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


METHODS
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.
Salloway
S
S
Butler Hospital, The Warren Alpert Medical School of Brown University, 345 Blackstone Blvd., Providence, RI 02906, USA. SSalloway@Butler.org
Sperling
R
R
Gilman
S
S
Fox
N C
NC
Blennow
K
K
Raskind
M
M
Sabbagh
M
M
Honig
L S
LS
Doody
R
R
van Dyck
C H
CH
Mulnard
R
R
Barakos
J
J
Gregg
K M
KM
Liu
E
E
Lieberburg
I
I
Schenk
D
D
Black
R
R
Grundman
M
M
D000368:Aged; D000544:Alzheimer Disease / Q000175:diagnosis / Q000188:drug therapy* / Q000235:genetics / Q000523:psychology*; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000009:adverse effects; D061067:Antibodies, Monoclonal, Humanized; D053327:Apolipoprotein E4 / Q000235:genetics; D015415:Biomarkers / Q000134:cerebrospinal fluid; D001921:Brain / Q000473:pathology; D001929:Brain Edema / Q000139:chemically induced / Q000175:diagnosis; D003071:Cognition / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005260:Female; D006579:Heterozygote; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D012720:Severity of Illness Index; D016896:Treatment Outcome
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D053327:Apolipoprotein E4; D015415:Biomarkers; C545458:bapineuzumab