Eisai Seeks FDA Approval for Subcutaneous Lecanemab Autoinjector in Alzheimer's
核心洞察
Eisai has submitted a Biologics License Application (BLA) to the FDA for a subcutaneous autoinjector formulation of lecanemab for weekly maintenance dosing in Alzheimer's disease.
The subcutaneous formulation offers a more convenient administration method, potentially allowing patients to self-administer the drug at home in approximately 15 seconds.
Clinical data suggests subcutaneous lecanemab may offer enhanced amyloid plaque removal compared to the currently approved intravenous formulation.
Eisai has formally submitted a Biologics License Application (BLA) to the U.S. Food and Drug Administration (FDA) for a subcutaneous autoinjector formulation of lecanemab (Leqembi) for the treatment of early Alzheimer's disease. This new formulation is designed for weekly maintenance dosing and offers a potentially more convenient method of administration for patients. If approved, the autoinjector could allow patients to self-administer the medication at home or in medical facilities, with each injection taking approximately 15 seconds.
Subcutaneous Lecanemab: A More Convenient Option
Lecanemab is currently approved as an intravenous (IV) injection for patients with mild cognitive impairment (MCI) or early-stage Alzheimer's disease. The proposed weekly 360 mg subcutaneous autoinjector maintenance regimen is intended for patients who have completed the bi-weekly IV initiation phase. This regimen aims to maintain effective drug levels, facilitating the clearance of highly toxic protofibrils, which can continue to cause neuronal damage even after amyloid-beta (搜索) (Aβ) plaques are removed from the brain.
Clinical Data Supporting Subcutaneous Formulation
The BLA for the subcutaneous formulation is supported by data from the Phase 3 Clarity AD trial (NCT03887455), its open-label extension (OLE), and pharmacokinetic modeling. Notably, prior to the BLA submission, the FDA indicated that approval of the subcutaneous formulation would require Fast Track designation, which was subsequently granted. Eisai also included 3-month immunogenicity data in the application.
Data presented at the 2023 Clinical Trials on Alzheimer's Disease (CTAD) conference indicated that subcutaneous lecanemab resulted in greater amyloid plaque removal compared to bi-weekly IV lecanemab. A preliminary 6-month analysis of the Clarity AD OLE, involving a subgroup of patients, showed a 14% increase in amyloid plaque removal with the subcutaneous method compared to IV administration. The analysis, led by Reisa Sperling, MD, from Brigham and Women’s Hospital, Harvard Medical School, included 72 patients who received lecanemab subcutaneously for the first time and 322 patients who received IV lecanemab in the Clarity AD core study followed by subcutaneous administration in the substudy. Pharmacokinetic data showed that 90% exposure for subcutaneous vs IV was within the bioequivalence limits of 80% to 125%, allowing Eisai to select a dose that achieves comparable area under the curve (AUC) to the IV formulation dose.
Safety Profile
In the Clarity AD core study, amyloid-related imaging abnormalities (ARIA)-edema were reported in 12.6% of patients, ARIA-H (cerebral microhemorrhage, cerebral hemorrhage, and brain surface hemosiderin deposition) in 17.3%, and ARIA-H alone in 8.9% of patients treated with intravenous lecanemab. Among the 72 patients receiving subcutaneous lecanemab in the new analysis, the incidence rates were 16.7%, 22.2%, and 8.3%, respectively. Eisai noted that no direct comparison was made due to the small sample size.
Long-Term Benefits
At the 2024 Alzheimer’s Association International Conference, three-year data from the OLE of Clarity AD highlighted the sustained clinical benefits of lecanemab IV treatment. Over three years, lecanemab reduced cognitive decline on the Clinical Dementia Rating-Sum of Boxes (CDR-SB) by -0.95 compared to the expected decline based on the Alzheimer’s Disease Neuroimaging Initiative (ADNI) group. This compares favorably to the -0.45 change (P = .00005) observed between lecanemab and placebo at the 18-month mark of the core study.
In an optional tau PET substudy of Clarity AD, 59% of patients with no or low tau accumulation in the brain showed improvement or no decline on the CDR-SB after three years of lecanemab treatment, and 51% showed improvement from baseline. On the Alzheimer’s Disease Assessment Scale-Cognitive subscale 14 (ADAS-Cog), 63% demonstrated improvement or no decline, and 61% showed improvement. Similarly, 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.