After 3 years of continuous treatment with lecanemab (Leqembi, Eisai) investigators have reported continued "clinically and personally meaningful benefit" among individuals with early-stage Alzheimer disease (AD) including continued positive impact on disease biomarkers after plaque clearance.¹

The new data, from the Clarity AD open label extension (OLE) trial, were presented at the 2024 Alzheimer’s Association International Conference held July 28-August 1, in Philadelphia, Pennsylvania.

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Clarity AD, a pivotal phase 3 placebo-controlled, double-blind, parallel-group clinical trial, enrolled 1795 people with early AD. Of this cohort, 95% of participants who completed the 18-month core study chose to continue in the OLE, where they continued on lecanemab treatment for up to 3 years. Over 3 years of treatment across main study and the OLE, lecanemab reduced cognitive decline on the Clinical Dementia Rating-Sum of Boxes (CDR-SB) by –0.95 points compared with the expected decline observed in the Alzheimer’s Disease Neuroimaging Initiative study. A change from 0.5 to 1.0 on key CDR score domains reflects the difference between “slight impairment and loss of independence,” according to the Eisai press release.¹

A tau PET substudy was offered to Clarity AD participants with no or low accumulation of tau in the brain. At the 3-year mark, 59% (24 of 41) of the substudy participants showed improvement or no decline on the CDR-SB and 51% (21 of 41) showed improvement from baseline on the assessment. In addition, 63% of the group had improvement or no decline and 61% demonstrated improvement on the Alzheimer’s Disease Assessment Scale-Cognitive subscale 14. On the Alzheimer’s Disease Cooperative Study-Activities of Daily Living Scale for use in Mild Cognitive Impairment, 63% of study participants showed improvement or no decline and 59% showed improvement.

In an interview with Patient Care® partner site NeurologyLive®, Clarity AD lead investigator Christopher van Dyck, MD, director of the Yale Alzheimer’s Disease Research Center, said, "The data point to the fact that participants with the lowest Alzheimer pathology at the start of the study—that is, both lower tau formulation in the brain and less amyloid deposition—seem to do particularly well. They have a better effect than the overall population does. "Many of them show no deterioration whatsoever over 36 months, and some actually show benefit over 36 months."

The safety analysis returned no new findings over the 3-year treatment period with lecanemab. According to Eisai, most of the amyloid-related imaging abnormalities (ARIA) observed were within the first 6 months of treatment and were not associated with accelerated long-term progression. After the first 6 months, ARIA rates remained low and similar to rates seen in placebo-treated participants.

Tau PET substudy. Lecanemab preferentially binds to toxic protofibrils with high affinity and substudy findings also included an impact on the rate of increase in tau accumulation across all brain regions as measured by tau PET. In lecanemab-treated participants, researchers observed slowed increase in cerebral spinal fluid MTBR-tau243, a biomarker highly correlated with tau PET and that increases with the progression of AD pathology. Observed improvements in phosphorylated tau 217 and other biomarkers related to neuroinflammation, and neurodegeneration suggests lecanemab exerts a disease modifying effect on tau pathophysiology, according to Eisai.

Study 201. Eisai additionally reported data from Study 201, the phase 2, double-blind, placebo-controlled trial preceding Clarity AD that included 856 participants with early AD. After participation in the 18-month core study a group of participants went off lecanemab treatment for an average of 24 months (range, 9 to 59 months). The lecanemab clinical effect persisted during the off-treatment period but the rate of decline among those who stopped treatment “reverted back” to the rate observed in participants receiving placebo, as measured by CDR-SB. “This indicates that even after amyloid-ß plaque is removed, AD continues to progress, and reverts to the placebo rate of decline when treatment is stopped," Eisai stated.

In June, the FDA accepted Eisai’s supplemental biologics license application for a monthly intravenous maintenance dosing of lecanemab, potentially allowing for more treatment flexibility. In the phase 2 and 3 studies, lecanemab was administered as a 10 mg/kg biweekly intravenous treatment, its approved indication. The FDA has set a Prescription Drug User Fee Act action date for January 25, 2025.

References
1. New clinical data demonstrate three years of continuous treatment with dual-acting Lequembi (lecanemab-irmb) continues to significantly benefit early Alzheimer's disease patients presented at AAIC 2024. News release. Eisai Co, Ltd. July 31, 2024. Accessed August 2, 2024.
2. Halsey G. Update 6-11-2024: Eisai files sBLA for lecanemab-irmb maintenance dosing. Patient Care. June 11, 2024. https://www.patientcareonline.com/view/eisai-files-sbla-for-lecanemab-irmb-maintenance-dose-reports-delay-on-sc-formulation