Field Study and Correlative Studies of Factor IX Variant FIX-R338L in Participants Treated with Fidanacogene Elaparvovec

• Published in: Thrombosis and haemostasis Vol. 124; no. 10; p. 912
• Main Authors: Pittman, Debra D, Carrieri, Charles, Soares, Holly, McKay, John, Tan, Charles Y, Liang, John Z, Rakhe, Swapnil, Marshall, Jean-Claude, Murphy, John E, Gaitonde, Puneet, Rupon, Jeremy
• Format: Journal Article
• Language: English
• Published: Germany 01.10.2024
• Subjects: Blood Coagulation - drug effects; Blood Coagulation Tests; Dependovirus - genetics; Factor IX - genetics; Factor IX - metabolism; Factor IX - therapeutic use; Genetic Therapy - methods; Genetic Vectors; Hemophilia B - blood; Hemophilia B - genetics; Hemophilia B - therapy; Humans; Thrombin - metabolism
• ISSN: 2567-689X
• DOI: 10.1055/s-0044-1787734

Fidanacogene elaparvovec, an adeno-associated virus-based gene therapy vector expressing the high-activity factor IX (FIX) variant FIX-R338L, is in development for hemophilia B. One-stage clotting (OS) assays and chromogenic substrate (CS) assays are commonly used to measure FIX-R338L variant activity. Data from ongoing trials suggest FIX activity varies between different OS and CS assays.  To better understand FIX-R338L activity in clinical samples, an international multisite field study was conducted across a central laboratory and 18 local laboratories, using standard protocols, reagents, and instrumentation, with individual participant samples from a phase 1/2a study of fidanacogene elaparvovec.  Unlike the wild-type FIX control, FIX-R338L activity was higher with the OS silica-based assay versus OS ellagic acid-based and CS assays. Variation in FIX activity was greater at the lowest activity levels. Activated FIX (FIXa) in plasma could result in higher OS assay activity or increased thrombin generation, which could overestimate FIX activity. However, FIXa was not detected in the participant samples, indicating that it was not contributing to the OS assay differences. Since individuals on gene therapy may receive exogenous replacement FIX products, replacement products were spiked into patient plasma samples to target a therapeutic concentration. Exogenous FIX was additive to endogenous FIX-R338L, with no interference from FIX-R338L.  These results demonstrate FIX-R338L activity can be measured with OS and CS assays in clinical laboratories and provide insight into assay variability when measuring FIX with endogenously produced FIX-R338L. The findings may help establish best practices for measuring FIX-R338L activity (Clinicaltrials.gov identifier: NCT02484092).