Trial of Solanezumab in Preclinical Alzheimer's Disease.

Abstract

BACKGROUND:

Trials of monoclonal antibodies that target various forms of amyloid at different stages of Alzheimer's disease have had mixed results.

METHODS:

We tested solanezumab, which targets monomeric amyloid, in a phase 3 trial involving persons with preclinical Alzheimer's disease. Persons 65 to 85 years of age with a global Clinical Dementia Rating score of 0 (range, 0 to 3, with 0 indicating no cognitive impairment and 3 severe dementia), a score on the Mini-Mental State Examination of 25 or more (range, 0 to 30, with lower scores indicating poorer cognition), and elevated brain amyloid levels on 18F-florbetapir positron-emission tomography (PET) were enrolled. Participants were randomly assigned in a 1:1 ratio to receive solanezumab at a dose of up to 1600 mg intravenously every 4 weeks or placebo. The primary end point was the change in the Preclinical Alzheimer Cognitive Composite (PACC) score (calculated as the sum of four z scores, with higher scores indicating better cognitive performance) over a period of 240 weeks.

RESULTS:

A total of 1169 persons underwent randomization: 578 were assigned to the solanezumab group and 591 to the placebo group. The mean age of the participants was 72 years, approximately 60% were women, and 75% had a family history of dementia. At 240 weeks, the mean change in PACC score was -1.43 in the solanezumab group and -1.13 in the placebo group (difference, -0.30; 95% confidence interval, -0.82 to 0.22; P = 0.26). Amyloid levels on brain PET increased by a mean of 11.6 centiloids in the solanezumab group and 19.3 centiloids in the placebo group. Amyloid-related imaging abnormalities (ARIA) with edema occurred in less than 1% of the participants in each group. ARIA with microhemorrhage or hemosiderosis occurred in 29.2% of the participants in the solanezumab group and 32.8% of those in the placebo group.

CONCLUSIONS:

Solanezumab, which targets monomeric amyloid in persons with elevated brain amyloid levels, did not slow cognitive decline as compared with placebo over a period of 240 weeks in persons with preclinical Alzheimer's disease. (Funded by the National Institute on Aging and others; A4 ClinicalTrials.gov number, NCT02008357.).

• Authors: Reisa A Sperling, Michael C Donohue, Rema Raman, Michael S Rafii, Keith Johnson, Colin L Masters, Christopher H van Dyck, Takeshi Iwatsubo, Gad A Marshall, Roy Yaari, Michele Mancini, Karen C Holdridge, Michael Case, John R Sims, Paul S Aisen, A4 Study Team
• Journal: The New England journal of medicine (N Engl J Med) Vol. 389 Issue 12 Pg. 1096-1107 (Sep 21 2023) ISSN: 1533-4406 [Electronic] United States
• PMID: 37458272 (Publication Type: Randomized Controlled Trial, Journal Article)
• Copyright: Copyright © 2023 Massachusetts Medical Society.

Chemical References

• Amyloid beta-Peptides
• Antibodies, Monoclonal, Humanized
• solanezumab

Topics

• Aged
• Female
• Humans
• Male
• Alzheimer Disease (diagnostic imaging, drug therapy, psychology)
• Amyloid beta-Peptides
• Antibodies, Monoclonal, Humanized (adverse effects, pharmacology, therapeutic use)
• Brain (diagnostic imaging, drug effects)
• Positron-Emission Tomography
• Aged, 80 and over