Vaccine trial non-outcome

http://news.bmn.com/news/story?day=020205&story=1

vaccine trial non-outcome

4 February 2002 18:10 GMT

by Apoorva Mandavilli, BioMedNet News

Alzheimer's researchers today told BioMedNet News that their field is in a certain turmoil, even though they are not surprised that a vaccine trial begun amid hype and haste was suspended last month due to severe complications. While the companies involved remain tight-lipped about the details, some researchers have put review articles on hold, others are revising their own experiments, and speculations and rumors are flying in emails and phone calls.

"We don't have enough details to know what's going on," said Todd Golde, associate professor of neuroscience at the University of South Florida.

"If you can make immunization work, it has some real attraction," he observed. "We need to understand it better before we write it off as insurmountable."

The Ireland-based Elan and its partner, Wyeth-Ayerst Laboratories, the pharmaceutical division of American Home Products Corporation (AHP), decided to temporarily suspend dosing in the Phase 2A study after 4 patients in France developed inflammation in the central nervous system. Although the official press release alluded to the presence of a virus, an AHP spokesperson today confirmed that the patients had non-infectious encephalitis.

"The knowledgeable people in the field were hoping to be pleasantly surprised," with the results of the trial, said Steve Ferris, director of New York University's Alzheimer's disease (AD) center. But realistically, Ferris added, many expected the immunization approach to be complicated.

Scientists do not yet understand the mechanism of beta-amyloid clearance by immunization, Golde says. The trials were mounted based only on studies in mouse animal models. Because mice have blunted inflammatory mechanisms, he adds, researchers do not yet know whether the efficacy of the approach is inevitably linked to pro-inflammatory mechanisms.

Elan's vaccine approach has been the center of a very vocal debate between two warring camps in AD. Based on early reports from the trial, the vaccine appeared to halt - and in some cases reverse - the disease, a result some researchers touted as evidence that accumulation of beta-amyloid causes AD.

The trial also commenced with a great deal of fanfare. While it normally takes 6 months to a year to recruit patients for most trials, Ferris recalled, the "very, very hyped" Elan trial completed enrollment in just 6 weeks.

But even among those who supported the immunization approach, several researchers expressed concerns that the full-length amyloid-beta peptide used in the Elan trials could traverse the blood brain barrier and prove toxic. "We were forecasting some problems, and indeed some problems have occurred," Tom Wisniewski, associate professor of neurology at New York University, told BioMedNet News today.

Wisniewski and colleagues in August announced a rival vaccine that they claim is safer than the Elan compound. But complications in Elan's trial will probably make it more difficult to get approval for clinical trials of other vaccine approaches, Wisniewski says.

The general approach - immunization - probably still makes sense, agreed Ferris. "I don't think people think it's the end of the immune approach," he said, "but it probably is the end of this particular vaccine."

Elan and AHP began phase 2A trials in July 2001 in the US and four European countries. Approximately 360 patients, 97 of them in France, have received multiple doses of AN-1792. All 4 reported cases of CNS inflammation were in French patients. That may be because the French researchers scanned the symptoms more carefully, Ferris suggests, adding that the US cases may now need to be reviewed.

Elan and AHP are currently conducting an investigation to be reported to the drug safety board and regulatory authorities in the US and Europe. An independent monitoring group will also determine whether the study should move forward.

Even if the obstacles to immunization prove insurmountable, it's worth remembering that there are several approaches under investigation, points out John Hardy, director of the Center for Neuroscience at the Mayo Clinic in Florida.

Passive immunization, cholesterol management drugs and inhibitors of enzymes in amyloidogenesis are all promising strategies, Hardy says. Complications in the vaccine trial is "of course a bad sign for vaccines" he told BioMedNet News. "But whether it's fatal or not remains to be seen."

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