Treatment with solanezumab is not effective in preventing Alzheimer’s disease
Posted in News
Katie Seidenberg and R. Scott Turner
Eli Lilly and collaborators released the topline results of the Anti-Amyloid Treatment in Asymptomatic Alzheimer’s disease (A4) Study March 8th (NCT02008357 on clinicaltrials.gov). The treatment, an anti-amyloid antibody called solanezumab, did not prevent cognitive decline in individuals with preclinical Alzheimer’s disease (AD). Individuals with preclinical AD have normal memory and cognition but elevated amyloid in the brain, and are considered at risk of impending cognitive decline. Participants receiving treatment did not exhibit plaque clearance or a slowed rate of amyloid accumulation in the brain.
The A4 study is a prevention trial that enrolled over 1100 individuals between the ages of 65 and 85 with preclinical AD. Participants received either monthly intravenous solanezumab or placebo treatment for approximately 4.5 years. Based on the primary outcome, the Preclinical Alzheimer Cognitive Composite[1], solanezumab treatment did not affect cognitive decline compared to the placebo group. Similarly, the rate of progression on the Clinical Dementia Rating-Global Scale[2] was comparable between the placebo and treated groups. Amyloid PET imaging revealed continued accumulation of amyloid in both groups. The treatment was safe – with no difference in side-effect profiles between groups.
These findings support the amyloid hypothesis of AD by showing that elevated amyloid is a significant risk factor of cognitive decline. These results also favor the working hypothesis that clinical benefits may require amyloid clearance from the brain. Solanezumab targets soluble amyloid aggregates but not amyloid plaques. The second-generation anti-amyloid antibodies, including lecanemab and donanemab, differ in that they target amyloid plaques. Lecanemab (Leqembiâ) was the first antibody shown to slow cognitive decline of individuals with mild AD or mild cognitive impairment, and demonstrated rapid amyloid clearance from the brain. A prevention trial of preclinical AD with lecanumab treatment, the AHEAD trial, is now recruiting volunteers and their study partners (NCT04468659 on clinicaltrial.gov). Studies with donanemab are also ongoing.
Despite these disappointing results with solanezumab, we learned a lot from the A4 study. For example, a higher amyloid level is strongly associated with risk of progression to AD. Additional discoveries will follow from continued analysis of the results over coming months. As always, we are very grateful to the participants and their study partners in the A4 study. We cannot make progress without you.
[1] A composite developed to measure the aspects of cognitive decline relevant in preclinical AD which is equally weighted to test episodic memory, timed executive function, and global cognition.
[2] A clinician-rated scale that provides an overall assessment of the participant’s clinical stage of AD.