Early Results of Alzheimer’s Passive Vaccine Trial Mixed

by Jim Schnabel

June 19, 2008

An experimental passive vaccine against Alzheimer’s-related amyloid-beta-42 protein shows a significant effect only in a subset of patients, and in this group the vaccine merely slows the progress of the disease instead of stopping it altogether, its developers announced this week. But given the current absence of effective Alzheimer’s therapies, it could end up making a significant impact on the disease.

The drug companies Elan and Wyeth, in a news release June 17, provided a summary of results from an early, “Phase 2” clinical trial of their jointly developed passive vaccine, composed of a monoclonal antibody known as bapineuzumab.

“It’s an encouraging Phase 2 result that now awaits a definitive Phase 3 trial,” says Sam Gandy, a neurologist and neuroscientist at Mount Sinai School of Medicine who chairs the medical and scientific advisory council for the Alzheimer’s Association.

The randomized, placebo-controlled trial included about 240 people with mild to moderate Alzheimer’s disease at 29 clinical centers around the United States. Over 18 months, slightly less than half the patients were given placebos while the rest were given four different doses of bapineuzumab, which targets the apparently harmful form of amyloid known as amyloid-beta-42. Although the study was designed primarily to determine the safety and appropriate dosing (if any) of bapineuzumab, its results have been eagerly awaited as an indication of the drug’s chances of success in larger clinical trials.

According to Elan and Wyeth, the study did not show a statistically significant effect for the drug in slowing disease among the 128 treated patients, as measured by the Alzheimer’s Disease Assessment Scale and other standard tools.

Given the small number of treated patients, however, with some receiving only low doses, and with a treatment period of only a year and a half, this does not necessarily mean that the drug is valueless against Alzheimer’s. In fact, the companies’ post-hoc analyses indicated that the drug did achieve statistically significant effects in slowing disease, by several measures, in a subset of patients who did not carry the key e4 variant of the apolipoprotein-E gene.

Having at least one copy of apoE4 is the second-strongest risk factor for Alzheimer’s (a person’s age is the first); apoE4 carriers also tend to have earlier onsets of disease than non-carriers. Researchers believe that apoE4, unlike the other common apo-E variants, interacts with amyloid-beta-42 in a way that prevents its normal degradation in and around brain cells.

It is so far unclear why bapineuzumab would have less effect in slowing disease in people with the apoE4 variant. However, studies suggest that at least half of the people diagnosed with Alzheimer’s are non-carriers, so if bapineuzumab is proven to be effective in this population, it could still be a popular and valuable drug.

That is now a plausible outcome, although Bruce Yankner, an Alzheimer’s researcher at Harvard, cautions that this Phase 2 study was “too short and limited to reach firm conclusions, except to indicate safety and possible efficacy to justify proceeding to Phase 3.”

Gandy, too, notes that a longer trial would have a better chance of revealing efficacy: “We have no idea how long we will need to treat patients before a maximal effect is attained.”

Elan and Wyeth began their Phase 3 trial, treating several thousand people with Alzheimer’s, last year. Unless the trial is terminated early due to obvious efficacy—or unacceptable side effects—its results won’t be announced until 2010 or 2011.

Side effects are a lingering issue for vaccine strategies against Alzheimer’s. A trial of Elan and Wyeth’s active amyloid-beta-42 vaccine in 2002 was halted early after 18 of 298 treated patients developed life-threatening meningoencephalitis—most likely from marauding, immune-system T cells that crossed from the bloodstream and began attacking healthy parts of the brain.

One of the ways the companies hoped to avoid such a problem was by using a passive vaccine made of monoclonal antibodies instead. But monoclonal antibodies can sometimes provoke harmful inflammation, and in the brain they are meant to target amyloid for clearance by other immune cells. In the Phase 2 study of bapineuzumab, company researchers observed “vasogenic edema”—a form of brain swelling, commonly indicating increased inflammation—among the treated patients, especially people with the apoE4 variant. The incidence and severity of this side effect were not enough to halt the study or to prevent the start of the Phase 3 trial; however, in their June 17 news release the companies said that they were using a lower dose of bapineuzumab for apoE4 carriers in the Phase 3 trial, to see if they can avoid this problem.

On the whole, it appears that bapineuzumab, even if it is shown to have positive effects in some or all people with Alzheimer’s disease, will still leave plenty of room for other, better Alzheimer’s therapies and preventives.

“There would appear to be no cause to abandon other approaches,” says Gandy, who serves on the scientific advisory board for an ongoing trial of an active amyloid vaccine, also made by Elan and Wyeth.