A subcutaneous version of the newly approved Alzheimer’s drug lecanemab (Leqembi) may be on the horizon.
Weekly subcutaneous lecanemab 100 mg/mL injection appeared to be as effective at amyloid plaque removal as biweekly IV administration, a preliminary analysis suggested.
Reduction of amyloid from baseline to 6 months in newly treated patients was -40.3 centiloids with subcutaneous lecanemab compared with -35.4 centiloids with IV administration, said Eisai vice president Michael Irizarry, MD, MPH, during a symposium at the 2023 Clinical Trials on Alzheimer’s Disease conference in Boston. This translated to a 14% relative reduction for the subcutaneous version.
The incidence of amyloid-related imaging abnormalities with edema (ARIA-E) or with cerebral hemorrhage, cerebral microhemorrhage, and hemosiderin deposition (ARIA-H) did not appear to be better with subcutaneous lecanemab.
The subcutaneous substudy was part of an open-label extension (OLE) of the phase III CLARITY AD trial and included 72 people with early Alzheimer’s who received lecanemab for the first time as the subcutaneous formulation, and 322 people who converted from IV lecanemab in CLARITY AD to subcutaneous administration in the OLE.
The phase III CLARITY AD trial — the basis for the FDA’s full approval decision — showed IV lecanemab led to less decline on cognitive and functional measures. The study met its primary and all key secondary endpoints.
The goal of the subcutaneous substudy was to assess pharmacokinetics, measured as area under the curve (AUC), and pharmacodynamics, measured as amyloid clearance. The mean age of lecanemab-naive patients treated subcutaneously was 73, and 51% were women. About 49% carried one APOE4 allele, and 8% carried two.
The weekly subcutaneous administration AUC was 11% higher than the biweekly IV formulation, with confidence intervals within bioequivalent levels, Irizarry said.
Subcutaneous administration led to 8.1% of patients overall having local injection site reactions (15.3% in lecanemab-naive patients). Most were mild and moderate in severity consisting of redness, irritation, or swelling. No skin rash or other hypersensitivities emerged.
In the CLARITY-AD trial of IV lecanemab, the incidence of ARIA-E was 12.6%; ARIA-H occurred in 17.3%, and isolated ARIA-H without ARIA-E occurred in 8.9%. In patients newly treated with subcutaneous lecanemab in the substudy, ARIA-E incidence was 16.7%, 22.2% for ARIA-H, and 8.3% for isolated ARIA-H. There were no intracerebral hemorrhages with subcutaneous lecanemab.
“The incidence, timing, radiographic severity, and clinical severity of ARIA was generally similar for subcutaneous relative to IV, taking into account the variability and also the greater exposure for the subcutaneous formulation,” Irizarry said.
“In general, ARIA-E tended to occur early in treatment, was generally asymptomatic, and was mild to moderate radiographically,” he added.
In the phase II and III lecanemab studies, maximum exposure was the strongest predictor of ARIA-E incidence with IV administration, he pointed out. In the subcutaneous substudy, steady-state exposure appeared to be a better predictor of ARIA-E rates.
“The subcutaneous formulation has comparable pharmacokinetics and amyloid clearance to IV, providing another convenient dosing option for lecanemab,” Irizarry noted. Drugmaker Eisai said it plans to submit an application for its lecanemab subcutaneous formulation to the FDA in the first quarter of 2024.
This research was supported by Eisai.
Irizarry is an employee of Eisai.
Clinical Trials on Alzheimer’s Disease
Source Reference: Irizarry M “Preliminary update on lecanemab safety in CLARITY AD open-label extension, including subcutaneous formulation” CTAD 2023.