New data from the open-label extension (OLE) of the Phase 3 Clarity AD trial indicates that early intervention with lecanemab may provide sustained benefits for individuals with early-stage Alzheimer's disease. The study, which followed participants for three years, revealed that nearly half of those with low baseline amyloid accumulation who received continuous lecanemab treatment experienced either improvement or no decline in cognitive and functional symptoms.
Sustained Cognitive Benefits
The Clarity AD OLE trial assessed the long-term effects of lecanemab in adults with early-stage Alzheimer's. According to Eisai, approximately 46% of participants with low baseline amyloid levels showed improvement or no decline on the Clinical Dementia Rating-Sum of Boxes (CDR-SB), a key measure of global function and cognition. Furthermore, about one-third (33%) demonstrated improvement from their baseline CDR-SB scores. Similar positive trends were observed in performance on the Alzheimer's Disease Assessment Scale-Cognitive Subscale 14 (ADAS-Cog14) and the Alzheimer's Disease Cooperative Study-Activities of Daily Living Inventory (ADCS MCI-ADL).
These findings, presented at the 17th Clinical Trials for Alzheimer’s Disease Conference, suggest that initiating lecanemab treatment earlier in the disease course may have a significant positive impact on disease progression and provide continued benefits over the long term.
Long-Term Efficacy and Safety
Earlier results from the Clarity AD trial, presented at the Alzheimer's Association International Conference (AAIC) in July 2024, showed a mean change from baseline CDR-SB of -0.45 at 18 months in lecanemab-treated participants. This change doubled to -0.95 at 36 months, compared to a pre-specified natural history cohort of Alzheimer's disease. The reduction in relative risk for progression to the next stage of disease severity was 30%. A substudy using tau positron-emission tomography (PET) revealed that 59% of participants with no or low tau levels at baseline had improvement in symptoms or no decline after three years of continuous lecanemab treatment, with 51% experiencing improvement from baseline on the CDR-SB scale.
Safety data from the OLE showed no new safety signals. Most amyloid-related imaging abnormalities (ARIA) were observed during the first six months of treatment, with subsequent rates being low and similar to those seen in the placebo-controlled phase of the study. While the incidence of ARIA was higher in ApoE4 homozygotes, the rates of new ARIA decreased after the completion of the 18-month core study, regardless of ApoEε4 status.
Advancing Preclinical Alzheimer's Screening
Eisai also provided an update on the Phase 3 AHEAD 3-45 clinical study, which focuses on individuals with preclinical Alzheimer's disease, characterized by the absence of clinical impairment but the presence of intermediate or elevated levels of brain amyloid. The study employs blood tests, cognitive function tests, amyloid PET scans, MRI, and tau PET scans to screen potential participants. Based on amyloid PET results, participants are assigned to either the A3 trial (borderline amyloid levels) or the A45 trial (positive amyloid levels), evaluating different dose levels of lecanemab.
The use of plasma Aβ42/40 ratio and p-tau217/tau217 ratio for initial screening has significantly improved the assessment of eligibility for amyloid PET testing, reducing the screening failure rate from over 70% to less than 30%. Plasma p-tau217 showed a strong correlation with amyloid PET, suggesting its utility as a biomarker for elevated brain amyloid. Enrollment for the AHEAD 3-45 trial was completed in October.
