Drug-Related Brain Swelling May Resolve Over Time, Research Suggests
By Charlene Laino
WebMD Health News
Reviewed By Laura J. Martin, MD
July 21, 2011 (Paris) -- An experimental drug that targets one of the underlying processes that may cause Alzheimer's disease may be safer over the long run than previously thought, researchers say.
Early studies of the drug, bapineuzumab, raised a red flag when some patients developed troublesome brain swelling that can lead to headache, loss of coordination, weakness, disorientation, memory loss, and hallucinations.
New longer-term safety data on bapineuzumab suggest that although the brain swelling may be more common than first reported, the risk appears to decline the longer a person is taking the drug.
Also, the brain swelling is often mild, causing no symptoms, according to the research presented here at the Alzheimer's Association International Conference.
Bapineuzumab is a monoclonal antibody designed to bind to and clear beta-amyloid plaque from the brain. Current belief holds that the plaque starts to build up in the brain seven to 10 years prior to the decline in cognitive skills that is often the first symptom of Alzheimer's.
The hope is that disease-modifying drugs like bapineuzumab will work early in the disease process, delaying mental decline and slowing the progressive degeneration of brain tissue. A number of the drugs, including bapineuzumab, are in late-stage phase III trials, but so far none has been approved by the FDA.
In animal research and early human studies, bapineuzumab appeared to work just as it was supposed to. But as the side effect of brain swelling surfaced -- formerly called vascular edema and now known as amyloid-related imaging abnormalities, or ARIA -- so did safety concerns.
The new findings "give us encouragement going forward," says Stephen Salloway, MD, professor of neurology at Brown Medical School.
Brain Swelling Often Symptomless
In one study, researchers reviewed more than 2,500 MRI brain scans from 262 patients who had participated in bapineuzumab studies and identified 15 cases of brain swelling that had been missed the first time around. But none caused any symptoms, says Reisa Sperling, MD, director of clinical research of the memory-disorders unit at Brigham and Women's Hospital in Boston.
The researchers also confirmed the 21 cases of brain swelling detected in earlier studies. Eight of these patients experienced symptoms, including headache and confusion, she tells WebMD.
The study also showed that people with the ApoE4 gene variant that has been linked to an increased risk of Alzheimer's and those who took higher doses of bapineuzumab appeared to be at increased risk for brain swelling.
Patients taking the highest dose in the early studies were switched to a lower dose after the first reports of brain swelling emerged.
Swelling Wanes Over Time
In the other study, Salloway and colleagues examined scans from 194 patients for signs of brain swelling.
The risk of brain swelling dropped from 7% after the first three doses to 3% for the fourth through 10th doses, he tells WebMD.
The patients took bapineuzumab, which is given by infusion every 13 weeks, for an average of about two-and-one-half years.
Brain swelling was the most common side effect of treatment, occurring in 9% of patients. Overall, about one in four participants experienced some effect that was thought to be related to bapineuzumab; 85% of them were mild to moderate.
Salloway says no conclusions about the drug's effectiveness can be drawn from these studies. Effectiveness data, from the phase III studies, should become available next year.
Ironically, brain swelling appears to be a sign the drug is doing what it is supposed to do in the early stages of treatment, Salloway says.
"Bapineuzumab mobilizes amyloid from the brain and it goes to the blood vessels. In people with a lot of amyloid, it might [clog] the blood vessels early on, causing some leakage of fluid [that can lead to edema]. Then, as the drug clears more amyloid away, there is not much leakage," he says.
Mary Sano, MD, of Mount Sinai School of Medicine in New York City, says that although the studies "help us to better understand the long-term safety of bapineuzumab, we still don't know anything about its potential positive effects."
The ongoing studies are important, she tells WebMD, as "they will hopefully tell us if going after and ridding the brain of amyloid can be helpful to patients."
The study was funded by Pfizer and Jannsen Pharmaceuticals.
These findings were presented at a medical conference. They should be considered preliminary as they have not yet undergone the "peer review" process, in which outside experts scrutinize the data prior to publication in a medical journal.
Alzheimer's Association International Conference 2011, Paris, July 16-21, 2011.
Stephen Salloway, MD, professor of neurology, Brown Medical School.
Reisa Sperling, MD, director, clinical research, memory disorders unit, Brigham and Women's Hospital, Boston.
Mary Sano, PhD, director, Alzheimer's disease research, Mount Sinai School of Medicine, New York.
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