BENEFIX® Clinical Studies

On-demand Treatment and Control of Bleeding Episodes

Fifty-six PTPs and sixty-three PUPs were treated for bleeding episodes on an on-demand treatment and control of bleeds (see Tables 6 and 7). The PTPs were followed over a median interval of 24 months (mean 23.4 ± 5.3 months) and for a median of 83.5. The PUPs were followed over a median interval of 37 months (mean 38.1 ± 16.4 months) and for a median of 89 exposure days.

Fifty-five PTPs and fifty-four PUPs received BeneFIX for the treatment of bleeding episodes (see Table 6). Bleeding episodes that were managed successfully included hemarthrosis and bleeding in soft tissue and muscle. Data concerning the severity of bleeding episodes were not reported. In the PTPs, 88% of total infusions administrated for on-demand treatment were rated as an "excellent" or "good" response.

A total of 20 PTPs were treated with BeneFIX for secondary prophylaxis (the regular administration of FIX replacement therapy to prevent bleeding in patients who may have already demonstrated clinical evidence of hemophilic arthropathy or joint disease) at some regular interval during the trial with a mean of 2 infusions per week (see Table 7). Thirty-two PUPs were administered BeneFIX for routine (primary and secondary) prophylaxis (see Table 7). Twenty-four PUPs were administered BeneFIX at least twice weekly, and eight PUPs were administered BeneFIX once weekly. Seven PTPs experienced a total of 26 spontaneous bleeding episodes within 48 hours after an infusion. Six spontaneous bleeds within 48 hours after an infusion were reported in 5 PUPs. Prophylaxis therapy was rated as "excellent" or "effective" in 93% of PTPs receiving prophylaxis one to two times per week.

Perioperative Management

Management of hemostasis was evaluated in the surgical setting in both PTPs and PUPs (see Table 8 and Table 9). Thirty-six surgical procedures have been performed in 28 PTPs with 23 major surgical procedures performed (including 6 complicated dental extractions). Thirty surgical procedures have been performed in 23 PUPs. Twenty-eight of these procedures were considered minor. Hemostasis was maintained throughout the surgical period; however, one PTP subject required evacuation of a surgical wound-site hematoma, and another PTP subject who received BeneFIX after a tooth extraction required further surgical intervention due to oozing at the extraction site. There was no clinical evidence of thrombotic complications in any of the subjects.

Among the PTP surgery subjects, the median increase in circulating factor IX activity was 0.7 IU/dL per IU/kg infused (range 0.3–1.2 IU/dL; mean 0.8 ± 0.2 IU/dL per IU/kg). The median elimination half-life for the PTP surgery subjects was 19.4 hours (range 10–37 hours; mean 21.3 ± 8.1 hours).

Nine of the major surgical procedures were performed in 8 PUPs using a continuous-infusion regimen. Five of the surgical procedures were performed in PUPs using a continuous-infusion regimen over 3 to 5 days. Although circulating factor IX levels targeted to restore and maintain hemostasis were achieved with both pulse replacement and continuous infusion regimens, clinical trial experience with continuous infusion of BeneFIX for perioperative management in hemophilia B has been too limited to establish the safety and clinical efficacy of administration of the product by continuous infusion.

Routine Prophylaxis

In an open-label trial of 25 patients (age range 12–54 years) comparing on-demand treatment versus prophylaxis when administered at a dose of 100 IU/kg once weekly, the annualized bleed rate (ABR) for the prophylaxis period was significantly lower (p < 0.0001) than the ABR for the on-demand period (mean ± standard deviation (SD): 3.6 ± 4.6, median: 2.0, min–max: 0–13.8 versus mean: 32.9 ± 17.4, median: 33.6, min–max: 6.1–69.0, respectively).

In an open-label crossover trial in patients aged 6–64 years, of 100 IU/kg once weekly (44 patients) and 50 IU/kg twice weekly (43 patients) with 4-month treatment periods, the ABR for the 100 IU/kg once-weekly prophylaxis period was mean 4.4 ± 10.0 episodes per year (median: 0.0, min–max: 0 – 50.5) and mean 2.8 ± 5.7 (median: 0.0, min–max: 0 – 24.1) for the 50 IU/kg twice-weekly period. Six patients aged <12 years had mean ABR of 1.6 ± 1.7 (median: 1.5, min–max: 0–3.3) in the 100 IU/kg once-weekly period, and mean ABR of 0 ± 0 (median: 0, min–max: 0–0) in the 50 IU/kg twice-weekly period.