Eisai Plans to Submit BLA for Subcutaneous Lecanemab After Findings Show Promising Results
New subcutaneous lecanemab considered more effective than IV for amyloid plaque removal in Alzheimer disease; FDA application planned by March 2024.
Reisa Sperling, MD
In a late breaking symposium presented at the 2023 Clinical Trials on Alzheimer’s Disease (CTAD) conference held October 24-27, in Boston, Massachusetts, data from an open-label extension (OLE) of the pivotal phase 3 Clarity AD study (NCT03887455) showed that a new novel subcutaneous form of lecanemab (Leqembi; Eisai) resulted in greater amyloid plaque removal than biweekly intravenous (IV) administration. The company plans to submit a biologics license application for the subcutaneous formulation to the FDA by March 31, 2024.1,2
In a preliminary 6-month analysis of the OLE, data from a subgroup of patients showed a 14% increased amyloid plaque removal with the subcutaneous method than IV administration, the administration for which it was FDA-approved under earlier this year. Presented by Reisa Sperling, MD, a neurologist at Brigham and Women’s Hospital, Harvard Medical School, the data comprised of 72 patients with early Alzheimer disease (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.
Clarity AD, a placebo-controlled, double-blind, parallel-group, randomized study assessing lecanemab 10 mg/kg bi-weekly for 18 months, was the premise behind the traditional approval of the agent in July 2023. In the newly presented analysis, investigators observed reductions of –40.3 (±2.27) centiloids at 6 months for newly treated patients on subcutaneous lecanemab vs reductions of –35.4 (±1.14) centiloids for those on IV administration. In addition, the weekly subcutaneous pharmacokinetic area under the curve (AUC) were 11% higher than the biweekly IV formulation.
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In the Clarity AD core study, 12.6%, 17.3%, and 8.9% of patients reported 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.
Cmax was considered the strongest predictor of ARIA-E incidence following IV administration based on the phase 2 and 3 studies while steady-state exposure was considered the better predictor of ARIA-E rates in the subcutaneously delivered lecanemab. 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 AUC that are comparable to the IV formulation dose.
In addition to data on the subcutaneous form of lecanemab, Eisai also presented findings from the open-label extension of Clarity AD, with patients on treatment for 24 months. Of the 1486 individuals who completed the 18-month double-blind study, 1385 of these enrolled in the OLE. Differences between treatment and placebo across clinical end points increased over time during the first 18 months, but then became parallel after the initiation of lecanemab in the core placebo group from 18 to 24 months, signifying a potential disease-modifying effect. Additional findings showed changes in prominent biomarkers as early as 3 months in newly treated lecanemab participants in the OLE.3
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