Phase 3 trials of solanezumab for mild-to-moderate Alzheimer's disease.
BACKGROUND
Alzheimer's disease is characterized by amyloid-beta plaques, neurofibrillary tangles, gliosis, and neuronal loss. Solanezumab, a humanized monoclonal antibody, preferentially binds soluble forms of amyloid and in preclinical studies promoted its clearance from the brain.


METHODS
In two phase 3, double-blind trials (EXPEDITION 1 and EXPEDITION 2), we randomly assigned 1012 and 1040 patients, respectively, with mild-to-moderate Alzheimer's disease to receive placebo or solanezumab (administered intravenously at a dose of 400 mg) every 4 weeks for 18 months. The primary outcomes were the changes from baseline to week 80 in scores on the 11-item cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-cog11; range, 0 to 70, with higher scores indicating greater cognitive impairment) and the Alzheimer's Disease Cooperative Study-Activities of Daily Living scale (ADCS-ADL; range, 0 to 78, with lower scores indicating worse functioning). After analysis of data from EXPEDITION 1, the primary outcome for EXPEDITION 2 was revised to the change in scores on the 14-item cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-cog14; range, 0 to 90, with higher scores indicating greater impairment), in patients with mild Alzheimer's disease.


RESULTS
Neither study showed significant improvement in the primary outcomes. The modeled difference between groups (solanezumab group minus placebo group) in the change from baseline was -0.8 points for the ADAS-cog11 score (95% confidence interval [CI], -2.1 to 0.5; P=0.24) and -0.4 points for the ADCS-ADL score (95% CI, -2.3 to 1.4; P=0.64) in EXPEDITION 1 and -1.3 points (95% CI, -2.5 to 0.3; P=0.06) and 1.6 points (95% CI, -0.2 to 3.3; P=0.08), respectively, in EXPEDITION 2. Between-group differences in the changes in the ADAS-cog14 score were -1.7 points in patients with mild Alzheimer's disease (95% CI, -3.5 to 0.1; P=0.06) and -1.5 in patients with moderate Alzheimer's disease (95% CI, -4.1 to 1.1; P=0.26). In the combined safety data set, the incidence of amyloid-related imaging abnormalities with edema or hemorrhage was 0.9% with solanezumab and 0.4% with placebo for edema (P=0.27) and 4.9% and 5.6%, respectively, for hemorrhage (P=0.49).


CONCLUSIONS
Solanezumab, a humanized monoclonal antibody that binds amyloid, failed to improve cognition or functional ability. (Funded by Eli Lilly; EXPEDITION 1 and 2 ClinicalTrials.gov numbers, NCT00905372 and NCT00904683.).
From the Alzheimer's Disease and Memory Disorders Center, Department of Neurology, Baylor College of Medicine, Houston (R.S.D.); Alzheimer's Disease Cooperative Study, Department of Family and Preventive Medicine (R.G.T., R.R., X.S.), and the Department of Neurosciences (R.G.T., R.R., P.S.A., R.M.), University of California at San Diego, San Diego; Indiana Alzheimer Disease Center, Indiana University (M.F.), and Eli Lilly (E.S., H.L.-S., R.M.) - both in Indianapolis; the Department of Neuropathology, School of Medicine, and the Department of Neuropathology and Neuroscience, School of Pharmacological Science, University of Tokyo, Tokyo (T.I.); Gerontopole, Unité Mixte de Recherche 1027, Centre Hospitalier Universitaire Toulouse, Toulouse, France (B.V.); the Department of Medical Ethics and Health Policy, University of Pennsylvania, Philadelphia (S.J.); and the Center for Human Experimental Therapeutics, University of Rochester Medical Center, Rochester, NY (K.K.).
Rachelle S
RS
Doody
Ronald G
RG
Thomas
Martin
M
Farlow
Takeshi
T
Iwatsubo
Bruno
B
Vellas
Steven
S
Joffe
Karl
K
Kieburtz
Rema
R
Raman
Xiaoying
X
Sun
Paul S
PS
Aisen
Eric
E
Siemers
Hong
H
Liu-Seifert
Richard
R
Mohs
D000203:Activities of Daily Living; D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000097:blood / Q000134:cerebrospinal fluid / Q000188:drug therapy*; D016229:Amyloid beta-Peptides / Q000097:blood / Q000134:cerebrospinal fluid; D061067:Antibodies, Monoclonal, Humanized / Q000009:adverse effects / Q000627:therapeutic use*; D001057:Apolipoproteins E / Q000097:blood / Q000235:genetics; D015415:Biomarkers / Q000097:blood / Q000134:cerebrospinal fluid; D003071:Cognition / Q000187:drug effects; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D057194:Intention to Treat Analysis; D008297:Male; D009483:Neuropsychological Tests; 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; C550616:solanezumab