More than 5 million Americans are currently suffering from Alzheimer's disease (AD) and scientists expect this number to nearly triple by 2050. The A4 Study (Anti-Amyloid Treatment in Asymptomatic Alzheimer's Disease Study) is testing whether solanezumab, an investigational treatment, can prevent or slow the development of symptoms associated with AD. Based on external findings from trials at later stages of AD dementia and ongoing observational studies in clinically normal individuals, the leadership of the A4 Study has decided to increase the dose of solanezumab and to extend the length of the A4 Study.
The A4 Study, launched in 2014, is the first-of-its-kind prevention trial in clinically normal older individuals, 65-85 years of age, who have evidence of elevated amyloid plaque accumulation -- a build-up of a protein found in the brain -- which may signal cognitive decline years before AD symptoms appear. The A4 Study is testing whether the investigational antibody, solanezumab, which targets the build-up of amyloid in the brain, can help to slow the progression of memory loss associated with Alzheimer's, before symptoms are clinically apparent.
Over the past few years, there have been multiple trials focused on AD dementia that have failed to show a clinical benefit. The disappointing results from these studies have left us with two unanswered questions: Too little? Too late? Now, researchers leading the A4 Study are making modifications to the study, which they believe will be crucial in providing answers to these questions. Changes to the A4 Study design, based on recent data from other studies, will include increasing the dose of solanezumab or placebo up to 1600mg IV every 4 weeks, with careful safety monitoring. The A4 Study will also be extended for an additional 72 weeks, for a total study duration of 240 weeks, to allow all participants to dose escalate and determine whether the investigational treatment can slow cognitive decline.
Recent findings from solanezumab trials that involved participants at later stages of Alzheimer's dementia suggested that the lower dose had a favorable safety profile, but that a higher dose may be necessary to test whether solanezumab can slow cognitive decline and achieve a meaningful clinical benefit. Additionally, two longitudinal observational studies, the Harvard Aging Brain Study (HABS) and the Alzheimer's Disease Neuroimaging Initiative (ADNI), have reported evidence of increased rates of cognitive decline over 3-5 years among cognitively normal older individuals with amyloid plaque build-up. As a result of these findings, leaders of the A4 Study decided to update the study design. It is important to note that the decisions were not based on any analyses of the A4 Study data itself, as the A4 Study remains fully blinded - neither participants nor researchers are aware of which participants are receiving solanezumab or placebo, and no interim analyses of the A4 data have been conducted.
"The A4 Study was started because we believe the best time to intervene with an anti-amyloid agent is in an asymptomatic population before there is irreversible damage to the brain," said Reisa Sperling, M.D., a neurologist at the Brigham and Women's Hospital, Harvard Medical School and the A4 Study Project Director. "We believe that by increasing the dose and extending the study, we will be able to provide more definitive answers and ultimately get us closer to finding a treatment for this devastating disease."
The A4 Study is a landmark public-private partnership, funded by the National Institute on Aging/NIH, Eli Lilly and Company, the Alzheimer's Association and several philanthropic organizations.
"This is a groundbreaking study for the Alzheimer's field and the NIA is very pleased to continue as an integral partner in this important trial," said Laurie Ryan, Ph.D., Chief of Dementias of Aging Branch, Division of Neuroscience, of the National Institute on Aging at NIH.