Gene therapy with fidanacogene elaparvovec results in less bleeding than FIX prophylaxis in adult patients with hemophilia B. This is the conclusion of Adam Cuker (Perelman School of Medicine, University of Pennsylvania, Philadelphia, USA) and fellow researchers based on the results of the BENEGENE- 2 study, which were recently published in The New England Journal of Medicine.
BENEGENE-2
Fidanacogene elaparvovec is an adenoviral vector (AAV) designed to carry the highly active transgene FIX-R338Leither FIX-Paduaconvey and express. In the international phase III study BENEGENE-2, patients with hemophilia B received fidanacogene elaparvovec (5 x 1011 genome copies per kg body weight) intravenously as a single dose. Participants were men aged 18-65 years with moderate or severe haemophilia (FIX activity ≤2%) who had received at least 6 months of FIX prophylaxis in the BENEGENE-1 pre-infusion study. Patients with neutralizing anti-AAV antibodies or FIX inhibitors, among others, were excluded from participation. The primary outcome measure was the annualized bleeding rate (ABR), measured from 12 weeks to 15 months after the infusion and compared with the pre-infusion phase. Key secondary outcome measures were the ABR of treated bleeding, the annual frequency of infusion of exogenous FIX (AIR) and the FIX activity. The safety of the gene therapy was also assessed.
A total of 45 patients received fidanacogene elaparvovec (mean age: 33.2 years), of whom 44 patients were followed for at least 15 months. Gene therapy with fidanacogene elaparvovec led to a 71% lower ABR in the post-infusion phase compared to FIX prophylaxis in the pre-infusion phase (1.28 vs. 4.42; difference [95%-BI]): -3,15 [-5,46 tot -0,83; p=0,008). De ABR van behandelde bloedingen daalde met 78%, van 3,34 in de pre-infusiefase naar 0,73 in de post-infusiefase (verschil [95%-BI]): -2,61 [-4,27 tot -0,96]; p=0.002). Also, treatment with fidanacogene elaparvovec resulted in a 92% lower AIR of exogenous FIX in the post-infusion phase, compared to FIX prophylaxis in the pre-infusion phase (4.54 vs. 58.83; difference [95%-BI]: -54,29 [-63,58 tot -45,01]; p
Adverse events
One or more adverse events (AEs) occurred in 38 patients (84%), of which an elevated ALT concentration (27%) was the most common. 28 patients (62%) had to be treated with glucocorticoids due to an increased ALT concentration and/or decreased FIX activity. One or more serious AEs occurred in 7 patients (16%). None of the patients developed a serious infusion-related AE, thrombotic event, FIX inhibitors or malignancy.
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