On 9 March, at the AD/PD 2024 International Conference on Alzheimer’s and Parkinson’s Diseases, during a symposium on amyloid beta (Aβ) targeting therapies in Alzheimer’s disease, further efficacy results from the Phase III Clarity AD trial (NCT03887455) evaluating Leqembi (lecanemab) for the treatment of early Alzheimer’s disease were presented.
These results focused on a sub-study in patients with earlier Alzheimer’s disease pathology estimated by tau pathology in the brain, measured using tau positron emission tomography (PET) scans, as such only patients with a baseline tau PET scan were included in the sub-group. Lower levels of tau are indicative of earlier pathology and less disease progression.
When looking at the tau PET sub-study group, the clinical outcomes, measured using Clinical Dementia Rating-Sum of Boxes (CDR-SB) score, Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) score, and Alzheimer’s Disease Cooperative Study-Activities of Daily Living for use in mild cognitive impairment (MCI) (ADCS MCI-ADL) score, were very similar when looking at the Clarity AD trial population as a whole, showing slowing in cognitive decline. Additionally, it was shown that Leqembi treatment slows the spread of tau, particularly in the temporal lobe region of the brain, which is the area of the brain where we see the earliest tau deposition. In an analysis of the group of patients with low tau levels, it was shown that the greatest intensity of tau was in the medial temporal lobe specifically in the entorhinal cortex, something that has not been reported previously in anti-amyloid antibody clinical trials.
Within the tau PET sub-study, patients were split into low tau, defined as a tau PET standardized uptake value ratio (SUVr) of less than 1.06, and intermediate/high tau, defined as tau PET SUVr ≥ 1.06, groups. Across the whole tau PET sub-study Leqembi treatment resulted in a consistent reduction in amyloid measured using amyloid PET, and in the low tau PET group 93% of patients reached low enough levels of amyloid PET to be considered “normal” at 18 months, compared with 57% in the intermediate/high tau PET group. In terms of clinical effect, the low tau PET group demonstrated numerically greater slowing of decline than the whole tau PET sub-group when looking at CDR-SB, ADAS-Cog14, and ADCS MCI-ADL scores. Further, for the low tau PET group, there is an appearance of improvement above baseline while looking at the CDR-SB score. However, these analyses are only exploratory, and as such the data is not significant. Despite this, the Leqembi data does follow the same trend as data from the Phase III TRAILBLAZER-ALZ 2 trial (NCT04437511) in which donanemab was significantly more effective in patients with low baseline tau compared to high baseline tau.
Participants in the low tau PET group also had low amyloid PET, with about an 80% concordance between the two. Therefore, low amyloid was used as a proxy for low pathology participants in the whole Clarity AD population to enable analysis of a larger group of low pathology patients. Looking at clinical outcomes for the low amyloid/low pathology group a greater slowing in cognitive decline was seen across CDR-SB, ADAS-Cog14, and ADCS MCI-ADL scores compared with the overall Clarity AD study population.
Further results from the open-label extension portion of the Clarity AD study were also presented in the same symposium at AD/PD 2024. At 24 months, there is a statistical difference in the CDR-SB score between patients treated with Leqembi continuously, and those who received Leqembi at 18 months after treatment with placebo. This separation between groups demonstrates the disease-modifying effect of Leqembi. Further, looking at the three clinical outcome measures, Leqembi treatment through 24 months demonstrates continued clinical benefit for patients.
When combined, the data presented indicate that the earlier treatment with Leqembi is initiated, so that Alzheimer’s disease pathology is lower, the more beneficial the outcomes will be, reflected in the increased slowing of cognitive decline. To this end, Eisai and Biogen are currently evaluating Leqembi in a preclinical Alzheimer’s disease population when cognitive performance is normal, but the disease pathology is beginning and there are detectable amyloid levels in the brain, in the Phase III AHEAD study (NCT04468659).
