Two phase 3 trials of bapineuzumab in mild-to-moderate Alzheimer's disease.
BACKGROUND
Bapineuzumab, a humanized anti-amyloid-beta monoclonal antibody, is in clinical development for the treatment of Alzheimer's disease.


METHODS
We conducted two double-blind, randomized, placebo-controlled, phase 3 trials involving patients with mild-to-moderate Alzheimer's disease--one involving 1121 carriers of the apolipoprotein E (APOE) ε4 allele and the other involving 1331 noncarriers. Bapineuzumab or placebo, with doses varying by study, was administered by intravenous infusion every 13 weeks for 78 weeks. The primary outcome measures were scores on the 11-item cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-cog11, with scores ranging from 0 to 70 and higher scores indicating greater impairment) and the Disability Assessment for Dementia (DAD, with scores ranging from 0 to 100 and higher scores indicating less impairment). A total of 1090 carriers and 1114 noncarriers were included in the efficacy analysis. Secondary outcome measures included findings on positron-emission tomographic amyloid imaging with the use of Pittsburgh compound B (PIB-PET) and cerebrospinal fluid phosphorylated tau (phospho-tau) concentrations.


RESULTS
There were no significant between-group differences in the primary outcomes. At week 78, the between-group differences in the change from baseline in the ADAS-cog11 and DAD scores (bapineuzumab group minus placebo group) were -0.2 (P=0.80) and -1.2 (P=0.34), respectively, in the carrier study; the corresponding differences in the noncarrier study were -0.3 (P=0.64) and 2.8 (P=0.07) with the 0.5-mg-per-kilogram dose of bapineuzumab and 0.4 (P=0.62) and 0.9 (P=0.55) with the 1.0-mg-per-kilogram dose. The major safety finding was amyloid-related imaging abnormalities with edema among patients receiving bapineuzumab, which increased with bapineuzumab dose and APOE ε4 allele number and which led to discontinuation of the 2.0-mg-per-kilogram dose. Between-group differences were observed with respect to PIB-PET and cerebrospinal fluid phospho-tau concentrations in APOE ε4 allele carriers but not in noncarriers.


CONCLUSIONS
Bapineuzumab did not improve clinical outcomes in patients with Alzheimer's disease, despite treatment differences in biomarkers observed in APOE ε4 carriers. (Funded by Janssen Alzheimer Immunotherapy and Pfizer; Bapineuzumab 301 and 302 ClinicalTrials.gov numbers, NCT00575055 and NCT00574132, and EudraCT number, 2009-012748-17.).
From Butler Hospital, Providence, RI (S.S.); Brigham and Women's Hospital, Boston (R.S.); University College London, Institute of Neurology, London (N.C.F.); University of Göteborg, Sahlgrenska University Hospital, Mölndal, Sweden (K.B.); University of Pittsburgh, Pittsburgh (W.K.); Veterans Affairs Medical Center, Seattle (M.R.); Cleo Roberts Center for Clinical Research/Sun Health Research Institute, Sun City, AZ (M.S.); Columbia University (L.S.H.) and New York University Langone Medical Center (S.F.), New York; University of Rochester School of Medicine and Dentistry, Rochester, NY (A.P.P.); Janssen Alzheimer Immunotherapy Research and Development, South San Francisco, CA (M.R., N.K., B.N., V.G., M.M., D.W., Y.L., I.C.T., E.L., E.Y., H.R.B.); Janssen Research and Development, Titusville, NJ (J.L.); Global R&D Partners and the University of California, San Diego - both in San Diego (M.G.); and Pfizer, Collegeville, PA (R.B.).
Stephen
S
Salloway
Reisa
R
Sperling
Nick C
NC
Fox
Kaj
K
Blennow
William
W
Klunk
Murray
M
Raskind
Marwan
M
Sabbagh
Lawrence S
LS
Honig
Anton P
AP
Porsteinsson
Steven
S
Ferris
Marcel
M
Reichert
Nzeera
N
Ketter
Bijan
B
Nejadnik
Volkmar
V
Guenzler
Maja
M
Miloslavsky
Daniel
D
Wang
Yuan
Y
Lu
Julia
J
Lull
Iulia Cristina
IC
Tudor
Enchi
E
Liu
Michael
M
Grundman
Eric
E
Yuen
Ronald
R
Black
H Robert
HR
Brashear
D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000134:cerebrospinal fluid / Q000188:drug therapy* / Q000235:genetics; D016229:Amyloid beta-Peptides / Q000032:analysis / Q000037:antagonists & inhibitors* / Q000134:cerebrospinal fluid; D061067:Antibodies, Monoclonal, Humanized / Q000009:adverse effects / Q000627:therapeutic use*; D001057:Apolipoproteins E / Q000235:genetics; D015415:Biomarkers / Q000032:analysis / Q000134:cerebrospinal fluid; D001921:Brain / Q000473:pathology; D003071:Cognition / Q000187:drug effects; D004311:Double-Blind Method; D004487:Edema / Q000139:chemically induced; D005260:Female; D006801:Humans; D057194:Intention to Treat Analysis; D008297:Male; D008875:Middle Aged; D009483:Neuropsychological Tests; D010766:Phosphorylation; D049268:Positron-Emission Tomography; D012720:Severity of Illness Index; D017211:Treatment Failure; D016875:tau Proteins / Q000134:cerebrospinal fluid
D016229:Amyloid beta-Peptides; D061067:Antibodies, Monoclonal, Humanized; D001057:Apolipoproteins E; D015415:Biomarkers; C054369:MAPT protein, human; D016875:tau Proteins; C545458:bapineuzumab