Lecanemab, a monoclonal antibody targeting amyloid-beta protofibrils, has shown sustained clinical benefits in patients with early Alzheimer's disease, according to long-term data from the Phase 2 study 201 and its open-label extension (OLE). The study, which included a gap period where treatment was interrupted, highlights the potential for lecanemab to modify the course of Alzheimer's disease by reducing brain amyloid and slowing cognitive decline.
Core Study Results
The core phase of study 201 involved 856 participants randomized to receive either placebo or lecanemab at various doses. The primary analysis revealed that lecanemab treatment led to a significant reduction in brain amyloid levels, as measured by amyloid PET scans. Specifically, 65% of subjects at 12 months and 81% at 18 months converted from amyloid positive to amyloid negative by visual read. This reduction in amyloid was associated with a consistent slowing of clinical decline across multiple clinical and biomarker endpoints, including the Clinical Dementia Rating-Sum of Boxes (CDR-SB), Alzheimer's Disease Composite Score (ADCOMS), and Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog14).
Impact of Treatment Discontinuation
Following the 18-month core treatment period, participants entered a gap period averaging 24 months (range 9-59 months) where lecanemab treatment was discontinued. During this period, the clinical benefits observed during the core study were maintained, with treated subjects continuing to perform better than the placebo group on clinical assessments. However, the rate of clinical progression during the gap period was similar between the lecanemab and placebo groups, indicating that the disease continued to progress at a similar pace once treatment was stopped. Amyloid levels, as measured by PET scans, reaccumulated slightly during this period, and plasma biomarkers such as Aβ42/40 ratio and p-tau181 began to revert towards pre-treatment levels.
Open-Label Extension (OLE) Findings
In the OLE phase, participants received open-label lecanemab 10 mg/kg biweekly for up to 24 months. Results showed that re-initiation of lecanemab led to further reductions in brain amyloid, with 43% of previously placebo-treated subjects converting to amyloid negative within 3 months of starting lecanemab. Both newly treated and retreated groups experienced improvements in plasma Aβ42/40 ratio and reductions in plasma p-tau181 levels. These biomarker changes were associated with a slowing of clinical decline, suggesting that continuous treatment with lecanemab may provide ongoing benefits.
Biomarker Correlations
Analysis of plasma biomarkers revealed strong correlations with treatment response. An increase in plasma Aβ42/40 ratio and a decrease in plasma p-tau181 levels were significant predictors of slower cognitive decline. Model-predicted disease progression rates for CDR-SB and ADCOMS were reduced by 6.92% and 6.12%, respectively, for every 0.25 unit increase from baseline in plasma Aβ42/40 ratio. Similarly, model-predicted reductions in disease progression rates for CDR-SB, ADCOMS, and ADAS-Cog14 were observed with decreases in plasma p-tau181 levels. These findings suggest that plasma biomarkers could be valuable tools for monitoring lecanemab treatment effects and potentially guiding dosing strategies.
Clinical Implications
The results from study 201 and its OLE provide further evidence that lecanemab can effectively target amyloid pathology and slow cognitive decline in early Alzheimer's disease. The data also suggest that continuous treatment may be necessary to maintain these benefits, as disease progression resumes when treatment is interrupted. These findings support the potential of lecanemab as a disease-modifying therapy for Alzheimer's disease, offering hope for improved outcomes for patients in the early stages of the disease.
