Solanezumab Fails Phase 3 A4 Study of Preclinical Alzheimer Disease
On PET imaging, amyloid continued to accumulate over time, with participants in the solanezumab and placebo groups showing similar increases over time.
Reisa Sperling, MD
Newly announced findings from the phase 3 Anti-Amyloid Treatment in Asymptomatic Alzheimer’s Disease (A4) study showed that solanezumab, an investigational agent developed by Eli Lilly, showed no effect on slowing of the progression of cognitive decline in patients with preclinical Alzheimer disease (AD).
Launched in 2013, the A4 study was a first-of-its-kind secondary progression trial, enrolling more than 1100 individuals between 65 and 85 years of age who had PET imaging evidence of amyloid plaque accumulation in the brain. Over the course of approximately 4.5 years, the agent did not statistically differ from placebo on the primary outcome of Preclinical Alzheimer Cognitive Composite (PAAC; solanezumab: –1.69 [95% CI, –2.13 to –1.26] vs placebo: –1.4 [95% CI, –1.76 to –1.04]; P = .26).
"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, Eli Lilly, said in a statement. "While this study was negative, the unique data generated have increased our understanding of preclinical Alzheimer's disease and will advance the next generation of AD prevention studies.
Solanezumab is a humanized monoclonal IgG1 antibody directed against the mid-domain of the amyloid-ß peptide. It recognizes soluble monomeric, not fibrillar, amyloid-ß. In A4, patients were randomly assigned to either solanezumab 400-1600 mg intravenously every 4 weeks for 240 weeks or placebo.
The study’s secondary end points, change in Cognitive Function index, Alzheimer’s Disease Cooperative Study-Activities Daily Living-Prevention Questionnaire, composite standardized uptake value ratio, and others, were consistent with the primary outcome, numerically favoring placebo over solanezumab. Additionally, 36.1% of participants in the preclinical AD stage progressed on the clinician-rated, Clinical Dementia Rating-Global Scale (CDR-GS). Similar rates of progression were seen with both the solanezumab and placebo groups.
Sims added, "Raw data and analyses will be made widely available to researchers through the public-private partnership with the NIH-funded Alzheimer's Clinical Trial Consortium. 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 Alzheimer's disease."
On amyloid PET imaging, amyloid continued to accumulate over time in both groups, demonstrated by centiloid increases of 17.5 and 12.1 in the solanezumab and placebo groups, respectively. Additionally, investigators found a strong association between higher baseline amyloid levels and greater risk of progression to symptomatic AD (P <.001). In terms of safety, solanezumab’s profile was consistent with what was previously observed, with a low rate of amyloid-related imaging abnormalities that were similar to placebo groups.
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"These findings indicate that amyloid is a key driver of cognitive decline at the preclinical stage of Alzheimer's disease," A4 Study project director Reisa Sperling, MD, neurologist, Brigham and Women’s Hospital, Harvard Medicial School, said in a statement. "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."
This was not the first time that solanezumab failed to show an effect on cognition. Published in the New England Journal of Medicine in 2018, EXPEDITION-3 was a large-scale, phase 3 study (NCT01900665) that featured 2129 enrolled individuals with mild dementia due to AD. After 80 weeks of treatment, the mean change from baseline in Alzheimer’s Disease Assessment Scale (ADAS-Cog14) was 6.65 in the solanezumab group and 7.44 in the placebo group, with no significant between-group difference observed (difference, –0.80; 95% CI, –1.73 to 0.14; P = .10).2
EXPEDITION-3 was a follow-up to EXPEDITION 1 and 2, a pair of double-blind trials that randomly assigned 1012 and 1040 patients, respectively, with mild-to-moderate AD to either placebo or solanezumab every 4 weeks for 18 months. All told, the modeled difference between groups in the change was –0.8 points for the ADAS-Cog11 score (95% CI, –2.1 to 0.5; P = .24) and –0.4 points for the ADCS-ADL score (95% CI, –2.3 to 1.4; P = .64) in EXPEDITION 1 and –1.3 points (95% CI, –2.5 to 0.3; P = .06) and 1.6 points (95% CI, –0.2 to 3.3; P = .08), respectively, in EXPEDITION 2.3
