What happened to the AN-1792 in clinical trials?
Elan reported its first promising preclinical animal studies in July 1999 in the journal Nature. These studies showed that injections of AN-1792 prevented formation of plaques in the brains of young mice genetically engineered to produce human amyloid. Inoculation also reduced numbers of existing plaques in older mice with the same genetic alteration. Later studies by an independent laboratory showed that inoculation with AN-1792 also improved the performance of these mice in memory tests involving mazes.

Based on these preclinical results, both the U.S. Food and Drug Administration (FDA) and the U.K. Medicines Control Agency permitted Phase I human trials of AN-1792 to assess its safety and tolerability in people with mild to moderate Alzheimer's. The U.K. trial enrolled about 80 participants and the U.S. trial enrolled about 24.

Results from these Phase I trials, announced in 2000, suggested that the vaccine was well tolerated in human recipients. Tests also showed that a portion of participants developed amyloid antibodies. Based on these outcomes, Elan late in 2001 began a small Phase IIA trial in the United States and Europe enrolling about 360 people with mild to moderate Alzheimer's disease. Approximately 300 participants were randomly assigned to receive AN-1792 and the rest were assigned to receive a placebo (inactive treatment).

In January 2002, Elan and Wyeth-Ayerst Laboratories suspended administration of medication in the Phase IIA trial after four participants who had received multiple doses of AN-1792 developed symptoms of inflammation of the brain and spinal cord. When an additional 11 participants developed these symptoms by the end of February 2002, scientists on the independent Safety Monitoring Committee concluded that no one should be given further doses of AN-1792.

Trial researchers continue to follow all participants to monitor their well-being and provide appropriate treatment if symptoms appear in any additional enrollees. All individuals who experienced inflammation received medical care and, according to Elan and Wyeth Ayerst, most have recovered.

The exact cause of the brain inflammation is not yet known. The companies and the investigators are involved in a comprehensive effort to understand why some participants developed these symptoms as well as to determine what conclusions can be drawn from trial data. In Nature Medicine of October 15, 2002, Christoph Hock, MD, and colleagues reported on the status of 30 participants in the Phase II trial in Zurich. Hock's data confirmed that participants did develop antibodies to beta-amyloid and that there did not appear to be any correlation between an individual's antibody levels and the risk of developing brain inflammation. Further, the antibodies did not react with beta-amyloid's parent molecule amyloid precursor protein, which is found widely in nerve and other cells throughout the body and whose function is not yet known.

What have we learned since administration of AN-1792 ended?
In the March 16, 2003, advance on-line edition of Nature Medicine, scientists reported that the first autopsy of a participant in the vaccine trial showed evidence that the drug produced powerful effects throughout her brain. The woman was one of the 15 participants who developed inflammation, and her brain showed widespread ongoing inflammation. However, significant areas of her brain also lacked the amyloid plaques targeted by the vaccine-a phenomenon not seen in the brains of seven "unvaccinated" individuals also included in the Nature Medicine study. Despite its apparent reduction of plaques, AN-1792 did not appear to affect the beta-amyloid deposits found in the blood vessels of this woman as well as most other individuals with Alzheimer's. AN-1792 also failed to affect certain other key pathological features, including neurofibrillary tangles.

The first hint of the vaccine's effect on cognitive function was reported in another study by Christoph Hock and colleagues in the May 22, 2003, issue of the journal Neuron. In 28 participants who remain enrolled at the University of Zurich trial site, the researchers found that 19 who developed antibodies to beta-amyloid experienced little or no cognitive decline compared with nine who did not develop antibodies. Although promising, these results represent data from less than 10 percent of all trial participants, and it is possible that data from the entire trial will not confirm these initial positive findings. According to Dale Schenk, PhD, senior vice president of discovery research at Elan, preliminary whole-trial analysis of performance on the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) has shown no statistically significant difference in vaccine recipients compared to those who received placebo. The ADAS-Cog is a widely used battery of tests of a variety of cognitive functions. Whole-trial data analysis remains ongoing.

What can we learn from the trial's failure?
Although the outcome has so far failed to confirm AN-1792's early promise, the trial has provided a reassuring demonstration of the basic soundness of the clinical investigation protocol. The cautious progression built in to the three-phase system is designed to provide necessary safeguards and scientific rigor. In the AN-1792 trials, the system worked as it should-symptoms were identified in the first few participants who developed them and investigators quickly took appropriate action.

Many experts believe that immune therapy may still be a viable approach to treatment or prevention. In addition to monitoring AN-1792 recipients, researchers are exploring strategies for refining the vaccine. One possible refinement would be based on a portion of beta-amyloid rather than on the entire fragment, which might be less likely to provoke inflammation. Another possibility would involve administering genetically engineered anti-amyloid antibodies directly rather than stimulating the body to produce its own.

updated May 22, 2003