1. In patients with mild Alzheimer’s disease solanezumab, an antibody designed to facilitate clearance of amyloid-beta plaques, did not significantly reduce cognitive decline over time.
2. There was no difference in overall rates of serious adverse events or death between the study and placebo arms of the trial.
Evidence Rating Level: 1 (Excellent)
Study Rundown: Alzheimer’s disease (AD) is a common neurodegenerative cause of irreversible dementia with few effective treatments. The pathogenesis is hypothesized to involve extracellular accumulation of amyloid-beta (Aβ) into plaques. Solanezumab is a monoclonal antibody designed to increase clearance of soluble Aβ. Secondary analyses of the EXPEDITION and EXPEDITION2 trials investigating this drug suggested a beneficial effect on cognitive decline in patients with mild AD. This trial, entitled EXPEDITION3, enrolled patients with mild AD and evidence of amyloid pathology on imaging or cerebrospinal fluid analysis. The primary outcome was change from baseline to 80 weeks on a validated AD cognitive assessment scale. There was no significant difference in change from baseline between the solanezumab and placebo treated groups. These data do not support the use of solanezumab in the treatment of mild AD.
A major strength of this study is the randomized trial design, which allows for an unbiased estimation of the causal effect of the study drug. Furthermore, the drug was evaluated in a population with known amyloid pathology; on a biological basis, these patients would be hypothesized to be more likely to respond to Aβ clearance.
Relevant Reading: Phase 3 Trials of Solanezumab for Mild-to-Moderate Alzheimer’s Disease
In-Depth [randomized controlled trial]: This phase 3, international, randomized controlled trial enrolled 2129 participants between 2013 and 2016. Eligible patients from 55 to 90 years old had mild AD, defined as a Mini-Mental State Examination score of 20 to 26 and evidence of amyloid pathology on either positron-emission tomography or cerebrospinal fluid analysis. Notably, this was not an inclusion criterion for previous studies of solanezumab (EXPEDITION, EXPEDITION2). Patients received the treatment drug or placebo every 4 weeks for 76 weeks. The primary outcome studied was a change from baseline to 80 weeks on the cognitive subscale of the Alzheimer’s Disease Assessment Scale (ADAS-cog14). Secondary outcomes included assessments of activities of daily living and other cognitive scales.
At 80 weeks, the change in cognitive score from baseline in the solanezumab group was 6.65, and 7.44 in the placebo group (difference= -0.80, p = 0.10). Given that the study did not meet its primary endpoint, the authors did not formally conduct statistical hypothesis tests for their secondary endpoints; results were overall unremarkable. At least 1 adverse event occurred in similar rates of patients in both groups, though vitamin D deficiency, nasal congestion, spinal osteoarthritis, and dysuria occurred more frequently in the solanezumab group. Although additional secondary biological outcomes are pending, the authors report that solanezumab reduced free plasma Aβ by over 90% though no clinical efficacy was observed. There were no significant differences in overall rates of death or serious adverse events between the study and placebo arm.
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