Eli Lilly treatment targets soluble amyloid beta and did not clear plaque or halt accumulation of amyloid in individuals treated with the drug in the A4 study.
Solanezumab did not slow the progression of cognitive decline related to Alzheimer disease (AD) when started in individuals with amyloid plaque but with no clinical symptoms of the disease, known as the preclinical stage of AD, according to a statement by Eli Lilly and Company.
Solanezumab targets soluble amyloid beta and did not clear plaque or halt accumulation of amyloid in individuals treated with the drug in the Anti-Amyloid Treatment in Asymptomatic Alzheimer disease (A4) study (NCT02008357).
“Results of the A4 study clearly showed that the primary and secondary endpoints were not met. Therefore, the A4 Study concludes our clinical development of solanezumab and indicates that targeting soluble amyloid beta through this mechanism is not effective in this population,” John Sims, head of Medical, Global Brand Development for solanezumab at Eli Lilly and Company, said in the statement.
"While this study was negative, the unique data generated have increased our understanding of preclinical [AD] and will advance the next generation of AD prevention studies. Raw data and analyses will be made widely available to researchers through the public-private partnership with the [National Institutes of Health]-funded Alzheimer's Clinical Trial Consortium,” Sims said.
“These data will serve the scientific community and enable Lilly and other drug developers to enhance our clinical trial designs for other potential medicines targeting [AD],” he said.
The A4 study was a first-of-its-kind secondary prevention trial. Investigators enrolled more than 1100 individuals aged 65 to 85 years. Participants had positron emission tomography (PET)-imaging evidence of amyloid plaque accumulation in the brain with no clinical impairment.
Investigators randomized individuals to either solanezumab or the placebo and treated them for approximately 4.5 years.
The results showed that solanezumab did not slow cognitive decline on the primary outcome measure, which was the Preclinical Alzheimer Cognitive Composite, which is used to measure the aspects of cognitive decline in association to preclinical AD. It uses tests that weigh episodic memory, global cognition, and timed executive function.
Secondary clinical outcomes were consistent with the primary outcomes, which favored the placebo.
Additionally, investigators found that 36.1% of individuals starting at the stage of preclinical AD progressed on the Clinical Dementia Rating-Global Scale, which provides an overall assessment of the clinical stage of AD.
They found similar rates of progression in individuals with solanezumab and the placebo.
The amyloid PET imaging showed that amyloid continued to accumulate over time in both the placebo and solanezumab groups. Higher baseline amyloid levels were also linked to a greater risk of progression to symptomatic AD.
Investigators reported that the solanezumab and placebo groups were well balanced at baseline and that the results were consistent across multiple analyses.
The safety results in the A4 study were also consistent with the safety profile previously observed in other phase 3 studies.
Eli Lilly developing other investigational antibodies in phase 3, which are intended to target deposited amyloid plaque and have been shown to lead to plaque clearance in individuals who are treated.
Lilly provides update on A4 study of solanezumab for preclinical Alzheimer's disease. News release. Lilly. March 8, 2023. Accessed March 9, 2023. https://investor.lilly.com/news-releases/news-release-details/lilly-provides-update-a4-study-solanezumab-preclinical