News Article
Solanezumab Does Not Protect Against Cognitive Loss in Alzheimers Disease
Binding of solanezumab to soluble amyloid beta may not suppress toxic effects in the synapses of Alzheimers disease patients
Andrea Blotta, PhD
April 3, 2019 – Patients with mild dementia due to Alzheimers disease do not present slower cognitive decline after 76-week treatment with solanezumab relative to placebo.
Lawrence Honig, MD, PhD, with the Taub Institute for Research on Alzheimer’s Disease and the Aging Brain, Columbia University at New York, and colleagues reported their findings in the January 25, 2018, issue of the New England Journal of Medicine.
Over the years, researchers have hypothesized that the early mechanism of pathogenesis of Alzheimers disease relies on overproduction or reduced clearance of extracellular amyloid beta plaques. Increased presence of amyloid beta plaques has been believed to culminate in synaptic and neuronal losses.
Solanezumab, a humanized immunoglobulin G1 monoclonal antibody that binds to the mid-domain of the amyloid beta peptide, was created to enhance the clearance of amyloid beta from the brain, preventing the deposition of the fibrillary form of this protein in the brain.
The aim of this study was to test whether solanezumab would slow the cognitive decline of Alzheimers disease. As opposed to two previous trials involving this antibody in the same settings, this one included only people who presented biomarker evidence of amyloid-related disease, increasing the probability of producing greater magnitude of treatment outcomes.
In a double-blind, placebo-controlled phase 3 trial, which included a total of 2129 people meeting the diagnostic criteria for mild Alzheimers disease, patients were randomly assigned to receive intravenous infusions of either solanezumab 400 mg or placebo every 4 weeks for 76 weeks.
At week 80, the change in Alzheimers Disease Assessment Scale-Cognitive subscale 14 (ADAS-cog14) scores from baseline was not significantly different between groups (between-group difference -0.80; P = .10). Additionally, the effect of this drug on the rate of cognitive decline was smaller than that observed in the two previous studies.
The authors posited several theories for the lack of efficacy of solanezumab. For example, the peripheral reductions in soluble amyloid beta may have not been sufficient to reduce pathobiologic events associated with clinical decline; the dose of the drug may not have been sufficient to produce meaningful effects; or the pathological changes of this stage of the disease may not be susceptible to a drug targeting soluble amyloid beta.
“Although the amyloid hypothesis is based on considerable genetic and biomarker data, if amyloid is not the cause of the disease, solanezumab would not be expected to slow disease progression,” the authors wrote. “A single study ought not to be viewed as disproving a hypothesis; nevertheless, the amyloid hypothesis will need to be considered in the context of accruing results from this trial and other clinical trials of antiamyloid therapies,” they concluded.
The study was supported by Eli Lilly.
New England Journal of Medicine - January 25th, 2018
(Unpublished sample)