Trial of Solanezumab for Mild Dementia Due to Alzheimer's Disease.

Abstract

BACKGROUND:

Alzheimer's disease is characterized by amyloid-beta (Aβ) plaques and neurofibrillary tangles. The humanized monoclonal antibody solanezumab was designed to increase the clearance from the brain of soluble Aβ, peptides that may lead to toxic effects in the synapses and precede the deposition of fibrillary amyloid.

METHODS:

We conducted a double-blind, placebo-controlled, phase 3 trial involving patients with mild dementia due to Alzheimer's disease, defined as a Mini-Mental State Examination (MMSE) score of 20 to 26 (on a scale from 0 to 30, with higher scores indicating better cognition) and with amyloid deposition shown by means of florbetapir positron-emission tomography or Aβ1-42 measurements in cerebrospinal fluid. Patients were randomly assigned to receive solanezumab at a dose of 400 mg or placebo intravenously every 4 weeks for 76 weeks. The primary outcome was the change from baseline to week 80 in the score on the 14-item cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-cog14; scores range from 0 to 90, with higher scores indicating greater cognitive impairment).

RESULTS:

A total of 2129 patients were enrolled, of whom 1057 were assigned to receive solanezumab and 1072 to receive placebo. The mean change from baseline in the ADAS-cog14 score was 6.65 in the solanezumab group and 7.44 in the placebo group, with no significant between-group difference at week 80 (difference, -0.80; 95% confidence interval, -1.73 to 0.14; P=0.10). As a result of the failure to reach significance with regard to the primary outcome in the prespecified hierarchical analysis, the secondary outcomes were considered to be descriptive and are reported without significance testing. The change from baseline in the MMSE score was -3.17 in the solanezumab group and -3.66 in the placebo group. Adverse cerebral edema or effusion lesions that were observed on magnetic resonance imaging after randomization occurred in 1 patient in the solanezumab group and in 2 in the placebo group.

CONCLUSIONS:

Solanezumab at a dose of 400 mg administered every 4 weeks in patients with mild Alzheimer's disease did not significantly affect cognitive decline. (Funded by Eli Lilly; EXPEDITION3 ClinicalTrials.gov number, NCT01900665 .).

• Authors: Lawrence S Honig, Bruno Vellas, Michael Woodward, Mercè Boada, Roger Bullock, Michael Borrie, Klaus Hager, Niels Andreasen, Elio Scarpini, Hong Liu-Seifert, Michael Case, Robert A Dean, Ann Hake, Karen Sundell, Vicki Poole Hoffmann, Christopher Carlson, Rashna Khanna, Mark Mintun, Ronald DeMattos, Katherine J Selzler, Eric Siemers
• Journal: The New England journal of medicine (N Engl J Med) Vol. 378 Issue 4 Pg. 321-330 (01 25 2018) ISSN: 1533-4406 [Electronic] United States
• PMID: 29365294 (Publication Type: Clinical Trial, Phase III, Journal Article, Multicenter Study, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)

Chemical References

• Amyloid beta-Peptides
• Antibodies, Monoclonal, Humanized
• Biomarkers
• Peptide Fragments
• amyloid beta-protein (1-42)
• solanezumab

Topics

• Activities of Daily Living
• Aged
• Aged, 80 and over
• Alzheimer Disease (diagnosis, drug therapy, psychology)
• Amyloid beta-Peptides (cerebrospinal fluid)
• Antibodies, Monoclonal, Humanized (adverse effects, therapeutic use)
• Biomarkers (cerebrospinal fluid)
• Double-Blind Method
• Female
• Humans
• Immunotherapy
• Infusions, Intravenous
• Male
• Mental Status and Dementia Tests
• Middle Aged
• Peptide Fragments (cerebrospinal fluid)
• Plaque, Amyloid (drug therapy)
• Positron-Emission Tomography
• Treatment Failure