Bapineuzumab Shows No Clinical Benefit for Mild-to-Moderate AD

Results of 2 phase 3, multicenter, randomized, double-blind trials show no clinical benefit of bapineuzumab to treat patients with mild-to-moderate Alzheimer’s disease (AD) [N Engl J Med. 2014;370:322-33].  

The study did find, however, that bapineuzumab was associated with a significant reduction in cerebrospinal fluid phosphor-tau concentrations—a biomarker of neurodegeneration—among carriers of the apolipoprotein E (APOE) Ɛ4 allele.

One trial included carriers of APOE Ɛ4 allele in which 1121 patients were randomized to at least 1 dose of 0.5 mg/kg of bapineuzumab (n=673) or placebo (n=448), and the other trial included noncarriers in which 1331 patients were randomized to at least 1 dose of 0.5 mg/kg bapineuzumab (n=337), 2 doses of 1 mg/kg bapineuzumab (n=329), and 2mg/kg bapineuzumab (n=141) or placebo (n=524).

Patients included in both trials were 50 to 88 years of ageand had probable AD based on criteria of the National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer’s Disease and Related Disorders Association, as well as findings on magnetic resonance imaging (MRI) consistent with AD. Patients were excluded from the study if they had neurological disease other than AD, a brain abnormality seen on brain MRI scan, a history of stroke or seizures, a major psychiatric disorder, or treatment with cognitive enhancers other than stable doses of acetylcholinesterase inhibitors or memantine.

The primary outcome of both trials was assessment of the efficacy of intravenous bapineuzumab compared to placebo based on 2 measures: (1) change from baseline to week 78 on the 11-item cognitive subscale of the Alzheimer’s Disease Assessment Scale (ADAS-Cog11); and (2) Disability Assessment for Dementia (DAD).

Based on a modified intention-to-treat analysis of 1090 carriers and 1114 noncarriers included in the efficacy analysis, the study found no significant between-group differences in the primary outcomes of the study. In the carrier study, the between-group differences (bapineuzumab group minus placebo group) in the change from baseline to week 78 were -0.2 (P=.80) in the ADAS-Cog11 score and -1.2 (P=.34) in the DAD scores. In the noncarrier group, the ADAS-Cog11 score was -0.3 (P=.64) for the 0.5 mg/kg dose and 0.4 (P=.62) for the 1 mg/kg dose. The DAD scores were 2.8 (P=.07) and 0.9 (P=.55), respectively.

The study also examined a number of key secondary outcomes, including assessment at week 78 of changes in baseline in 3 disease biomarkers using positron-emission tomographic amyloid imaging with the use of Pittsburgh compound B: (1) brain amyloid burden; (2) whole-brain volume; and (3) cerebrospinal fluid phosphor-tau concentrations.

The study found a significant reduction in the cerebrospinal fluid phosphor-tau concentration among carriers receiving bapineuzumab compared to placebo at week 71 (-5.80 ± 1.49 pg/mL vs 0.95 ± 1.83 pg/mL). This represented a significant between-group difference of -6.75 pg/mL (P=.005). No significant between-group difference was seen among noncarriers.

A key safety finding highlighted by the investigators was amyloid-related imaging abnormalities with edema in patients treated with bapineuzumab. These abnormalities increased with bapineuzumab dose and APOE Ɛ4 allele number, and subsequently led to the discontinuation of the 2 mg/kg dose in the study.

“We learned important lessons from the study,” said lead author of the study, Stephen Salloway, MD, MS, director of neurology and the memory and aging program, Butler Hospital, professor of neurology and psychiatry, The Warren Alpert Medical School of Brown University, Providence, Rhode Island, during an interview with First Report Managed Care. “These include treating AD early before nerve cell loss is well established, combining treatments to maximize benefit as we do in HIV and cancer, and using new imaging and fluid biomarkers to treat only patients who have clear evidence of AD pathology.”