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.
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.
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).
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.).