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.).

Figure 1. Screening, Randomization, and Follow-up.

The modified intention-to-treat population included randomly assigned participants who received at least one dose of solanezumab or placebo and underwent assessment for the primary end point. Participants who completed visit 66 (target, 240 weeks) were considered to have completed the double-blind phase. ApoE denotes apolipoprotein E, Covid-19 coronavirus disease 2019, and PET positron-emission tomography.

Figure 2. Primary and Secondary End Points over the Course of the Trial.

All panels show results for the modified intention-to-treat population. The 95% confidence intervals (indicated by shaded regions) were adjusted for multiplicity according to the prespecified graphical testing scheme. Panel A shows the primary end point, the Preclinical Alzheimer Cognitive Composite (PACC) score. The PACC is the sum of four z scores, with higher scores indicating better cognitive performance. The adjusted means, 95% confidence intervals, and P value were estimated with the use of a natural cubic spline model. Panel B shows the spline model–adjusted mean Cognitive Function Index (CFI) combined score (participant and partner). Scores for participant or partner range from 0 to 15, with higher scores indicating greater subjective concerns about cognitive function (range for combined score, 0 to 30). Panel C shows the spline model–adjusted mean score on the Alzheimer’s Disease Cooperative Study Activities of Daily Living (ADL) Prevention Questionnaire, as assessed by the participant’s partner. Scores range from 0 to 45, with higher scores indicating more difficulty in performing activities of daily living. Panel D shows the spline model–adjusted mean Clinical Dementia Rating (CDR)–Sum of Boxes (CDR-SB) score. Scores range from 0 to 18, with higher scores indicating greater impairment in global functioning. Panel E shows Kaplan–Meier estimates of progression of the global CDR score, defined as two consecutive scores greater than zero or a final-visit score greater than zero. Global CDR scores range from 0 to 3, with 0 indicating no cognitive impairment and 3 indicating severe dementia.