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In the wake of concerns that all amyloid-modifying therapies may cause VE, a workgroup of the Alzheimer's Association Research Roundtable, a consortium of scientists from the pharmaceutical, biotechnology, diagnostics, imaging and cognitive testing industries, and senior staff and advisors from the Association, reviewed the relevant publicly available information. This included natural history studies and spontaneous occurrence of these adverse events in aging and Alzheimer's populations, occurrence in the setting of trials of amyloid-lowering agents for Alzheimer's and similar clinical conditions from which parallels might be drawn, and existing animal models that may elucidate the underlying mechanisms.
The workgroup developed specific recommendations regarding the conduct of Alzheimer's clinical trials in the setting of what are now referred to as amyloid-related imaging abnormalities (ARIA), which were published last week in Alzheimer's & Dementia: The Journal of the Alzheimer's Association. ARIA include MRI signal abnormalities thought to represent "vasogenic edema" and sulcal effusions (ARIA-E) and GRE/MRI signal abnormalities thought to represent hemosiderin deposits (ARIA-H).
Two studies reported at AAIC 2011 describe a re-evaluation of the Phase II study safety results in the light of these new perspectives on ARIA and the first report of long-term safety data for bapineuzumab treatment beyond 78 weeks.
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Two Studies Report Updated Phase II and Long-Term Safety Data on Bapineuzumab, an Experimental Immunotherapy for Alzheimer's
Long-term Safety Data
Stephen Salloway, MD, MS; Butler Hospital and Brown University, Providence, Rhode Island, and colleagues monitored the long-term safety of bapineuzumab in an ongoing open-label Phase II extension study in 194 participants; 158 were from a 78-week study in mild to moderate Alzheimer's and 36 were from a study evaluating bapineuzumab delivered subcutaneously. Treatment was given every 13 weeks without a placebo group. Eighty-six (86) people received bapineuzumab treatment for at least three years and 43 for at least four years at the time of this interim analysis.
The researchers found that most participants (91 percent) in the study population reported adverse events (AEs). AEs in more than 10 percent of subjects were: fall (14.4 percent), agitation (13.4 percent), urinary tract infection (12.4 percent), upper respiratory tract infection (12.4 percent) and anxiety (10.8 percent).
Approximately 24 percent of patients reported AEs that were considered related or possibly related to bapineuzumab; most of these (approx. 85 percent) were considered mild or moderate. Reported treatment-related AEs in more than one percent of study participants included: Amyloid-Related Imaging Abnormalities or ARIA-E (9.3 percent), headache (2.1 percent), evidence of microscopic bleeding in the brain (1.5 percent), convulsion (1.5 percent) and flushing (1.5 percent).
Approximately 35 percent of participants reported serious AEs (SAEs); SAEs in more than two percent of subjects included: ARIA-E (6.2 percent), fall (2.6 percent), hip fracture (2.1 percent), convulsion (2.1 percent), worsening dementia of the Alzheimer's type (2.1 percent), and confusion (2.1 percent).
The risk of developing ARIA-E diminished with an increasing number of infusions of the drug; cumulative risk of developing ARIA-E dropped from 6.7 percent for infusions 1-3 compared to 2.7 percent for infusions 4-10.
"Overall, bapineuzumab was generally well-tolerated and side-effects tended to be mild," Salloway said. "Open label extension studies such as this one can supplement randomized trial data to help us better understand safety and long term clinical effects. However, only adequately powered, randomized, prospective, placebo-controlled clinical trials can give us objective evaluations of safety and efficacy. Phase III trials with bapineuzumab are now underway."
Re-evaluation of Phase II Safety Data
Reisa Sperling, MD, MMSc; Brigham and Women's Hospital, Harvard Medical School, Boston, and colleagues conducted a systematic review of more than 2,000 MRI scans from 262 Alzheimer's patients who participated in the Phase II bapineuzumab studies to investigate the occurrence of amyloid-related imaging abnormalities on MRI though to represent vasogenic edema and sulcal effusions (ARIA-E).
"Because radiologists may not have detected all ARIA-E during the Phase II studies, we conducted a systematic, central review of all study MRIs to better estimate the incidence and risk factors for ARIA-E related to bapineuzumab," Sperling said.
Subjects included in risk analyses had at least one dose of bapineuzumab, no evidence of ARIA-E abnormalities at baseline, and at least one post-treatment MRI.
The researchers identified 36 cases that were thought to be associated with bapineuzumab treatment, 21 (60 percent) of which were identified during the Phase II trials. Eight subjects with ARIA-E, all previously identified during the clinical studies, had symptoms reported as related to study drug. The additional 15 cases (40 percent) of ARIA-E identified only during this study showed more subtle MRI changes, according to the researchers. These patients did not appear to exhibit symptoms related to ARIA-E.
The scientists found that risk factors for ARIA-E included both the apolipoprotein E e4 allele (APOE-e4, a common genetic risk factor for Alzheimer's) and a higher dose of bapineuzumab, consistent with previous observations.
"The underlying cause of ARIA-E is under active investigation," Sperling said, "but the risk factors identified in this study suggest that these imaging abnormalities may be related to accumulation and clearance of amyloid from blood vessels in the brain. The Phase 3 bapineuzumab trials have incorporated adjustments to dose and attention to APOE e4 status, and these data support those choices."
"Clinical observations from the more subtle ARIA-E cases are encouraging and suggest that the milder end of the ARIA-E spectrum may be asymptomatic," Sperling added.
"The most encouraging finding from these studies is that ARIA-E seems to occur less frequently as time goes on," Thies observed. "In addition, the risk factor findings suggest that we may be able to test people ahead of time for increased risk of this side effect and possibly administer a lower dose to patients identified as being at higher risk to minimize the likelihood that the side effect will occur. The other side effect findings are generally consistent with clinical trials in almost any disease with a patient population in this older age group."
Source Alzheimer's Association International Conference (AAIC)
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Original content Bob DeMarco, the Alzheimer's Reading Room