Trial of Solanezumab in Preclinical Alzheimer's Disease
Reisa A Sperling1, Michael C Donohue1, Rema Raman1
1From the Center for Alzheimer Research and Treatment, Brigham and Women's Hospital, Massachusetts General Hospital, Harvard Medical School (R.A.S., G.A.M.), and the Departments of Neurology and Radiology, Massachusetts General Hospital, Harvard Medical School (K.J.) - both in Boston; Alzheimer's Therapeutic Research Institute, Keck School of Medicine, University of Southern California, San Diego (M.C.D., R.R., M.S.R., P.S.A.); the Florey Institute, University of Melbourne, Melbourne, VIC, Australia (C.L.M.); the Departments of Psychiatry, Neurology, and Neuroscience, Yale School of Medicine, New Haven, CT (C.H.D.); the Department of Neuropathology, Graduate School of Medicine, University of Tokyo, Tokyo (T.I.); and Eli Lilly, Indianapolis (R.Y., M.M., K.C.H., M.C., J.R.S.).
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.).
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