Once-Weekly Prophylactic Treatment Versus on-Demand Treatment of Nonacog Alfa in Patients with Moderately Severe to Severe Hemophilia B

Introduction: Hemophilia B is characterized by a functional deficiency in factor IX (FIX), which results in spontaneous or trauma-induced bleeding into soft tissue, muscles, and joints. Replacing deficient FIX with plasma-derived or recombinant FIX products, either prophylactically or on an on-demand basis, is a mainstay in the prevention and treatment of bleeding episodes in patients with hemophilia B. A previous study of patients with moderately severe to severe hemophilia B compared the efficacy and safety of 2 secondary prophylaxis regimens of a recombinant coagulation FIX product (nonacog alfa, 50 IU/kg twice weekly or 100 IU/kg once weekly) with on-demand treatment. The study found a significant reduction (P<.0001) in the annualized bleeding rate (ABR) for the prophylaxis regimens compared with on-demand therapy. No significant differences in the ABR were observed between the once-weekly and twice-weekly prophylaxis regimens, and safety and tolerability profiles were similar for both.

Objective: To demonstrate that once-weekly prophylaxis with nonacog alfa reduces the ABR compared with on-demand treatment in patients with moderately severe to severe hemophilia B.

Methods: This open-label, 2-period study enrolled males aged 12 to 65 years with moderately severe to severe hemophilia B (FIX plasma activity ≤2%), ≥100 prior exposure days to FIX products, and no history of or current FIX inhibitor. Patients received on-demand therapy with nonacog alfa for 6 months (dose selected at the investigator's discretion) followed by prophylactic treatment with nonacog alfa 100 IU/kg once weekly for 12 months. Recovery was assessed on day 1, week 26, and week 78, after a 72-hour washout from any FIX product. Plasma samples were collected before administration and at 30 minutes after nonacog alfa infusion. The primary efficacy end point was the ABR (number of bleeding events/[days on treatment period/365.25]). Secondary end points included the response to on-demand treatment of a bleeding event, incidence of less-than-expected therapeutic effect (LETE) in the prophylaxis setting; and FIX inhibitor development. Safety was also assessed.

Results: In total, 25 patients were enrolled and received at least 1 dose of study medication; all patients completed the study. Mean ±SD age was 31.3 ±12.6 years; 5 patients were <18 years; 9 patients were Asian and 16 were white. ABR results are summarized in the Table; ABR for the prophylaxis period was significantly lower (P<.0001) than the ABR for the on-demand period. Of the 507 bleeding events treated over the study, 271 (53.5%) first infusions resulted in an “excellent” response and 177 (34.9%) resulted in a “good” response; the majority of bleeding events (416/507; 82.1%) resolved with 1 infusion. Of the 1254 prophylaxis infusions administered during the study, none were associated with an occurrence of LETE. No patient developed a FIX inhibitor or experienced a thrombotic event during the study. The most commonly reported treatment-emergent AEs (≥20%) were inappropriate schedule of drug administration (24%), arthralgia (20%), upper respiratory tract infection (20%), and toothache (20%) during the prophylaxis period, and headache (32%) and arthralgia (20%) during the on-demand period. Five patients (20%) experienced a total of 6 serious AEs; blood pressure decreased, pain resulting in hospitalization, chicken pox, lipoma, and nephrolithiasis (2 events in 1 patient). Only the serious AE of blood pressure decreased was considered related to study drug. No deaths occurred during the study.

Conclusions: Prophylactic treatment with nonacog alfa 100 IU/kg once weekly significantly reduced the number of bleeding events compared with on-demand treatment in patients with moderately severe to severe hemophilia B. Nonacog alfa 100 IU/kg once weekly was well tolerated; no new safety issues were observed.

*P<.0001 for comparison of on-demand vs prophylaxis treatment.