Eisai Formally Submits BLA for Subcutaneous Autoinjector of Lecanemab

According to a new announcement, Eisai has submitted its biologics license application (BLA) for lecanemab-irmb (Leqembi) subcutaneous autoinjector for weekly maintenance dosing. If approved by the FDA, the autoinjector will serve as a more convenient method of administration for patients at home or at medical facilities, totaling on average 15 seconds to administer.¹

Lecanemab, approved in 100 mg/mL injection for intravenous (IV) use, is indicated for patients with mild cognitive impairment (MCI) or early-stage Alzheimer disease (AD). If approved by the FDA, the autoinjector will serve as a more convenient method of administration for patients at home or at medical facilities, totaling on average 15 seconds to administer.

The therapy is currently approved in the U.S., Japan, China, South Korea, Hong Kong, Israel, UAE, and Great Britain, while it remains investigational and under review in several other countries and regions, including the European Union. In the proposed weekly 360 mg subcutaneous autoinjector maintenance regimen, patients who completed the biweekly IV initiation phase would receive weekly doses to maintain effective drug levels. This helps clear highly toxic protofibrils, which can still cause neuronal damage even after amyloid-beta (Aβ) plaque is cleared from the brain.

Earlier this year, prior to the BLA submission, the FDA claimed it would not approve the subcutaneous formulation of lecanemab unless it gained fast track designation specific to the subcutaneous dosing. Months later, the therapy gained fast track designation for the subcutaneous formulation, thus meeting the FDA’s needs. In addition, Eisai also submitted 3-month immunogenicity data regarding the subcutaneous formulation, which also completed the application.² The BLA for the subcutaneous formulation is based on data from the phase 3 Clarity AD trial (NCT03887455), the supportive trial that led to lecanemab’s approval, its open-label extension (OLE), and modeling of observed data.

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At the 2023 Clinical Trials on Alzheimer’s Disease (CTAD) conference, treatment with subcutaneous lecanemab produced greater amyloid plaque removal than biweekly IV lecanemab, the administration route it was approved in. In a preliminary 6-month analysis of the Clarity AD OLE, data from a subgroup of patients revealed a 14% increased amyloid plaque removal with the subcutaneous method than IV administration.³

Led by Reisa Sperling, MD, a neurologist at Brigham and Women’s Hospital, Harvard Medical School, the analysis comprised of 72 patients with early AD who received lecanemab for the first time in a subcutaneous way and 322 patients who received IV lecanemab in the Clarity AD core study followed by subcutaneous administration in the substudy. Pharmacokinetic data also revealed that 90% exposure for subcutaneous vs IV was within the bioequivalence limits of 80% to 125%, allowing Eisai to select a dose for future patients that achieve area under the curve (AUC) that are comparable to the IV formulation dose.

In the Clarity AD core study, 12.6%, 17.3%, and 8.9% of patients reported amyloid-related imaging abnormalities (ARIA)-edema, ARIA-H (cerebral microhemorrhage because of ARIA, cerebral hemorrhage, and brain surface hemosiderin deposition) and ARIA-H alone, respectively, with intravenous lecanemab. Among the subgroup of 72 patients on subcutaneous lecanemab in the new analysis, investigators observed incidence rates of 16.7%, 22.2%, and 8.3%, respectively; however, Eisai noted that no exact comparison was made because of the sample size of individuals.

Earlier this year, at the 2024 Alzheimer’s Association International Conference, new 3-year data from the OLE of Clarity AD highlighted the clinically and personally meaningful benefits observed with lecanemab IV treatment. 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.⁴

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.

REFERENCES
1. Eisai Completes Rolling Submission to US FDA for LEQEMBI® (lecanemab-irmb) Biologics License Application for Subcutaneous Maintenance Dosing for the Treatment of Early Alzheimer's Disease Under the Fast Track Status. Eisai. October 31, 2024. Accessed November 1, 2024. https://www.prnewswire.com/news-releases/eisai-completes-rolling-submission-to-us-fda-for-leqembi-lecanemab-irmb-biologics-license-application-for-subcutaneous-maintenance-dosing-for-the-treatment-of-early-alzheimers-disease-under-the-fast-track-status-302293541.html
2. Eisai Initiates Rolling Biologics License Application to US FDA for LEQEMBI® (lecanemab-irmb) for Subcutaneous Maintenance Dosing for the Treatment of Early Alzheimer’s Disease Under the Fast Track Status. News release. May 15, 2024. Accessed November 1, 2024. https://www.eisai.com/news/2024/news202430.html
3. Irizarry M, Li D, Dhadda S, Hersch S, Reyderman L, Kramer L. Preliminary update on lecanemab safety in Clarity AD open-label extension, including subcutaneous formulation. Presented at: CTAD conference; October 24-27, 2023; Presentation 4.
4. 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 November 1, 2024. https://www.multivu.com/players/English/9282551-eisai-leqembi-clinical-data-aaic-2024-alzheimers/