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.

Figure 1 Patient disposition

Figure 2 Estimated mean change from baseline over time on Alzheimer's Disease Assessment Scale–Cognitive subscale (ADAS-Cog) and Disability Assessment for Dementia (DAD) for the 4 combined dose cohorts in the modified intent-to-treat (mITT) and completer populations Error bars represent one standard error. A positive change from baseline represents improvement. The p values are not adjusted for multiple comparisons. (A) ADAS-Cog, mITT; (B) ADAS-Cog, completers; (C) DAD, mITT; (D) DAD, completers.

Figure 3 Serial MRI scans (fluid-attenuated inversion recovery) in a patient with vasogenic edema (VE) This 69-year-old woman is an APOE ε4 homozygote who was treated with bapineuzumab 1.0 mg/kg IV. She remained asymptomatic despite the appearance of multiple areas of VE evident on the MRI. The VE was apparent on MRI by 7 weeks after her first infusion and resolved by 19 weeks. The patient was redosed at 0.5 mg/kg of bapineuzumab IV and followed for over 2 years without recurrence of VE.