Open Label Extension Data Shows Lecanemab’s Continued Effect on Alzheimer Disease After 3 Years

Christopher van Dyck, MD

At the 2024 Alzheimer’s Association International Conference (AAIC), held July 28-August 1 in Philadelphia, Pennsylvania, Eisai presented new 3-year data from an open-label extension (OLE) of its pivotal phase 3 Clarity AD trial (NCT03887455) highlighting lecanemab (Leqembi), an FDA-approved therapy for early-stage Alzheimer disease (AD). At 3 years, investigators observed a continued clinically and personally meaningful benefit among treated patients, with continued positive impacts on biomarkers after plaque removal.

In total, 95% of patients 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 the core study and OLE, lecanemab reduced cognitive decline on the Clinical Dementia Rating-Sum of Boxes (CDR-SB) by –0.95 compared with the expected decline based on those in the Alzheimer’s Disease Neuroimaging Initiative (ADNI) group. For context, a change of –0.45 (P = .00005) was observed between lecanemab and placebo at the 18-month mark of the core study.

In an optional tau PET substudy of Clarity AD that included patients with no tau or low accumulation of tau in the brain, results showed that 59% (24 of 41) of these patients showed improvement or no decline, and 51% (21 of 41) showed improvement from baseline on the CDR-SB after 3 years of lecanemab. On the Alzheimer’s Disease Assessment Scale-Cognitive subscale 14 (ADAS-Cog), 63% of patients demonstrated improvement or no decline and 61% showed improvement. Furthermore, 63% of patients showed improvement or no decline and 59% showed improvement on the Alzheimer’s Disease Cooperative Study-Activities of Daily Living Scale for use in Mild Cognitive Impairment (ACDS-MCI-ADL).

"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," lead investigator Christopher van Dyck, MD, director of the Yale Alzheimer’s Disease Research Center, told NeurologyLive®. "Many of them show no deterioration whatsoever over 36 months, and some actually show benefit over 36 months."

Safety, which was a concern for some throughout its approval process, showed no new findings over the 3-year 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 those on placebo.

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When asked about how to identify patients at the earliest stage who may be eligible for lecanemab, van Dyck said, “Memory specialists are already very good at that, at least at the leading academic centers. But it’s true for other centers that I’ve communicated with, a lot of it is just logistics. It’s ‘how do you streamline into short clinic visits?’ We are always doing full diagnostic assessments to start with. Building on the required preliminaries, like the right MRI scans that are going to be read now by trained radiologists who work in [treating] ARIA, necessary testing like apolipoprotein, and then training infusion centers, which already exist, but will have to be trained for every new therapeutic and new protocol."

He added, "but what I’ve observed is all of this is getting better all the time. The key issue is the time to get smoother at it. There’s no real logistic or inherent barrier to doing it, it’s just getting better and smoother at it."

Lecanemab, which preferentially binds to toxic protofibrils with high affinity, also showed an impact on the rate of increase in tau accumulation across all brain regions in the tau substudy. All told, lecanemab-treated patients demonstrated a slowing in the increase of cerebrospinal fluid MTBR-tau243, which is highly correlated with tau PET and increases with the progression of AD pathology. Furthermore, the therapy demonstrated disease-modifying effects by improving phosphorylated tau 217 and other biomarkers related to neuroinflammation and neurodegeneration.

Study 201, the phase 2, double-blind, placebo-controlled trial that preceded Clarity AD, included 856 patients with AD. Following the 18-month core study, some patients participated in the OLE after an off-treatment period of 9-59 months. Here, investigators observed that lecanemab’s effect during the off-treatment period was maintained but the rate of decline in patients who stopped therapy reverted back to the decline in patients on placebo, as measured by CDR-SB. All told, "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."

Modeling data from the Study 201, Clarity AD, and retrospective OLE studies showed that the half-life of the treatment effect on key AD fluid biomarkers plasma amyloid-ß (Aß)42/40 ratio, pTau181, and glial fibrillary acidic protein (GFAP) are lost within 0.5 year, 1.6 years, and 1.7 years, respectively, while the half-life of the treatment amyloid plaque is gradually lost in 12.1 years. When lecanemab was resumed in the phase 2 study OLE after off-treatment period, all fluid biomarkers, as well as pTau217, were improved.

More recently, in early June, the FDA accepted Eisai’s supplemental biologics license application for a new 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.

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REFERENCES
1. New Clinical Data Demonstrates Three Years of Continuous Treatment with Dual-Acting LEQEMBI® (lecanemab-irmb) Continues to Significantly Benefit Early Alzheimer’s Disease Patients Presented at The Alzheimer’s Association International Conference (AAIC) 2024. News release. Eisai. July 30, 2024. Accessed July 31, 2024. https://www.multivu.com/players/English/9282551-eisai-leqembi-clinical-data-aaic-2024-alzheimers/
2. DA Accepts Eisai's Filing of LEQEMBI® (lecanemab-irmb) Supplemental Biologics License Application for IV Maintenance Dosing for the Treatment of Early Alzheimer's Disease. Eisai. June 9, 2024. Accessed July 31, 2024. https://www.prnewswire.com/news-releases/fda-accepts-eisais-filing-of-leqembi-lecanemab-irmb-supplemental-biologics-license-application-for-iv-maintenance-dosing-for-the-treatment-of-early-alzheimers-disease-302167814.html