Fidanacogene elaparvovec (Beqvez), a gene therapy, has shown promising results in an open-label Phase 3 study for hemophilia B, outperforming prophylaxis factor IX concentrate in reducing bleeding and stabilizing factor IX levels. The study, published in the New England Journal of Medicine, suggests gene therapy could offer a more lasting treatment option for individuals with hemophilia B.
The current standard treatment for hemophilia B involves regular intravenous administration of plasma-derived or recombinant factor IX products. However, this approach places a significant burden on families due to the frequent injections required and does not completely eliminate symptoms. While newer therapies like small interfering RNA agents (e.g., fitusiran) offer advancements in symptom prevention, they still necessitate regular administration. Thus, there remains a need for a more durable solution.
Mechanism of Action
Fidanacogene elaparvovec is an adeno-associated virus vector designed to deliver transgene production of FIX-R338L. The transgene utilizes the hepatic-control region of the gene encoding apolipoprotein E (APOE), a liver-specific human α1-antitrypsin promoter, and a codon-optimized FIX-R388L minigene. The therapy aims to restore factor IX activity to levels ranging from mild hemophilia to normal, thereby reducing bleeding episodes.
Phase 3 Trial Results
The Phase 3, open-label, non-inferiority study involved 45 male patients aged 18-65 with hemophilia B and factor IX levels of 2% or less. Patients received a dose of 5x10¹¹ vector genome copies per kilogram of body weight. Forty-four patients completed at least 15 months of follow-up.
The annualized rate of bleeding decreased from 4.42 (95% CI, 1.80 to 7.05) at baseline to 1.28 (95% CI, 0.57 to 1.98) after therapy. At 15 months, the mean factor IX activity was 26.9% (median, 22.9%; range, 1.9 to 119.0%) by one-stage SynthASil assay.
Glucocorticoid Use and Resumption of Prophylaxis
62% of participants (28 patients) received glucocorticoids, predominantly for increased aminotransferase levels, suggesting cellular immune responses. Six patients resumed factor IX prophylaxis despite an initial response to fidanacogene elaparvovec; all six had been treated with glucocorticoids. However, the majority (79%) of patients treated with glucocorticoids did not resume prophylaxis, indicating the need for further research to understand why some patients required resumption.
Safety and Benefit-Risk Profile
Overall, the investigators concluded that fidanacogene elaparvovec demonstrated a favorable benefit-risk profile, even at a low dose.
