Mild-to-moderate Alzheimer's disease: Solanezumab, a humanized monoclonal antibody that binds amyloid, has failed to improve cognition or functional ability
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 ), researchers have 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 ( P=0.24 ) and -0.4 points for the ADCS-ADL score ( P=0.64 ) in EXPEDITION 1 and -1.3 points ( P=0.06 ) and 1.6 points ( 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 ( P=0.06 ) and -1.5 in patients with moderate Alzheimer's disease ( 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 ).
In conclusion, Solanezumab, a humanized monoclonal antibody that binds amyloid, failed to improve cognition or functional ability. ( Xagena )
Doody RS et al, N Engl J Med 2014; 370: 311-321