“The next step will be to create, test, and verify a single protocol for MRI-based evaluation of Alzheimer’s disease-related hippocampal shrinkage,” Dr. Frisoni said. “This initial quantification will help our international panel of experts define which key components should be included in an international harmonized protocol.”
A Trial Update on the Experimental Immunotherapy Drug Bapineuzumab
Stephen Salloway, MD, MS, of 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 disease, and 36 were from a study evaluating bapineuzumab delivered subcutaneously. Treatment was given every 13 weeks without a placebo group. Eighty-six 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%) in the study population reported adverse events. Adverse events in more than 10% of subjects were: falls (14.4%), agitation (13.4%), urinary tract infection (12.4%), upper respiratory tract infection (12.4%), and anxiety (10.8%).
Approximately 24% of patients reported adverse events that were considered related or possibly related to bapineuzumab; most of these (about 85%) were considered mild or moderate. Reported treatment-related adverse events in more than 1% of study participants included: amyloid-related imaging abnormalities or ARIA-E (9.3%), headache (2.1%), evidence of microscopic bleeding in the brain (1.5%), convulsion (1.5%), and flushing (1.5%).
Approximately 35% of participants reported serious adverse events (SAEs); SAEs in more than 2% of subjects included: ARIA-E (6.2%), falls (2.6%), hip fracture (2.1%), convulsion (2.1%), worsening dementia of the Alzheimer’s type (2.1%), and confusion (2.1%).
The risk of developing ARIA-E diminished with an increasing number of infusions of the drug; cumulative risk of developing ARIA-E decreased from 6.7% for infusions 1 to 3, compared with 2.7% for infusions 4 to 10.
“Overall, bapineuzumab was generally well tolerated, and side effects tended to be mild,” Dr. 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 under way.”
In a separate study, Reisa Sperling, MD, MMSc, of Brigham and Women’s Hospital, Harvard Medical School, Boston, and colleagues conducted a systematic review of more than 2,000 MRI scans from 262 patients with Alzheimer’s disease who participated in the phase II bapineuzumab studies to investigate the occurrence of amyloid-related imaging abnormalities on MRI thought to represent vasogenic edema and sulcal effusions (ARIA-E).
Subjects in the 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 thought to be associated with bapineuzumab treatment, 21 (60%) 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%) of ARIA-E identified only during this study showed more subtle MRI changes. These patients did not appear to exhibit symptoms related to ARIA-E.
The researchers found that risk factors for ARIA-E included both the apolipoprotein E (APOE) ε4 allele and a higher dose of bapineuzumab, consistent with previous observations.
“The underlying cause of ARIA-E is under investigation,” Dr. 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. Phase III bapineuzumab trials have incorporated adjustments to dose and attention to APOE ε4 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,” Dr. Sperling added.