SEATTLE—Although bapineuzumab—a humanized monoclonal antibody to β-amyloid—had no effect on cognitive and functional outcomes in patients with mild to moderate Alzheimer’s disease in prespecified analyses, post hoc analyses found potential benefit in study completers who were noncarriers of apolipoprotein E (APOE) ε4, researchers reported at the 61st Annual Meeting of the American Academy of Neurology. However, patients taking high doses of bapineuzumab were more likely to develop vasogenic edema.
According to principal investigator Stephen Salloway, MD, the phase II trial was “based on the fact that β-amyloid is a main factor in the pathogenesis of Alzheimer’s disease and that antibodies against amyloid have the potential to promote amyloid clearance and hopefully have a positive clinical effect.”
A total of 234 subjects were randomized to receive six infusions of either IV bapineuzumab (0.15, 0.5, 1, or 2 mg/kg) or placebo, given at 13-week intervals. The final assessment was completed at week 78. Primary end points included safety and efficacy, as measured by the Alzheimer’s Disease Assessment Scale–Cognitive Subscale (ADAS-Cog) and the Disability Assessment of Dementia (DAD). Secondary outcome measures included the Neuropsychological Test Battery, the Mini-Mental State Examination (MMSE), and the Clinical Dementia Rating Scale Sum of Boxes. MRI scans were conducted at baseline, week 6, and every 13 weeks thereafter until week 71.
The average age of participants was 68 in the placebo group and 70 in the bapineuzumab group. Mean duration of Alzheimer’s disease was 3.6 years. More than 60% of subjects in both groups were APOE ε4 carriers. The mean baseline MMSE score was 20.9 in the bapineuzumab group and 20.7 in the placebo group.
Five patients received the initial infusion but did not return for follow-up assessment and were excluded from the analyses. Therefore, the modified intention-to-treat (MITT) population consisted of 229 subjects: 122 randomized to bapineuzumab and 107 randomized to placebo.
Cognitive and Functional Outcomes
The primary prespecified analysis of this study compared drug versus placebo in the 0.5-, 1-, and 2-mg/kg dose groups. At week 78, no statistically significant change from baseline was seen on ADAS-Cog and DAD scores in the MITT population, said Dr. Salloway, Professor of Clinical Neurosciences and Psychiatry at Brown Medical School in Providence, Rhode Island.
However, additional exploratory analyses, which pooled all dose cohorts and focused on completers (ie, participants who received all six infusions and had a week 78 follow-up visit), suggested a potential treatment difference in favor of bapineuzumab. When the investigators looked at APOE ε4 carrier status, they found a potential treatment difference in noncarriers but no significant treatment difference in carriers.
Safety Profile of Bapineuzumab
Adverse events occurred in 94% of patients treated with bapineuzumab and 90% of the placebo group. In the bapineuzumab groups, 6% of adverse events were severe, compared with 3.5% in the placebo group.
Coinvestigator Lawrence S. Honig, MD, PhD, noted that 23% of participants withdrew from the study. The most frequent causes were voluntary factors, such as caregiver fatigue and perceptions of inefficacy. Eight patients in the bapineuzumab groups and three patients in the placebo group withdrew due to adverse events.
Adverse events that occurred in more than 5% of bapineuzumab patients, and in twofold more bapineuzumab than placebo patients, included vasogenic edema, back pain, anxiety, paranoia, vomiting, hypertension, weight loss, skin laceration, gait disturbance, and muscle spasm.
Four patients died, all of whom were in the bapineuzumab group; these deaths were unrelated to treatment. No hypersensitivity reactions, bapineuzumab-specific antibodies, or intergroup laboratory value differences were detected.
“No particular dose cohort suffered an overwhelming proportion of the frequent adverse events, nor was any particular adverse event dose-related, with the exception of vasogenic edema,” commented Dr. Honig, Associate Professor of Clinical Neurology in the Gertrude H. Sergievsky Center, the Taub Institute for Research on Alzheimer’s Disease and the Aging Brain, and the Department of Neurology, Division of Aging and Dementia at Columbia University in New York City.
Vasogenic Edema
Vasogenic edema occurred in 12 (10%) of 124 patients randomized to bapineuzumab, compared with none of 110 patients randomized to placebo. Ten of the 12 vasogenic edema cases were detected on routine MRI. Six cases were asymptomatic; of the remaining six, four had mild transient symptoms, including lethargy, confusion, headache, and/or visual disturbances. Two patients had clinical symptoms prompting off-protocol MRI, and one was treated with steroids. Although CSF was generally normal, two patients had elevated white blood cell counts and increased protein levels.
Patients were more likely to develop vasogenic edema early in the course of treatment. “Nearly two-thirds of the cases occurred after the first infusion,” said coinvestigator Reisa Sperling, MD, Associate Professor of Neurology at Harvard Medical School in Boston.