Title | Phase 3 trials of solanezumab for mild-to-moderate Alzheimer's disease. |
Publication Type | Journal Article |
Year of Publication | 2014 |
Authors | Doody, RS, Thomas, RG, Farlow, M, Iwatsubo, T, Vellas, B, Joffe, S, Kieburtz, K, Raman, R, Sun, X, Aisen, PS, Siemers, E, Liu-Seifert, H, Mohs, R |
Corporate Authors | Alzheimer's Disease Cooperative Study Steering Committee, Solanezumab Study Group |
Journal | N Engl J Med |
Volume | 370 |
Issue | 4 |
Pagination | 311-21 |
Date Published | 2014 Jan 23 |
ISSN | 1533-4406 |
Keywords | Activities of Daily Living, Aged, Aged, 80 and over, Alzheimer Disease, Amyloid beta-Peptides, Antibodies, Monoclonal, Humanized, Apolipoproteins E, Biomarkers, Cognition, Double-Blind Method, Female, Humans, Intention to Treat Analysis, Male, Neuropsychological Tests, Severity of Illness Index, tau Proteins, Treatment Failure |
Abstract | 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.). |
DOI | 10.1056/NEJMoa1312889 |
Alternate Journal | N. Engl. J. Med. |
PubMed ID | 24450890 |