A phase 2 multiple ascending dose trial of bapineuzumab in mild to moderate Alzheimer disease.

Abstract

BACKGROUND:

Bapineuzumab, a humanized anti-amyloid-beta (Abeta) monoclonal antibody for the potential treatment of Alzheimer disease (AD), was evaluated in a multiple ascending dose, safety, and efficacy study in mild to moderate AD.

METHODS:

The study enrolled 234 patients, randomly assigned to IV bapineuzumab or placebo in 4 dose cohorts (0.15, 0.5, 1.0, or 2.0 mg/kg). Patients received 6 infusions, 13 weeks apart, with final assessments at week 78. The prespecified primary efficacy analysis in the modified intent-to-treat population assumed linear decline and compared treatment differences within dose cohorts on the Alzheimer's Disease Assessment Scale-Cognitive and Disability Assessment for Dementia. Exploratory analyses combined dose cohorts and did not assume a specific pattern of decline.

RESULTS:

No significant differences were found in the primary efficacy analysis. Exploratory analyses showed potential treatment differences (p < 0.05, unadjusted for multiple comparisons) on cognitive and functional endpoints in study "completers" and APOE epsilon4 noncarriers. Reversible vasogenic edema, detected on brain MRI in 12/124 (9.7%) bapineuzumab-treated patients, was more frequent in higher dose groups and APOE epsilon4 carriers. Six vasogenic edema patients were asymptomatic; 6 experienced transient symptoms.

CONCLUSIONS:

Primary efficacy outcomes in this phase 2 trial were not significant. Potential treatment differences in the exploratory analyses support further investigation of bapineuzumab in phase 3 with special attention to APOE epsilon4 carrier status.

CLASSIFICATION OF EVIDENCE:

Due to varying doses and a lack of statistical precision, this Class II ascending dose trial provides insufficient evidence to support or refute a benefit of bapineuzumab.

• Authors: S Salloway, R Sperling, S Gilman, N C Fox, K Blennow, M Raskind, M Sabbagh, L S Honig, R Doody, C H van Dyck, R Mulnard, J Barakos, K M Gregg, E Liu, I Lieberburg, D Schenk, R Black, M Grundman, Bapineuzumab 201 Clinical Trial Investigators
• Journal: Neurology (Neurology) Vol. 73 Issue 24 Pg. 2061-70 (Dec 15 2009) ISSN: 1526-632X [Electronic] United States
• PMID: 19923550 (Publication Type: Clinical Trial, Phase II, Journal Article, Multicenter Study, Randomized Controlled Trial, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antibodies, Monoclonal
• Antibodies, Monoclonal, Humanized
• Apolipoprotein E4
• Biomarkers
• bapineuzumab

Topics

• Aged
• Alzheimer Disease (diagnosis, drug therapy, genetics, psychology)
• Antibodies, Monoclonal (administration & dosage, adverse effects)
• Antibodies, Monoclonal, Humanized
• Apolipoprotein E4 (genetics)
• Biomarkers (cerebrospinal fluid)
• Brain (pathology)
• Brain Edema (chemically induced, diagnosis)
• Cognition (drug effects)
• Dose-Response Relationship, Drug
• Female
• Heterozygote
• Humans
• Magnetic Resonance Imaging
• Male
• Severity of Illness Index
• Treatment Outcome