AD, were lower in anti beta amyloid antibody responders.
Brain volume was lower in anti beta amyloid antibody responders as measured by magnetic resonance imaging (MRI).
"The significance of any of these data individually is not clear; however, collectively the study results from AN-1792 underscore the importance of our novel immunotherapeutic approach to the treatment of this devastating disease and indicate that further study of this approach is warranted," said Gary L Stiles, chief medical officer, executive vice president, Wyeth Pharmaceuticals. "That is why Wyeth and Elan are now in the clinic evaluating a new compound, AAB-001, a humanized monoclonal antibody," he added.
The AN-1792 Phase IIa study was an international, double-blind placebo-controlled trial that assessed 372 patients with mild to moderate Alzheimer's disease. Because of an expected 25 per cent antibody response rate in those treated with AN-1792, patients were randomized 4:1 to receive either active immunization with AN-1792 or placebo. The study was designed to evaluate the clinical impact of eliciting an immune response (formation of antibodies) to the beta amyloid peptide.
The evaluation included standard clinical assessments of cognition as well as the assessment of surrogate markers of Alzheimer's disease. Dosing was halted in January 2002 after reports of encephalitis in a subset of patients; however, the trial remained blinded and patients were followed in the study until December 2002. Because Alzheimer's disease is a terminal diagnosis, autopsies were performed on the patients in the clinical study who have since died to confirm previous diagnosis of the disease.