Lilly Provides Update on A4 Study of Solanezumab for Preclinical Alzheimer's Disease
Results showed solanezumab did not slow cognitive decline in preclinical Alzheimer's disease or reduce risk of progression to symptomatic Alzheimer's disease
Solanezumab targets soluble amyloid beta, and treatment did not result in clearance of brain amyloid plaque
"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," said
Launched in 2013, the A4 Study was a first-of-its-kind secondary prevention trial, enrolling more than 1,100 individuals between 65 and 85 years of age who had PET-imaging evidence of amyloid plaque accumulation in the brain and who did not have clinical impairment. Participants were randomized to either solanezumab or placebo and then treated for approximately 4.5 years.
Solanezumab binds only to soluble amyloid-beta protein and was not expected to significantly remove deposited amyloid plaques. Donanemab and remternetug, other
More than 6.5 million Americans are currently suffering dementia due to Alzheimer's disease2, and scientists expect this number to nearly triple by 20503. It is estimated that more than 20 million Americans and approximately 315 million people globally have preclinical Alzheimer's disease, the earliest stages of the disease 4, 5.
During the double-blind portion of the study, results showed:
- Solanezumab did not slow cognitive decline on the primary outcome measure, the Preclinical Alzheimer Cognitive Composite (PACC) [mean change (95% CI): placebo -1.4 (‑1.76, ‑1.04); solanezumab -1.69 (-2.13, -1.26); p-value 0.26)]. The PACC was developed to measure the aspects of cognitive decline relevant in preclinical AD and is an equally weighted composite that tests episodic memory, timed executive function, and global cognition.
- Secondary clinical outcome results were consistent with the primary outcome, numerically favoring placebo compared with solanezumab.
- 36.1% of participants starting at the stage of preclinical AD progressed on the Clinical Dementia Rating-Global Scale (defined as CDR-global score greater than 0 at two consecutive visits or final visit). CDR-GS is a clinician-rated scale that provides an overall assessment of the participant's clinical stage of AD. Similar rates of progression were seen with both the solanezumab and placebo groups.
- On amyloid PET imaging, amyloid continued to accumulate over time in both the placebo (65.9 Centiloid baseline, 17.5 Centiloid increase) and solanezumab (66.2 Centiloid baseline, 12.1 Centiloid increase) groups.
- Higher baseline amyloid levels were strongly associated with a greater risk of progression to symptomatic Alzheimer's disease (p-value<0.001).
- The solanezumab and placebo groups were well-balanced at baseline, and results were consistent across multiple analysis methods and models.
- Safety results in the A4 Study were consistent with the safety profile observed in previous solanezumab Phase 3 studies. Amyloid-Related Imaging Abnormalities with edema/effusion (ARIA-E) were uncommon and similar between treatment and placebo groups.
"These findings indicate that amyloid is a key driver of cognitive decline at the preclinical stage of Alzheimer's disease. Solanezumab did not substantially impact amyloid plaque burden in the brain, and unfortunately did not slow cognitive decline. These data suggest that we may need to be more aggressive with amyloid removal even at this very early stage of disease," said
The A4 Study is a landmark public-private partnership, funded by the
Full disclosure of the study results will be shared later in the year at a scientific conference.
About the A4 Study
The Anti-Amyloid Treatment in Asymptomatic Alzheimer's disease (A4) Study is a Phase 3, double-blind, placebo-controlled study in males and females ages 65 to 85 years with preclinical AD (that is, in individuals with evidence of brain amyloid pathology on PET amyloid imaging who are clinically unimpaired but at high risk for cognitive decline).
The A4 Study tested whether solanezumab could slow the progression of Alzheimer's disease-related cognitive decline, brain imaging, and other biomarkers over the course of approximately 4.5 years. The study included more than 1,100 participants at 67 sites throughout
This press release contains forward-looking statements (as that term is defined in the Private Securities Litigation Reform Act of 1995) about A4 Study results, the conclusion of
- Sperling, Aisen, et
al Alzheimer& Dementia 2011. Centers for Disease Control and Prevention. Alzheimer's Disease. Available at:
November 9, 2022. Alzheimer's Disease International. Dementia Statistics.
November 9, 2022.
- Brookmeyer, R. et al. "Forecasting the prevalence of preclinical and clinical Alzheimer's disease in
the United States." Alzheimer's & Dementia 14 (2018) 121-129.
- Gustavsson, A. et al. "Global estimates on the number of persons across the Alzheimer's disease continuum." Alzheimer's & Dementia (2022) 1-13.
View original content to download multimedia:https://www.prnewswire.com/news-releases/lilly-provides-update-on-a4-study-of-solanezumab-for-preclinical-alzheimers-disease-301766069.html